Psychological And Methodological Issues In Drug Abuse Tx

在这些项目中，我们试图增加文献的主体，证明美沙酮维持的好处，并加强这些好处。过去一年的研究领域包括美沙酮维持对月经周期和不良事件发生率的影响，以及美沙酮及其代谢物的血浆和唾液对映体水平与治疗结果之间的关系。我们已经完成了一项研究，以评估在美沙酮维持期间月经周期是否变得更有规律。虽然海洛因的月经紊乱已被证实，但很少有关于美沙酮维持和月经功能的公开数据。我们回顾性分析了来自两项临床试验的191名用药妇女的数据，持续时间为25-29周；每名妇女维持70-100毫克的美沙酮。收集每次月经的开始/结束日期。月经模式分为规律、不规则、短暂性闭经、持续性闭经和周期重启。使用重复测量回归模型确定周期长度的相关性以及长周期（40天以内）和短周期（<20天）的预测因子。出血发作（从“开始”到“停止”的天数）定义为一个或多个出血天数，至少两个无出血天数。相关因素/预测因素包括体重指数、药物使用、美沙酮剂量和种族。在133名可以确定月经模式的女性中，月经周期长度不规律是常见的；其中：不规则62例（46.7%）；普通37人（27.8%）；循环重启，16次（12%）；持续性闭经11例（8.3%）；短暂性闭经7例（5.3%）。每增加一周的美沙酮维持与较长周期（OR=0.96, p=0.001）和较短周期（OR=0.92, p=0.001）的风险降低相关。在27名继发性闭经的女性中，16名（59%）在美沙酮维持期间重新开始月经。阿片类药物或可卡因阳性与短周期或长周期无显著相关性。因此，在美沙酮维持期间，周期长度开始正常化，并可能出现月经恢复。维持美沙酮，尽管在绝对意义上干扰月经功能，但可能比非法滥用海洛因干扰更小。我们还进行了一系列分析，以表征美沙酮维持患者接受行为治疗的不良事件（ae）的患病率和性质。我们在这里的目的是加强安全监测，这是复杂的参与者？高水平的医疗和精神合并症。在第一组分析中，我们的论文描述了我们的一项大型（N = 286）， 29周门诊突发事件管理研究中报告的ae。总共报告了884例ae（3.1例/患者，0.12例/患者-周），最常见的是感染（26.8%）、胃肠道（20.5%）、肌肉骨骼（12.3%）和一般（10%）疾病。严重ae不常见（占总数的1.6%）。女性受试者报告的ae发生率显著较高（发生率密度比，IDR = 1.38, p < 0.0001）；非裔美国人报告的不良事件发生率较低（IDR = 0.73, p < 0.0001）， 40岁以上的参与者报告的不良事件发生率较低（IDR = 0.84, p = 0.0095）。AE的发生率与研究干预或精神合并症无关。我们注意到，需要进一步的工作来适应AE编码系统对物质依赖的行为试验；国际药品制造商协会联合会（MedDRA）编码系统的规范活动标准医学词典没有为最常见的AE类型之一——牙齿问题单独分类。尽管如此，我们的数据应该有助于提供一个背景，研究人员和irb可以解释他们遇到的ae模式。我们目前正在扩展该项目，以检查既往医疗状况的影响，描述急诊室对常规医疗需求的使用，并确定美沙酮剂量上限（有时在我们的临床试验中用于主要与研究设计相关的目的）是否应该引起对补偿性静脉注射海洛因和随之而来的ae的伦理关注。最后，我们正在进行方法学研究，以改进我们对药物使用和剂量适当性的监测。例如，我们正在研究美沙酮的游离和蛋白结合对映体及其主要代谢物EDDP在血浆和唾液中的浓度之间的关系。我们的合作者已经为这些目的开发了新的分析方法，现在正在分析我们完成的临床试验中的一个标本。我们将确定分析物浓度、美沙酮剂量和治疗结果之间的关系。我们在这个项目中的发现可能有助于我们的治疗药物监测，因为我们开始了另一个大型临床试验，将灵活的、个性化的每日美沙酮剂量与固定的高剂量进行双盲比较——这是一种从未系统进行过的比较。

In these projects, we seek to add to the body of literature demonstrating the benefits of methadone maintenance and to enhance those benefits. Areas of research in the past year include the effects of methadone maintenance on menstrual cycle and on the rates of adverse events and the relationships between plasma and saliva levels of the enantiomers of methadone and its metabolites and treatment outcome. We have completed a study to evaluate whether menstrual cycles become more regular during methadone maintenance. While heroin's menstrual disruption has been demonstrated, there are few published data concerning methadone maintenance and menstrual function. We retrospectively examined data from 191 drug-using women from two clinical trials, lasting 25-29 weeks; each woman was maintained on 70-100 mg of methadone. Start/end dates of each menses were collected. Patterns of menstruation were classified as regular, irregular, transient amenorrhea, persistent amenorrhea, or cycle restart. Repeated-measures regression modeling was used to determine correlates of cycle length and predictors of long cycles (>40 days) and short cycles (<20 days). Bleeding episodes (days from "start" to "stop") were defined as one or more bleeding days, bound by at least two non-bleeding days. Correlates/predictors examined were body mass index, drug use, methadone dose, and race. In the 133 women for whom menstrual patterns could be determined, cycle-length irregularity was common; the patterns seen were: irregular, 62 (46.7%); regular, 37 (27.8%); cycle restart, 16 (12%); persistent amenorrhea, 11 (8.3%); transient amenorrhea, 7 (5.3%). Each additional week on methadone maintenance was associated with decreased risk of long (OR=0.96, p=0.001 and short (OR=0.92, p=0.001) cycles. Of 27 women with secondary amenorrhea pre-study, 16 (59%) restarted menses while maintained on methadone. Positivity for opioids or cocaine was not significantly associated with short or long cycles. Thus, cycle length begins to normalize during methadone maintenance, and menses resumption may occur. Methadone maintenance, despite interfering with menstrual function in an absolute sense, may interfere less than illicit heroin abuse. We have also undertaken a series of analyses to characterize the prevalence and nature of adverse events (AEs) in methadone-maintained patients undergoing behavioral treatment. Our aim here is to enhance safety monitoring, which is complicated by participants? high levels of medical and psychiatric comorbidity. In the first set of analyses, now in press, we paper describe AEs reported in one of our a large (N = 286), 29-week outpatient contingency-management studies. A total of 884 AEs were reported (3.1 per patient, 0.12 per patient-week), the most common being infections (26.8%), gastrointestinal (20.5%), musculoskeletal (12.3%), and general (10%) disorders. Serious AEs were uncommon (1.6% of total). Female participants reported significantly higher rates of AEs (incidence density ratio, IDR = 1.38, p < 0.0001); lower rates of AEs were reported by African Americans (IDR = 0.73, p < 0.0001) and participants over age 40 reported lower rates of AEs (IDR = 0.84, p = 0.0095). AE incidence was not associated with the study intervention or with psychiatric comorbidity. We noted that further work is needed to adapt AE coding systems for behavioral trials for substance dependence; the standard Medical Dictionary for Regulatory Activities, International Federation of Pharmaceutical Manufacturers Associations (MedDRA) coding system does not contain a separate category for one of the most common types of AE, dental problems. Nonetheless, our data should help provide a context in which investigators and IRBs can interpret the patterns of AEs they encounter. We are currently extending this project to examine the effects of preexisting medical conditions, to characterize the use of emergency rooms for routine healthcare needs, and to determine whether methadone dose ceilings (sometimes used in our clinical trials for purposes related mostly to study design) should raise ethical concerns about compensatory intravenous heroin use and consequent AEs. Finally, we are conducting methodological studies to refine our monitoring of drug use and dose adequacy. For example, we are investigating the relationships among the concentrations of free and protein-bound enantiomers of methadone and its major metabolite EDDP in plasma and saliva. Our collaborators have developed new assays for these purposes and are now analyzing specimens from one of our completed clinical trials. We will determine associations among analyte concentrations, methadone dose, and treatment outcome. Our findings in this project may contribute to our therapeutic drug monitoring as we begin another large clinical trial in which flexible, individualized daily methadone doses are compared double-blind to fixed high doses--a comparison that has never been systematically made. A second objective of this project is to examine the roles of other psychological and physiological aspects of drug use in addiction and treatment. We are testing whether craving for cocaine and heroin predicts subsequent drug use more strongly when tested with 45-item, multifactor questionnaires than with single-item questionnaires?and, if so, whether 16-item multifactor questionnaires are an adequate substitute for the 45-item versions. In a study that represents a departure for our section, both substantively and methodologically, we are exploring the use of qualitative methods to gain insight into our patients? views on the roles of religion and spirituality in their recovery. In collaboration with outside experts on qualitative research and on the psychology of religion, we have been conducting focus groups in which our patients discuss how they reconcile their lives as drug abusers with their spiritual lives, and how (or indeed whether) issues of spirituality could be addressed in formal treatment settings. Finally, we are examining expression of the Nurr1 gene (which helps regulate expression of the dopamine-transporter gene) in peripheral blood lymphocytes of methadone-maintained patients who continue to use cocaine. Ultimately, the aim of this study is to determine whether the Nurr1 gene can be used as a biological marker of drug abuse and to determine whether treatment might reverse changes in Nurr1 gene expression.