Ibuprofen and False-Positive Alprazolam Urine Drug Screens
Ibuprofen does not cause false-positive results for alprazolam (or benzodiazepines generally) on urine immunoassay testing. The available evidence demonstrates that NSAIDs like ibuprofen have minimal cross-reactivity with benzodiazepine immunoassays.
Evidence for Lack of Cross-Reactivity
A prospective study of 102 individuals taking therapeutic doses of ibuprofen (200-1200 mg/day), naproxen, or fenoprofen found zero false-positive results for benzodiazepines across 510 urine samples tested by enzyme-mediated immunoassay (EMIA) 1
The same study documented only rare false-positives for cannabinoids (2/510 samples) and barbiturates (2/510 samples) with NSAIDs, but again no benzodiazepine cross-reactivity 1
A comprehensive 2014 review of false-positive interferences in urine drug screens covering literature from 2000-2014 does not identify ibuprofen or other NSAIDs as causes of false-positive benzodiazepine results 2
Important Caveats About Benzodiazepine Testing
Standard Immunoassays May Miss Alprazolam
Standard benzodiazepine immunoassays may not reliably detect alprazolam or clonazepam, meaning a negative screen does not rule out use of these specific agents 3
Immunoassays are designed to detect benzodiazepines with specific structural features, and alprazolam's triazolobenzodiazepine structure may not cross-react adequately with antibodies optimized for other benzodiazepines 3
Designer Benzodiazepines Can Cause Apparent "False-Positives"
Non-FDA-approved designer benzodiazepines (flualprazolam, flubromazolam, etizolam, clonazolam) can trigger positive benzodiazepine screens but may not be detected by standard confirmatory LC-MS-MS panels, leading to misinterpretation as false-positives 4
When a benzodiazepine screen is positive but standard confirmatory testing is negative, consider the possibility of designer benzodiazepines rather than assuming a false-positive from medication interference 4
Recommended Approach to Unexpected Positive Benzodiazepine Results
Obtain Complete Medication History
Ask specifically about all prescribed benzodiazepines, over-the-counter medications, supplements, and herbal products before interpreting any positive result 5, 6
Document whether the patient is prescribed alprazolam or other benzodiazepines, as this would explain a positive result 5
Order Confirmatory Testing
Request gas chromatography-mass spectrometry (GC-MS) or LC-MS-MS confirmatory testing before making any consequential clinical decisions based on immunoassay results 5, 6, 2
Immunoassay screening tests are presumptive only and susceptible to cross-reactions; they require confirmation by an independent chemical technique 5, 2
If confirmatory testing is negative and the patient denies benzodiazepine use, consider requesting expanded testing for designer benzodiazepines if clinically indicated 4
Avoid Premature Clinical Actions
Never dismiss patients from care or make punitive decisions based solely on immunoassay results without confirmatory testing, as this may constitute patient abandonment 5, 7
Discuss unexpected results with the patient in a non-judgmental manner before taking action, keeping in mind the possibility of laboratory error or designer drug use 7, 6
Establish a working relationship with your local toxicology laboratory or toxicologist for consultation on complex or unexpected results 5, 7
Clinical Pitfalls to Avoid
Do not assume ibuprofen or other NSAIDs are causing a positive benzodiazepine screen—the evidence does not support this cross-reactivity 1, 2
Recognize that false-positive results are more common when screening low-risk populations, reducing the positive predictive value of the test 6
Understand that many providers have inadequate training in interpreting urine drug tests, and incorrect interpretation can have severe consequences including legal implications 5, 7
Be aware that standard immunoassays have known limitations in both sensitivity (may miss alprazolam) and specificity (may cross-react with designer benzodiazepines), requiring clinical correlation and confirmatory testing 3, 8