Ask The Expert: False-Positive Screen for Benzodiazepines
Question: What can cause a false-positive urine drug screening for benzodiazepines?
Answer: First introduced in the 1960s, benzodiazepines fall under the class of drugs referred to as sedative-hypnotics.1 Traditionally, benzodiazepines have been used as anxiolytics, sedatives, muscle relaxants, sedative-hypnotics to treat alcohol withdrawal, as well as for other conditions.2
It is not uncommon, however, for physicians to prescribe benzodiazepines along with opioids for patients with chronic pain. When used in conjunction with opioid pain medications, benzodiazepines have been shown to enhance pain relief, but the combination can be accompanied by increased risks for abuse and accidental overdose.3 Table 1 provides a list of generic and brand names, parent drug half-lives, and speeds of onset for the commonly prescribed benzodiazepines.
Given the increasing and widespread use of benzodiazepines, both alone and in conjunction with other medications, it is important for clinicians to use and understand urine drug screen (UDS) to fully manage patients. UDS results can help optimize treatment by providing information about the presence of possibly illicit or non-prescribed drug use. However, clinicians need to be aware that false positive results can occur, necessitating confirmatory testing.
What could cause a false-positive screen for benzodiazepines? A search of false positive benzodiazepine screenings showed the selective serotonin reuptake inhibitor (SSRI) sertraline (Zoloft, others) and the non-steroidal anti-inflammatory drug (NSAID) oxaprozin (Daypro, others) to be associated with, or possible causes of, these false-positive results.4-7
Although the mechanism is unknown, sertraline, which is used to treat depression, obsessive-compulsive disorder, panic disorder, and anxiety, has been shown to increase levels of benzodiazepines when used in combination.2 In addition, the package inserts for both oxaprozin and sertraline state that false positive UDS results for benzodiazepines have been reported.4,5 Both package inserts state that initial screening tests result in a lack of specificity and that confirmatory tests, such as gas chromatography/mass spectrometry (GC-MS) or liquid chromatography/mass spectrometry (LC-MS), should be used.
Nasky et al performed a 2-year retrospective examination of records identifying patients with positive benzodiazepine screenings that GC-MS confirmed were falsely positive.6 After identifying the patients, assays were cross-referenced with the pharmacy database to see if patients with a confirmed false-positive benzodiazepine screening also had an active prescription for sertraline at the time of the initial screening. There were 522 positive UDS, 160 of which were later determined by GC-MS to be false positives. Sixty-two of the 160 positive screens determined by cross-referencing with the pharmacy database also had an active benzodiazepine prescription. In the remaining 98 patients without an active benzodiazepine prescription, 26 (26.5%) of the total false positives had an active sertraline prescription.6
Most benzodiazepines undergo extensive metabolism in the liver, and there have been reports of cross reactivity to these metabolites. Typical detection windows for benzodiazepines in the urine are 2 to 7 days, depending on the individual benzodiazepine drug used and other factors, such as time of last dose, drug half-life, route of administration, and individual differences in pharmacokinetics.8 Following administration, diazepam, for example, undergoes metabolism to yield the active metabolites nordiazepam and temazepam. Nordiazepam and temazepam then are metabolized further to the final active metabolic product oxazepam. Thus, the presence of nordiazepam, temazepam, and oxazepam together on a UDS is consistent with diazepam use.
One study compared the cross reactivity of oxaprozin with benzodiazepine assays using the fluorescence polarization immunoassay (Abbott FPIA), the enzyme multiplied immunoassay technique (Behring EMIT d.a.u.), and the cloned enzyme donor immunoassay (Boehringer Mannheim CEDIA DAU).7 Negative screenings were established at baseline. Twelve individuals participated and supplied urine at baseline, 24 hours, 48 hours, and 72 hours following a one-time dose of 1,200 mg of oxaprozin. Baseline urine samples were available from 4 participants; all screened negative for benzodiazepines. Oxaprozin cross-reactivity was low (1.6%-2.5%) in the urine, but there was evidence for false-positive benzodiazepine immunoassays after participants had a dose of oxaprozin. The results showed that 35 urine samples screened positive for benzodiazepines after 48 hours. The investigators used a GC-MS for confirmatory analysis. The study concluded that all positive urine screenings should be confirmed by another analysis to rule out potential false-positive results.7
With conflicting evidence concerning the different benzodiazepine immunoassays, a 2014 study by Darragh et al, examined 3 different immunoassays specific for benzodiazepines to determine diagnostic accuracy.9 This study targeted the high-sensitivity-CEDIA (HS-CEDIA) to look at its sensitivity and specificity compared to that of other traditionally used benzodiazepine immunoassays. The kinetic interaction of microparticles in solution (KIMS) assay was calibrated to a positive/negative cutoff of 100 ng/mL, the CEDIA and HS-CEDIA assays were calibrated to a positive/negative cutoff of 200 ng/mL. Out of 299 urine screenings, 141 were confirmed positive by LC-MS for 1 or more benzodiazepines.9
The highest sensitivities were found with samples containing alpha-hydroxyalprazolam and the lowest sensitivities were found with samples containing lorazepam and 7-aminoclonazepam. The HS-CEDIA assay demonstrated the highest sensitivity, at 78% (110/141), compared to 55% (78/141) with the CEDIA, and 47% (66/141) with the KIMS. Though the HS-CEDIA displayed higher sensitivity compared to the other two, it still missed 22% (31/141) of benzodiazepine-positive samples; this was the lowest false-negative rate of the 3 immunoassays. This study shows that even with a high sensitivity immunoassay such as the HS-CEDIA, there are still discrepancies that could lead to false reports if not confirmed.9
The use of urine drug analysis in patient care settings is useful for clinicians. Although cross-sensitivity with oxaprozin is low, patients with a positive screening for benzodiazepines who also have an active prescription for oxaprozin or sertraline should have a confirmed GC-MS or LC-MS analysis. It is not known whether sertraline or oxaprozin is a direct cause for false positive UDS, but the association cannot be ruled out. Benzodiazepine-positive screenings and any other positive screening results should be confirmed using another technique to rule out false positives that otherwise may compromise therapy.