Benzodiazepines (BZDs) are psychoactive medications commonly prescribed to treat anxiety, insomnia, seizures, and muscle spasms. Due to their central nervous system depressant effects and potential for misuse, screening for BZDs is often required in clinical, occupational, and legal settings. The initial monitoring method is usually a rapid and affordable urine drug screen (UDS). However, this screening test is not always perfectly accurate, and other substances can sometimes cause a positive result, known as a false positive.
Understanding the Screening Test and Cross-Reactivity
The initial urine drug screen relies on an immunoassay technique, often called an Enzyme Multiplied Immunoassay Technique (EMIT). This test uses antibodies engineered to bind to the primary breakdown products, or metabolites, of benzodiazepines, such as oxazepam or nordiazepam. When a urine sample is introduced, target metabolites bind to these antibodies, triggering a measurable reaction that indicates a “positive” result.
The problem arises from cross-reactivity, which is the inherent limitation of these screening tests. Certain compounds chemically unrelated to benzodiazepines possess a molecular structure similar to BZD metabolites. This structural resemblance allows these non-BZD substances or their metabolites to mistakenly bind to the benzodiazepine antibodies in the immunoassay.
The antibodies cannot perfectly distinguish between the intended target and the look-alike compound, leading to a false signal. Consequently, an initial positive screen does not confirm BZD use; it only indicates the presence of a substance the test antibodies recognized. The likelihood of a false positive depends on the specific immunoassay kit used and the concentration of the cross-reacting substance in the urine.
Non-Benzodiazepine Substances That Trigger a Positive Screen
A variety of commonly available prescription and over-the-counter medications can cause a false positive result for benzodiazepines due to molecular cross-reactivity. These substances come from several different drug classes. It is important to remember that such a result is presumptive and typically only occurs on the initial immunoassay screen.
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)
Certain NSAID medications, used for pain and inflammation, have been reported to trigger false positive BZD results in urine screens. The most frequently cited example is Oxaprozin, often prescribed for arthritis pain. Studies confirm that Oxaprozin and its metabolites can bind to the antibodies used in immunoassay systems, leading to a presumptive positive result. The presence of Oxaprozin metabolites in the urine is the mechanism behind this interference.
Antidepressants
Several psychiatric medications, particularly those used to treat depression and anxiety, have chemical structures that can cross-react with BZD assays. Sertraline (Zoloft), a Selective Serotonin Reuptake Inhibitor (SSRI), has a well-documented history of causing false positives for benzodiazepines. Fluoxetine (Prozac), another widely used SSRI, has also been implicated in reports of false-positive BZD screens.
Antihistamines and Sleep Aids
Over-the-counter medications are a frequent source of false positives, especially those containing sedating antihistamines. Diphenhydramine, the active ingredient in many nighttime sleep aids and allergy medications (e.g., Benadryl), has metabolites that can mimic benzodiazepine compounds in the initial screen. Doxylamine, another antihistamine found in some sleep aids, has also been reported to cause interference in certain immunoassay systems.
Other Medications
Beyond these common classes, various other pharmacological agents have been associated with presumptive positive BZD results in isolated cases or specific test kits. For example, the atypical antipsychotic medication Quetiapine has been reported to cause false positives. Certain quinolone antibiotics, while often linked to false positives for opioids, have metabolites that could potentially interfere with other drug assays.
How to Confirm a True Positive Result
An initial positive result on a urine drug screen should always be considered a “presumptive positive” because of the known possibility of cross-reactivity. Determining whether a true benzodiazepine is present requires a secondary, more specific testing method. This step is necessary to rule out a false positive caused by a non-BZD substance.
The gold standard for confirmation is Gas Chromatography/Mass Spectrometry (GC/MS) or Liquid Chromatography/Mass Spectrometry (LC/MS). Unlike the immunoassay, these methods separate the chemical components of the urine sample and analyze their unique molecular fingerprints. GC/MS and LC/MS precisely identify the exact chemical structure of every compound present, distinguishing between a true BZD metabolite and a cross-reacting substance like Oxaprozin or Sertraline.
If a patient receives a presumptive positive result, they should inform the testing facility or healthcare provider of all prescription and over-the-counter medications they are taking. They should request that a confirmatory test, such as GC/MS or LC/MS, be performed on the sample. This secondary analysis eliminates the possibility of a false positive, providing an accurate and legally defensible result that confirms or rules out the presence of benzodiazepines.