The effect of a methadone-initiated memory reconsolidation updating procedure in opioid use disorder: A translational study.

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).

Prevalence of restless legs syndrome during pregnancy: A systematic review and meta-analysis.

Pregnant women are more likely to be affected by restless legs syndrome (RLS) than the general population. Restless legs syndrome during pregnancy is associated with adverse maternal and fetal outcomes. Currently unknown is the worldwide and regional prevalence of RLS in pregnant women. We performed a meta-analysis to provide a full profile of the prevalence of RLS during pregnancy. A systematic search of the PubMed, Medline, EMBASE, and Web of Science databases was performed to identify studies that were published up to April 2017, followed by random-effects meta-analyses. A total of 196 articles were identified, among which 27 longitudinal and cross-sectional observational studies with 51,717 pregnant subjects were included in the analysis. The pooled overall prevalence of RLS across all three trimesters was 21%. According to the regional classification of the World health organization, the prevalence of RLS during pregnancy in the European Region, Western Pacific Region, Eastern Mediterranean Region, and Region of the Americas was 22%, 14%, 30%, and 20%, respectively. The regional prevalence in the African Region and South-East Asia Region was not assessed because of insufficient data. We also analyzed the prevalence of RLS in the first, second, and third trimesters of pregnancy, and the rates of RLS were 8%, 16%, and 22%, respectively. We also found that the high prevalence of RLS decreased to 4% after delivery. No publication bias was found in these analyses. The findings emphasize the high occurrence of RLS during pregnancy. Future studies should examine the effects of RLS during pregnancy on maternal and fetal outcomes.