A Difficult Challenge for the Clinical Laboratory: Accessing and Interpreting Manufacturer Cross-Reactivity Data for Immunoassays Used in Urine Drug Testing

Abstract

Urine drug testing by immunoassay is widely used to detect nonmedical drug use and to monitor patients prescribed controlled substances. A key attribute of urine drug testing immunoassays is cross-reactivity, namely the response of various compounds compared to the target of the assay. In this report, we analyzed the variability in how manufacturer cross-reactivity data are summarized in package inserts for commercially available amphetamines, benzodiazepines, and opiates immunoassays, 3 broad drug classes commonly included in routine drug testing panels. Specifically, we determined the number of compounds tested for cross-reactivity, manner in which cross-reactivity is measured, concentration units used, how often compounds known to be cross-reactive with marketed urine drug testing immunoassays prior to 2010 were tested, availability of the package insert online, and how often cross-reactivity on "designer drugs" was found in the package inserts. There was wide variability in the number of compounds tested (both positive and negative), with the highest number of tested compounds generally found in point-of-care urine drug testing applications. Most package inserts used ng/mL as the concentration units and expressed cross-reactivity in terms of equivalent concentrations to the assay calibrator. Approximately 50% of package inserts were directly available online. Cross-reactivity data were sparse with respect to "off-target" drugs known to be cross-reactive prior to 2010 (an example being quinolone antibiotics and opiates immunoassays) and designer drugs. The present study indicates lack of consistency in cross-reactivity information in package inserts, complicating the interpretation of urine drug testing results. We use 3 example clinical cases to illustrate practical challenges accessing and interpreting cross-reactivity data.

Keywords: amphetamines; benzodiazepines; designer drugs; false positives; immunoassay; opiates.

Figure 1.

Variability of information in urine drug testing package inserts for amphetamines (n = 30), benzodiazepines (n = 23), and opiates (n = 28) immunoassays. A, Breakdown on concentration units (ng/mL, μg/mL, or both units) used to describe cross-reactivity data. B, Breakdown of whether package insert reported concentration equivalents for cross-reactivity data. C, Breakdown of whether package insert reported percent cross-reactivity (relative to standard such as morphine for opiates). Note that some package inserts reported in both concentration equivalents and percent cross-reactivity. D, Breakdown of whether package inserts was directly available online. See Methods for more details on definitions.

Figure 2.

Number of compounds tested for cross-reactivity as reported in urine drug testing package inserts for (A) amphetamines (n = 30), (B) benzodiazepines (n = 23), and (C) opiates (n = 28) immunoassays. Data are broken down into compounds showing measurable cross-reactivity and those reported as having no cross-reactivity (at least within limits of concentrations tested by the manufacturer).

Figure 3.

Concentrations of oxycodone and oxymorphone (oxycodone metabolite) producing equivalent signal to 300 ng/mL for morphine urine immunoassays, as reported in package inserts analyzed in this study. The oxycodone concentrations outlined by the red box are within the range of concentrations seen in a detailed pharmacokinetic study of 20 mg oxycodone administered to healthy adult volunteers. The 4 data points plotted at 75 000 ng/mL for the oxycodone concentration were reported in the package inserts as >75 000 ng/mL.