Benzodiazepines (BZDs) are psychoactive medications prescribed for anxiety, insomnia, seizures, and muscle spasms. They function by enhancing the effect of the neurotransmitter gamma-aminobutyric acid (GABA), resulting in a calming or sedative effect. Due to their potential for misuse, BZDs are frequently included in standard drug screenings for employment, pain management, and legal purposes. A complication arises when a patient taking a legitimate, non-benzodiazepine medication receives a positive result on the initial screen. This article explains why these non-BZD drugs can trigger a positive test and how to distinguish a true positive from a false one.
Understanding Benzodiazepine Drug Screens
The initial step in drug testing typically involves a rapid and cost-effective technique called an immunoassay. This screening method uses antibodies designed to bind to a specific drug or its metabolic byproducts, indicating its presence in the sample.
The imprecision stems from a phenomenon known as cross-reactivity, where the antibodies mistakenly recognize a compound other than the targeted benzodiazepine. If a non-benzodiazepine drug possesses a chemical structure similar enough to a BZD or its metabolites, the antibody will bind to it, leading to a presumptive positive result. This lack of specificity means that the initial positive finding is never considered definitive proof of BZD use.
A positive result merely establishes that a substance resembling a benzodiazepine is present above the test’s cutoff threshold. The concentration of the substance and the specific formulation of the immunoassay can greatly influence whether a non-target drug causes a false reading. Therefore, a presumptive positive result only warrants further, more precise analysis to determine the exact identity of the compound.
Medications That Cross-React with Benzodiazepine Tests
A variety of commonly prescribed and over-the-counter medications interfere with benzodiazepine immunoassays due to structural or metabolic similarities.
Psychiatric Medications
The antidepressant sertraline (Zoloft) is a frequent culprit for false-positive results. Package inserts for this selective serotonin reuptake inhibitor (SSRI) explicitly acknowledge its potential to cause an inaccurate screening result for BZDs. Similarly, the HIV medication efavirenz has been shown to cause false positives for benzodiazepines in a significant number of patients taking the drug.
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)
Nonsteroidal anti-inflammatory drugs (NSAIDs) also represent a class of medications known to exhibit cross-reactivity. The prescription NSAID oxaprozin, used for conditions like arthritis, is particularly well-known for triggering a false positive for BZDs. Studies have demonstrated that urine specimens containing common therapeutic concentrations of oxaprozin can consistently yield presumptive positive results across several different commercial immunoassay brands.
Over-the-Counter Products and Sleep Aids
A number of common over-the-counter products also contain ingredients that can lead to an unexpected positive test result. Antihistamines, such as diphenhydramine (Benadryl) and doxylamine, sometimes cross-react with the BZD antibodies. Furthermore, some non-benzodiazepine sleep aids, often called Z-drugs like zolpidem, may occasionally cause an interference. While these medications are chemically distinct from BZDs, their presence can still mimic the signal detected by the initial screening test.
The Necessity of Confirmatory Testing
When an initial immunoassay yields a presumptive positive for benzodiazepines, the only way to obtain a definitive and medically accurate result is through confirmatory testing. This secondary analysis employs highly specific laboratory techniques that are fundamentally different from the broad antibody-based screen. The most common methods used for confirmation are Gas Chromatography/Mass Spectrometry (GC/MS) or Liquid Chromatography/Mass Spectrometry (LC/MS).
These advanced technologies first separate the chemical components within the urine sample. The compounds are then directed into a mass spectrometer, which acts as a molecular fingerprinting device. The mass spectrometer identifies the exact chemical structure of the substance by measuring its molecular mass and fragmentation pattern. This process allows for precise differentiation between a true benzodiazepine and a cross-reacting medication like oxaprozin or sertraline.
The definitive result provided by GC/MS or LC/MS is highly accurate and is required before any medical or legal action can be taken based on the drug test. If a patient is taking a prescribed medication known to cause a false positive, they should immediately inform the medical review officer or testing facility and provide documentation of their prescription. Confirmatory testing will then prove whether the positive screen was caused by the prescribed cross-reacting drug or a genuine benzodiazepine.