The effect of a methadone-initiated memory reconsolidation updating procedure in opioid use disorder: A translational study
Jing-Li Yue,
Kai Yuan,
Yan-Ping Bao,
Shi-Qiu Meng,
Le Shi,
Qing Fang,
Xiao-Jie Guo,
Lu Cao,
Ye-Kun Sun,
Tang-Sheng Lu,
Na Zeng,
Wei Yan,
Ying Han,
Jie Sun,
Jie Shi,
Thomas R. Kosten,
Yan-Xue Xue,
Ping Wu,
Lin Lu
Affiliations
Jing-Li Yue
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
Kai Yuan
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
Yan-Ping Bao
National Institute on Drug Dependence, Beijing Key Laboratory of Drug Dependence, Peking University, Beijing 100191, China
Shi-Qiu Meng
National Institute on Drug Dependence, Beijing Key Laboratory of Drug Dependence, Peking University, Beijing 100191, China
Le Shi
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
Qing Fang
Department of Clinical Psychology, Tianjin Medical University General Hospital, Tianjin 300052, China
Xiao-Jie Guo
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
Lu Cao
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; Peking-Tsinghua Centre for Life Sciences and PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing 100871, China
Ye-Kun Sun
School of Psychology and Mental Health, North China University of Science and Technology, Tangshan 063210, Hebei, China
Tang-Sheng Lu
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
Na Zeng
National Institute on Drug Dependence, Beijing Key Laboratory of Drug Dependence, Peking University, Beijing 100191, China
Wei Yan
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
Ying Han
National Institute on Drug Dependence, Beijing Key Laboratory of Drug Dependence, Peking University, Beijing 100191, China
Jie Sun
Department of Anesthesiology, Center for Pain Medicine, Peking University Third Hospital, Beijing 100191, China
Jie Shi
National Institute on Drug Dependence, Beijing Key Laboratory of Drug Dependence, Peking University, Beijing 100191, China
Thomas R. Kosten
Department of Psychiatry, Pharmacology, Neuroscience, Immunology, Baylor College of Medicine, Houston, TX 77030, USA; Corresponding author.
Yan-Xue Xue
National Institute on Drug Dependence, Beijing Key Laboratory of Drug Dependence, Peking University, Beijing 100191, China; Chinese Institute for Brain Research, Beijing 102206, China; Corresponding authors at: National Institute on Drug Dependence, Peking University, 38 Xueyuan Road, Beijing 100191, China.
Ping Wu
National Institute on Drug Dependence, Beijing Key Laboratory of Drug Dependence, Peking University, Beijing 100191, China; Corresponding authors at: National Institute on Drug Dependence, Peking University, 38 Xueyuan Road, Beijing 100191, China.
Lin Lu
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; Peking-Tsinghua Centre for Life Sciences and PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing 100871, China; Corresponding authors at: National Institute on Drug Dependence, Peking University, 38 Xueyuan Road, Beijing 100191, China.
Summary: Background: 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. Methods: 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. Findings: 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 (8,80) = 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 (12, 63·3) = 2.41, p = 0.01). Interpretation: 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. Funding: 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)