Millennium Laboratories Research Institute, San Diego, CA 92127, USA.
Pain Physician. 2010 Jan-Feb;13(1):71-8.
Physicians determine patient compliance with their medications by use of urine drug testing. It is known that measurement of benzodiazepines is limited by immunoassay specificity and cutoff limits and therefore does not offer physicians an accurate picture of their patients' compliance with these medications. A few studies have used lower cutoffs to demonstrate patient compliance.
To define more appropriate cutoffs for compliance monitoring of patients prescribed clonazepam as determined using immunoassay and liquid chromatography-tandem mass spectrometry (LC-MS/MS).
A diagnostic accuracy study of the urinary excretion of clonazepam.
Millennium Laboratories performed measurements on the urinary excretion of pain patients prescribed clonazepam as the indicator test. This benzodiazepine was chosen because it forms one major metabolite, 7-aminoclonazepam which is specific for that drug. Patients whose only benzodiazepine medication was clonazepam were selected as the test population. The Millennium Laboratories test database was filtered first to select patients on clonazepam, then a second filter was used to eliminate patients with any other listed benzodiazepine medications. Samples were tested using the Microgenics DRI benzodiazepine assay with a 200 ng/mL cutoff. The same samples were quantitatively assessed for 7-aminoclonazepam by LC-MS/MS with a cutoff of 40 ng/mL. The results from the immunoassay were scored as positive or negative while the quantitative results from the LC-MS/MS were also scored as positive or negative depending upon their concentration.
Samples from 180 patients met these medication criteria. The positivity rates were 21% (38 samples) by immunoassay. The positivity rate was 70% (126 samples) if the LC-MS/MS cutoff was set at 200 ng/mL. However, the positivity rate was 87% (157 samples) if the LC-MS/MS was set at 40 ng/mL. Concentration distributions revealed a significant fraction (7%) in the 40 - 100 ng/mL range.
A limitation of the study was the inability to measure lower than 40 ng/mL. There may be another fraction of the population that was positive below the cutoff value.
The difference in positivity rate between the immunoassay and the LC-MS/MS result showed that the nominal 200 ng/mL cutoff of the immunoassay did not apply to 7-aminoclonazepam. This low immunoassay positivity rate is inconsistent with the manufacturer's published cross reactivity data for clonazepam and 7-aminoclonazepam. These data illustrate the limitations of using a 200 ng/mL cutoff to monitor clonazepam compliance and suggest that a cutoff of 40 ng/mL or less is needed to reliably monitor use of this drug.
医生通过尿液药物检测来确定患者对药物的依从性。已知，苯二氮䓬类药物的测定受到免疫测定特异性和截止值的限制，因此无法为医生提供其患者对这些药物的依从性的准确情况。一些研究已经使用较低的截止值来证明患者的依从性。
为了确定更合适的截止值，以监测开处方氯硝西泮的患者的依从性，该药物使用免疫测定和液相色谱-串联质谱法（LC-MS/MS）进行测定。
对氯硝西泮尿液排泄进行诊断准确性研究。
千禧实验室对开处方氯硝西泮的疼痛患者的尿液排泄进行了测量。选择这种苯二氮䓬类药物是因为它形成一种主要代谢物，即 7-氨基氯硝西泮，该代谢物是该药物特有的。选择唯一的苯二氮䓬类药物为氯硝西泮的患者作为测试人群。首先，千禧实验室的测试数据库经过过滤，以选择氯硝西泮患者，然后使用第二个过滤器排除其他列出的苯二氮䓬类药物的患者。使用 Microgenics DRI 苯二氮䓬测定法，以 200ng/mL 的截止值对样本进行检测。使用 LC-MS/MS 对相同的样本进行定量评估，截止值为 40ng/mL。免疫测定的结果被评分阳性或阴性，而 LC-MS/MS 的定量结果也根据其浓度被评分阳性或阴性。
180 名患者的样本符合这些药物标准。免疫测定的阳性率为 21%（38 个样本）。如果将 LC-MS/MS 的截止值设定为 200ng/mL，则阳性率为 70%（126 个样本）。然而，如果将 LC-MS/MS 设定为 40ng/mL，则阳性率为 87%（157 个样本）。浓度分布显示在 40-100ng/mL 范围内有显著的分数（7%）。
研究的局限性在于无法测量低于 40ng/mL 的浓度。可能还有一部分人群的检测结果低于截止值。
免疫测定和 LC-MS/MS 结果之间的阳性率差异表明，免疫测定的 200ng/mL 截止值不适用于 7-氨基氯硝西泮。这种低免疫测定阳性率与氯硝西泮和 7-氨基氯硝西泮的制造商公布的交叉反应性数据不一致。这些数据说明了使用 200ng/mL 截止值来监测氯硝西泮依从性的局限性，并表明需要设定 40ng/mL 或更低的截止值才能可靠地监测该药物的使用。
