Which medications can cause a false‑positive blood immunoassay result for alprazolam?

Medications Causing False-Positive Blood Tests for Alprazolam

Oxaprozin (Daypro), a nonsteroidal anti-inflammatory drug, is the primary medication documented to cause false-positive benzodiazepine immunoassay results that could be misinterpreted as alprazolam, though standard immunoassays detect benzodiazepines as a class rather than alprazolam specifically. 1

Critical Testing Limitations You Must Understand

• Standard benzodiazepine immunoassays (EMIT, FPIA, CEDIA) are designed to detect oxazepam and its metabolites as the primary target, not alprazolam specifically—meaning a "positive benzodiazepine screen" does not confirm alprazolam presence. 2, 3

• Alprazolam has notoriously low cross-reactivity with standard benzodiazepine immunoassays and may not be reliably detected even when present, making false-positive results for alprazolam specifically extremely unlikely with standard screening methods. 2, 3

• Gas chromatography-mass spectrometry (GC-MS) confirmatory testing is essential before making any clinical decisions, as immunoassay screens are presumptive only and cannot definitively identify specific benzodiazepines like alprazolam. 2, 4

Documented Medication Causing False-Positive Benzodiazepine Results

Oxaprozin (Daypro)

• Oxaprozin produces presumptive positive benzodiazepine results at concentrations between 5,000-10,000 ng/mL on EMIT and approximately 10,000 ng/mL on FPIA and CEDIA assays. 1

• In clinical studies, 35-36 out of 36 urine specimens from patients taking a single 1,200 mg dose of oxaprozin tested positive for benzodiazepines across all three major immunoassay platforms (EMIT, FPIA, CEDIA). 1

• This cross-reactivity is due to oxaprozin or its metabolites, not actual benzodiazepine presence, and confirmatory testing will be negative for alprazolam. 1

Designer Benzodiazepines: A Growing Concern

• Designer benzodiazepines including flualprazolam (an alprazolam analog), flubromazolam, clonazolam, and etizolam show high cross-reactivity with standard benzodiazepine immunoassays and may cause positive results that could be confused with prescribed alprazolam. 5, 6

• In emergency department studies, 30 out of 35 specimens with "false-positive" benzodiazepine screens (negative for prescribed benzodiazepines on standard LC-MS-MS panels) actually contained designer benzodiazepines not included in routine confirmatory testing. 6

• Standard LC-MS-MS confirmatory panels typically test only 19 prescribed benzodiazepines and will miss designer benzodiazepines, leading laboratories to incorrectly report immunoassay results as false-positives when designer drugs are actually present. 6

Other Benzodiazepines With Testing Implications

• Clonazepam and lorazepam are poorly detected by standard benzodiazepine immunoassays that primarily target oxazepam, potentially causing false-negative results rather than false-positives. 2

• Pinazepam, delorazepam, and brotizolam show high cross-reactivity with EMIT immunoassays, while 3-hydroxy-flunitrazepam, 7-amino-nitrazepam, and α-hydroxy-midazolam show very low cross-reactivity. 7

Clinical Approach When Encountering Unexpected Results

Immediate Actions

• Order confirmatory testing with GC-MS before making any clinical decisions that could adversely affect the patient, as the CDC explicitly warns against dismissing patients from care or making punitive decisions based solely on immunoassay results. 2, 4

• Obtain complete medication history specifically asking about oxaprozin, other NSAIDs, all prescribed benzodiazepines, over-the-counter medications, and supplements. 2, 4

• Discuss the unexpected result with the patient in a non-judgmental manner before ordering confirmatory testing, as this may yield a candid explanation. 2

Confirmatory Testing Strategy

• Request GC-MS analysis that can definitively identify whether alprazolam is present and distinguish it from other benzodiazepines or interfering substances. 2, 4

• If standard confirmatory testing is negative but clinical suspicion remains for designer benzodiazepines, request expanded testing using LC-QTOF-MS or targeted LC-MS-MS panels that include designer benzodiazepines. 6

• Contact your laboratory's toxicology department to understand which specific benzodiazepines are included in their confirmatory panel, as many do not test for designer benzodiazepines. 4, 6

Critical Pitfalls to Avoid

• Never assume a positive benzodiazepine immunoassay represents alprazolam specifically—the test detects benzodiazepines as a class with varying sensitivity to different compounds. 2, 3

• Do not dismiss patients from care, make punitive decisions, or assume medication diversion based solely on a positive screen without confirmatory testing, as this could represent patient abandonment. 2, 4

• Recognize that false-positive results are 8 times more frequent than true positives in routine testing populations, emphasizing the need for confirmatory testing before clinical action. 8

• Understand that many healthcare providers have inadequate training in interpreting drug test results, and incorrect interpretation can have severe consequences including legal implications. 8, 4

Special Considerations for Blood vs. Urine Testing

• While most published data addresses urine immunoassays, the same cross-reactivity principles apply to blood/serum immunoassays using similar antibody-based detection methods. 3

• Blood specimens may show different concentration thresholds for cross-reactivity compared to urine, but oxaprozin and designer benzodiazepines remain the primary concerns for false-positive results. 1, 3

• There is particular risk of missing alprazolam intoxication due to its low therapeutic range and low cross-reactivity with standard immunoassays, even when alprazolam is actually present. 3