Psychological/Methodological Issues In Substance Abuse

在临床试验的背景下，本节评估与研究和治疗相关的方法学问题，例如监测药物使用。在先前发表的研究中，我们发现可卡因的半衰期在活跃的街头使用者中比在偶尔使用者中更长，尽管其主要代谢物苯甲酰芽子碱的半衰期没有变化，这表明可卡因的定期使用改变了其处置和消除（Moolchan ET，Cone EJ，Wtsadik A，Huestis MA，普雷斯顿KL. J Analytical Toxicology，24，458-466，2000）。在另一项先前发表的研究中，我们表明，汗片可以作为监测药物使用的替代方法，具有每周检测窗口的优点（Huestis MA，普雷斯顿KL，Wong CJ，Umbricht A，Cone EJ，. J Analytical Toxicology，24，509-521，2000）。在第三项研究中，我们评估了6-乙酰吗啡（6-AM）的新尿液检测方法的性能，6-AM是海洛因代谢物，是海洛因使用的特异性标志物。6-AM检测在临床上很重要，因为罂粟籽或合法阿片类镇痛剂的摄入可以在尿阿片类药物测试中产生阳性结果，该测试仅筛选海洛因非特异性代谢物，如吗啡和可待因。在联邦政府授权的工作场所药物检测计划中，现在需要进行上午6点的GC-MS分析。同样，卫生与公众服务部（HHS）要求吗啡阳性标本通过GC/MS重新检测6-AM，截止浓度为 * 10 ng/mL。(In在这两套指南中，吗啡和可待因的筛选截止值已从 * 300 ng/mL提高到 * 2000 ng/mL。筛查6-AM的一个缺点是它的半衰期只有0.6小时，这使得它在海洛因暴露后的几个小时内只能在尿液中检测到。我们每周三次从美沙酮维持治疗项目的44名参与者中收集尿液样本，以评估新的检测方法及其在新的截止浓度下的性能。在筛选的1377份尿液标本中，261份（18.9%）对 * 300 ng/mL的阿片类药物呈阳性，153份（11.1%）对 * 2000 ng/mL的阿片类药物呈阳性，55份（4.0%）对 * 10 ng/mL的6 AM呈阳性。在253份 * 300 ng/mL且可用于GC/MS分析的标本中，231份（91.3%）确认为吗啡或可待因（* 300 ng/mL）。在151 * 2000 ng/mL且可用于GC/MS分析的样品中，确认了122或80.8%为 * 2000 ng/mL的吗啡或可待因。在 * 10 ng/mL下，所有6-AM筛选阳性标本也经GC/MS确认为阳性。此外，在 * 300但小于2000 ng/mL的阿片类药物筛选样本中，没有一份在 * 10 ng/mL时证实为6-AM阳性。在55份阳性6AM尿液标本中，有44份（80%）的浓度在201至9096 ng/mL之间，表明近期使用过海洛因。将联邦工作场所药物检测计划的阿片类药物筛查和确认截止值从300 ng/mL增加到2000 ng/mL，导致参加美沙酮维持治疗计划的个人中阿片类药物阳性检测减少8%。然而，最近使用海洛因，定义为尿液浓度为6-AM * 10 ng/mL，不受此变化的影响。尽管6-AM筛选试验确定的阳性阿片剂试验要少得多，4%，而阿片剂 * 2000 ng/mL试验中为11%，但与可能的罂粟籽或可待因使用相比，它清楚地确定了海洛因。此外，虽然6-AM和总吗啡浓度之间有显着的相关性，总尿吗啡不能可靠地预测从GC/MS 6-AM浓度。用针对6-AM的测定法代替针对总吗啡测量的阿片剂筛选测定法将导致较少的阿片剂阳性试验的检测。6-AM检测可能是有用的，在检测最近的海洛因暴露，并在减少潜在的“携带”在治疗和员工援助计划连续尿检阳性。在一项大型研究中，我们正在比较美沙酮在各种生物基质（包括血浆、唾液和汗液）中的治疗药物监测效用;我们还计划测定皮质醇和催乳素的水平，作为美沙酮药效学疗效的可能标志。

Within the context of clinical trials, the section evaluates methodological issues relevant to both research and treatment, such as monitoring drug use. In a previously published study, we found that cocaine's half-life is longer in active street users than in occasional users despite there being no change in the half-life of its main metabolite benzoylecgonine, suggesting that regular use of cocaine alters its the disposition and elimination (Moolchan ET, Cone EJ, Wtsadik A, Huestis MA, Preston KL. J Analytical Toxicology, 24, 458-466, 2000). In another previously published study, we showed that sweat patches could be an alternate method for monitoring drug use, with the advantage of a week-ly window of detection (Huestis MA, Preston KL, Wong CJ, Umbricht A, Cone EJ,. J Analytical Toxicology, 24, 509-521, 2000). In a third study, we assessed the performance of a new urine assay for 6-acetylmorphine (6-AM), a heroin metabolite that is a specific marker for heroin use. 6-AM detection is clinically important because the ingestion of poppy seeds or licit opiate analgesics can produce positive results on urine opiate tests that screen only for heroin-nonspecific metabolites such as morphine and codeine. In the federally mandated workplace drug-testing program, 6-AM GC-MS analysis is now required. Similarly, the Department of Health and Human Services (HHS) requires morphine-positive specimens to be retested by GC/MS for 6-AM at a cutoff concentration of * 10 ng/mL. (In both sets of guidelines, the screening cutoff for morphine and codeine has been raised from * 300 ng/mL to * 2000 ng/mL.) One drawback of screening for 6-AM is its half-life of only 0.6 hours, which makes it detectable in urine for only a few hours after heroin exposure. We collected urine specimens three times per week from 44 participants in a methadone-maintenance program in order to assess the new assay and its performance at the new cutoff concentrations. Of the 1377 urine specimens screened, 261 or 18.9% were positive for opiates at * 300 ng/mL, 153 or 11.1% were positive for opiates at * 2000 ng/mL, and 55 or 4.0% were positive for 6AM at * 10 ng/mL. Of the 253 specimens * 300 ng/mL and available for GC/MS analysis, 231 or 91.3% were confirmed for morphine or codeine at * 300 ng/mL. Of the 151 * 2000 ng/mL and available for GC/MS analysis, 122 or 80.8% were confirmed for morphine or codeine at * 2000 ng/mL. All specimens screening positive for 6-AM also confirmed positive by GC/MS at * 10 ng/mL. Furthermore, none of the specimens screening at * 300 but less than 2000 ng/mL for opiates confirmed positive for 6-AM at * 10 ng/mL. Forty-four (80%) of the 55 positive 6AM urine specimens had concentrations between 201 and 9096 ng/mL, suggesting recent heroin use. Increasing the opiate screening and confirmation cutoffs for the federal workplace drug-testing program from 300 to 2000 ng/mL, resulted in 8% fewer opiate positive tests in individuals participating in a methadone maintenance treatment program. However, recent heroin use, as defined by a urine concentration of 6-AM * 10 ng/mL, was not affected by this change. Although the 6-AM screening assay identified far fewer positive opiate tests, 4% as compared to 11% in the opiate * 2000 ng/mL assay, it clearly identified heroin, as compared to possible poppy seed or codeine use. In addition, although there was a significant correlation between 6-AM and total morphine concentrations, total urinary morphine could not be reliably predicted from the GC/MS 6-AM concentrations. Replacement of an opiate screening assay directed at the measurement of total morphine with an assay directed toward 6-AM would result in the detection of fewer opiate positive tests. The 6-AM assay could be useful in detection of recent heroin exposure and in reducing potential "carryover" positives in consecutive urine tests in treatment and employee assistance programs. In a large study now nearing completion, we are comparing the utility of therapeutic drug monitoring for methadone across a variety of biological matrices, including plasma, saliva, and sweat; we are also planning to assay levels of cortisol and prolactin as possible markers of methadone's pharmacodynamic efficacy.