NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Peking University Sixth Hospital, Peking University Institute of Mental Health, Beijing 100191, China.
National Institute on Drug Dependence, Beijing Key Laboratory of Drug Dependence, Peking University, Beijing 100191, China.
EBioMedicine. 2022 Nov;85:104283. doi: 10.1016/j.ebiom.2022.104283. Epub 2022 Sep 28.
Opioid use disorder (OUD) is a chronic relapsing psychiatric disorder. An unconditioned stimulus (US)-triggers a memory reconsolidation updating procedure (MRUP) that has been developed and demonstrated its effectiveness in decreasing relapse to cocaine and heroin in preclinical models. However, utilizations of abused drugs as the US to initiate MRUP can be problematic. We therefore designed a translational rat study and human study to evaluate the efficacy of a novel methadone-initiated MRUP.
In the rodent study, male rats underwent heroin self-administration training for 10 consecutive days, and were randomly assigned to receive saline or methadone at 10 min, 1 h or 6 h before extinction training after 28-day withdrawal. The primary outcome was operant heroin seeking after reinstatement. In the human experimental study, male OUD patients were randomly assigned to get MRUP at 10 min or 6 h after methadone or methadone alone. The primary outcomes included experimental cue-induced heroin craving change, sustained abstinence and retention in the study at post intervention and the 5 monthly follow-up assessments. The secondary outcomes were changes in physiological responses including experimental cue-induced blood pressure and heart rate.
Methadone exposure but not saline exposure at 10 min or 1 h before extinction decreased heroin-induced reinstatement of heroin seeking after 28-day of withdrawal in rats (F = 8.26, p < 0.001). In the human study, when the MRUP was performed 10 min, but not 6 h after methadone dosing, the MRUP promoted sustained abstinence from heroin throughout 5 monthly follow-up assessments compared to giving methadone alone without MRUP (Hazard Ratio [95%CI] of 0.43 [0.22, 0.83], p = 0.01). The MRUP at 10 min, but not at 6 h after dosing also decreased experimental cue-induced heroin craving and blood pressure increases during the 6-month study duration (group × months × cue types, F = 2.41, p = 0.01).
The approach of MRUP within about 1 to 6 h after a methadone dose potently improved several key outcomes of OUD patients during methadone maintenance treatment, and could be a potentially novel treatment to prevent opioid relapse.
National Natural Science Foundation of China (NO. U1802283, 81761128036, 82001400, 82001404 and 31671143) and Chinese National Programs for Brain Science and Brain-like Intelligence Technology (NO. 2021ZD0200800).
阿片类药物使用障碍（OUD）是一种慢性复发性精神障碍。非条件刺激（US）引发记忆再巩固更新程序（MRUP），该程序已在可卡因和海洛因的临床前模型中得到开发和证明其有效性，可降低复发率。然而，将滥用药物用作引发 MRUP 的 US 可能存在问题。因此，我们设计了一项转化大鼠研究和人类研究，以评估一种新型美沙酮引发的 MRUP 的疗效。
在啮齿动物研究中，雄性大鼠接受海洛因自我给药训练 10 天，然后在 28 天戒断后进行消退训练前 10 分钟、1 小时或 6 小时接受生理盐水或美沙酮。主要结局是复吸后的操作性海洛因寻求。在人类实验研究中，男性 OUD 患者随机接受美沙酮或美沙酮加 MRUP，分别在 10 分钟或 6 小时后进行。主要结局包括实验线索诱导的海洛因渴求变化、干预后和 5 个月随访评估时的持续禁欲和保留率。次要结局是包括实验线索诱导的血压和心率在内的生理反应的变化。
与生理盐水暴露相比，10 分钟或 1 小时前接触美沙酮可降低 28 天戒断后海洛因诱导的海洛因复吸（F=8.26，p<0.001）。在人类研究中，与单独给予美沙酮而不进行 MRUP 相比，当 MRUP 在美沙酮给药后 10 分钟而不是 6 小时进行时，MRUP 促进了整个 5 个月随访评估期间的海洛因持续禁欲（风险比[95%CI]为 0.43[0.22, 0.83]，p=0.01）。MRUP 在 10 分钟，而不是在 6 小时后，也降低了实验线索诱导的海洛因渴求和血压在 6 个月研究期间的升高（组×月×线索类型，F=2.41，p=0.01）。
在美沙酮剂量后 1 至 6 小时内进行 MRUP 可显著改善美沙酮维持治疗期间 OUD 患者的多项关键结局，可能是预防阿片类药物复发的一种潜在新治疗方法。
国家自然科学基金（NO. U1802283、81761128036、82001400、82001404 和 31671143）和中国国家脑科学与类脑智能技术计划（NO. 2021ZD0200800）。
