Transdermal Rotigotine as Adjunct to Behavioral Therapy for Cocaine Use Disorder

可卡因使用障碍(CocUD)造成很高的社会经济负担，但没有食品和药物管理局 美国食品和药物管理局(FDA)批准的药物疗法可用于治疗COUD。我们提出了一项概念验证临床试验 多多巴胺受体(D2/D3/D4/D5)激动剂罗替戈汀(RTG)可促进可卡因戒断 增加DA依赖的执行功能(EF)。EF是一组认知能力，如工作记忆， 实现目标所需的信息更新和思维灵活性。在慢性充血性心力衰竭和射血分数低的患者中， 在认知行为疗法(CBT)中关注和保留心理教育信息可能是 受损的、可预测毒品的线索可能更容易将注意力从戒酒目标上转移开。事实上，低EF 与COUD治疗结果不佳有关。这类患者可以从增加DA的药物中受益 来帮助保持节欲。事实上，释放多巴胺的处方兴奋剂已被证明可以减少可卡因 使用，但有问题，因为兴奋剂本身有滥用的可能性。一种多多巴胺受体激动剂 可能是改善DA功能和EF的一种更安全的选择。尽管RTG被FDA批准用于帕金森氏症 在疾病治疗中，RTG已被证明可以改善阿尔茨海默病患者的皮质可塑性和EF。此外， 缓释RTG贴片可促进稳态药物水平。因此，我们建议进行一项临床试验。 每日六周的罗替戈汀透皮贴片(Neupro®)作为CBT的辅助药物，用于减少可卡因的使用 COCOUD。可卡因的使用结果将在n=30(完成)参与者之间进行比较，随机分为6组 4 mg/d透皮注射RTG，n=30名参与者随机服用透皮安慰剂。根据NIDA目标 在临床试验中确定禁欲以外的与生活质量相关的替代终点，我们也将获得 通过获得功能磁共振成像(FMRI)和神经认知对RTG作用的洞察 作为次要终点的给药前后与EF相关的评估。这将获得证据，证明 RTG是否增加EF的脑激活和显性行为特征。这些发现将提供 RTG通过提高EF和/或促戒断作用的关键机制证据 减少冲动。最后，为了向COUD的精准医学迈进一步，我们将确定RTG如何受益 大脑和行为作为基线EF的函数。从以前对DA特工的审判中获得的几条证据 提示患有SUD和EF较差的个体从DA增强中获益最多，而患有 基线时正常到超常的EF较少或没有从DA物质增强中获益 禁欲。因此，我们将进行有计划的事后分析，以发现外汇储备和外汇储备的差异变化- RTG后相关的大脑连接和功能作为参与者得分是否高于VS的函数 低于RTG治疗臂在经过验证的计算机化认知电池得分中的中位数 探头EF。这项事后分析发现，RTG选择性地使EF较低的个体受益 预示着未来其他DA促进剂治疗COUD的临床试验中有一种新的精确医学方法。

Cocaine Use Disorder (CocUD) incurs a high socioeconomic burden, yet no Food and Drug Administration (FDA)-approved pharmacotherapies are available for CocUD. We propose a proof of concept clinical trial of multiple dopamine (DA) receptor (D2/D3/D4/D5) agonist rotigotine (RTG) that could improve cocaine abstinence by increasing DA-dependent executive function (EF). EF is the set of cognitive abilities such as working memory, information updating and mental flexibility required for goal attainment. In patients with CocUD and poor EF, attention to and retention of psychoeducation information during cognitive behavioral therapy (CBT) could be impaired, and drug-predictive cues may capture attention away from sobriety goals more readily. Indeed, low EF has been linked to poor CocUD treatment outcomes. Such patients could benefit from DA-increasing medication to help maintain abstinence. In fact, prescription stimulants that release DA have been shown to reduce cocaine use, but are problematic because stimulants themselves have abuse potential. A multiple DA receptor agonist may be a safer alternative to improve DA function and EF. Although RTG is FDA-approved for Parkinson’s Disease treatment, RTG has been shown to improve cortical plasticity and EF in Alzheimer’s Disease. Moreover, the sustained-release RTG patches promote steady state drug levels. Therefore, we propose a clinical trial of six weeks of daily transdermal rotigotine (Neupro®) patches as an adjunct to CBT for cocaine use reduction in CocUD. Cocaine use outcomes will be compared between n = 30 (completed) participants randomized to six weeks of 4mg/d transdermal RTG, and n = 30 participants randomized to transdermal placebo. Per NIDA goals of identifying alternative quality of life-related endpoints beyond abstinence in clinical trials, we will also attain insights into RTG action by obtaining functional magnetic resonance imaging (fMRI) and neurocognition assessments pertinent to EF prior and following dosing as secondary endpoints. This will garner evidence as to whether RTG increases brain activation and overt behavioral signatures of EF. Such findings would provide critical mechanistic evidence that RTG induces its abstinence-promoting effect by way of improving EF and/or reducing impulsivity. Finally, in a step toward precision medicine for CocUD, we will determine how RTG benefits brain and behavior as a function of baseline EF. Several lines of evidence from previous trials of DA agents suggest that individuals with SUD and poor EF benefit most from DA enhancement, whereas participants with normal to supranormal EF at baseline derive lesser or no benefit from DA enhancement on substance abstinence. We will thus conduct a planned post-hoc analysis to detect differential change in EF and in EF- related brain connectivity and function following RTG as a function of whether the participant scored above vs below the median value of the RTG treatment arm in scores of a validated computerized cognitive battery that probes EF. A finding in this post-hoc analysis that RTG selectively benefited individuals with lower EF would augur a novel precision medicine approach in future clinical trials of other DA-promoting agents for CocUD.