From the Peter O'Donnell Jr. Brain Institute at the University of Texas Southwestern Medical Center (M.H.T.) and the University of Texas Southwestern Medical Center (R.W., A.C., T.C., M.K., K.S.-W., S.W.), Dallas, the University of Texas Health Science Center at Houston, Houston (J.S.), and Texas Tech University, Permian Basin, Odessa (A.J.R.); the University of California, Los Angeles, Los Angeles (W.L., S. Shoptaw); the Emmes Company, Rockville (G.S., A.W.), and the National Institute on Drug Abuse Center for the Clinical Trials Network (U.E.G., S. Sparenborg [retired]), Rockville - both in Maryland; the San Francisco Department of Public Health and the University of California, San Francisco, San Francisco (P.C.); CODA, Portland, OR (K.W.); Hennepin Healthcare, University of Minnesota, Minneapolis (G.B.); Medical University of South Carolina, Charleston (S.C.S.); Duke-National University of Singapore, Singapore (A.J.R.); Duke Medical School, Durham, NC (A.J.R.); and Columbia University, New York (E.V.N.).
N Engl J Med. 2021 Jan 14;384(2):140-153. doi: 10.1056/NEJMoa2020214.
The use of naltrexone plus bupropion to treat methamphetamine use disorder has not been well studied.
We conducted this multisite, double-blind, two-stage, placebo-controlled trial with the use of a sequential parallel comparison design to evaluate the efficacy and safety of extended-release injectable naltrexone (380 mg every 3 weeks) plus oral extended-release bupropion (450 mg per day) in adults with moderate or severe methamphetamine use disorder. In the first stage of the trial, participants were randomly assigned in a 0.26:0.74 ratio to receive naltrexone-bupropion or matching injectable and oral placebo for 6 weeks. Those in the placebo group who did not have a response in stage 1 underwent rerandomization in stage 2 and were assigned in a 1:1 ratio to receive naltrexone-bupropion or placebo for an additional 6 weeks. Urine samples were obtained from participants twice weekly. The primary outcome was a response, defined as at least three methamphetamine-negative urine samples out of four samples obtained at the end of stage 1 or stage 2, and the weighted average of the responses in the two stages is reported. The treatment effect was defined as the between-group difference in the overall weighted responses.
A total of 403 participants were enrolled in stage 1, and 225 in stage 2. In the first stage, 18 of 109 participants (16.5%) in the naltrexone-bupropion group and 10 of 294 (3.4%) in the placebo group had a response. In the second stage, 13 of 114 (11.4%) in the naltrexone-bupropion group and 2 of 111 (1.8%) in the placebo group had a response. The weighted average response across the two stages was 13.6% with naltrexone-bupropion and 2.5% with placebo, for an overall treatment effect of 11.1 percentage points (Wald z-test statistic, 4.53; P<0.001). Adverse events with naltrexone-bupropion included gastrointestinal disorders, tremor, malaise, hyperhidrosis, and anorexia. Serious adverse events occurred in 8 of 223 participants (3.6%) who received naltrexone-bupropion during the trial.
Among adults with methamphetamine use disorder, the response over a period of 12 weeks among participants who received extended-release injectable naltrexone plus oral extended-release bupropion was low but was higher than that among participants who received placebo. (Funded by the National Institute on Drug Abuse and others; ADAPT-2 ClinicalTrials.gov number, NCT03078075.).
纳曲酮联合安非他酮治疗甲基苯丙胺使用障碍的效果尚未得到充分研究。
我们采用多中心、双盲、两阶段、安慰剂对照试验，采用序贯平行比较设计，评估了缓释注射用纳曲酮（每 3 周 380mg）联合口服缓释安非他酮（每天 450mg）治疗中重度甲基苯丙胺使用障碍成人患者的疗效和安全性。在试验的第一阶段，参与者以 0.26:0.74 的比例随机分配接受纳曲酮-安非他酮或匹配的注射用和口服安慰剂治疗 6 周。在第一阶段未出现应答的安慰剂组参与者在第二阶段进行重新随机分组，以 1:1 的比例随机分配接受纳曲酮-安非他酮或安慰剂治疗另外 6 周。每周两次从参与者处采集尿样。主要结局为应答，定义为第一阶段或第二阶段结束时 4 个尿样中至少 3 个为阴性，报告两个阶段的加权平均应答。治疗效果定义为两组间总体加权应答的差异。
共纳入 403 名参与者进入第一阶段，225 名参与者进入第二阶段。在第一阶段，纳曲酮-安非他酮组 109 名参与者中有 18 名（16.5%）和安慰剂组 294 名参与者中有 10 名（3.4%）出现应答。在第二阶段，纳曲酮-安非他酮组 114 名参与者中有 13 名（11.4%）和安慰剂组 111 名参与者中有 2 名（1.8%）出现应答。两个阶段的加权平均应答率分别为纳曲酮-安非他酮组 13.6%和安慰剂组 2.5%，总体治疗效果为 11.1 个百分点（Wald z 检验统计量，4.53；P<0.001）。纳曲酮-安非他酮的不良反应包括胃肠道疾病、震颤、不适、多汗和厌食。223 名接受纳曲酮-安非他酮治疗的参与者在试验期间发生了 8 例严重不良事件（3.6%）。
在患有甲基苯丙胺使用障碍的成年人中，接受缓释注射用纳曲酮联合口服缓释安非他酮治疗 12 周的应答率较低，但高于接受安慰剂的参与者。（由国家药物滥用研究所等资助；ADAPT-2 ClinicalTrials.gov 编号，NCT03078075。）
