How can labs differentiate between prescribed medications that may cause false positive results on a drug screen?

How Labs Differentiate Prescribed Medications from False Positive Drug Screens

Labs distinguish prescribed medications from false positives by using confirmatory testing with gas chromatography-mass spectrometry (GC-MS), which can definitively identify specific drug molecules and differentiate them from structurally similar compounds that cause cross-reactivity on initial immunoassay screens. 1

Understanding the Two-Tier Testing System

Initial Screening (Immunoassay)

• Immunoassay screening tests are presumptive only and have inherent limitations in specificity due to cross-reactivity with structurally similar compounds 1, 2
• These qualitative tests use antibodies that can cross-react with certain drug classes, making them highly sensitive but prone to false positives 1
• Standard enzyme-linked immunoassays cannot distinguish between prescribed medications and illicit substances 2

Confirmatory Testing (The Definitive Answer)

• Gas chromatography-mass spectrometry (GC-MS) or liquid chromatography-tandem mass spectrometry (LC-MS/MS) can positively identify specific substances and generate quantitative concentrations 1
• These confirmatory methods are selective enough to differentiate specific opioids and metabolites from one another 1
• GC-MS will distinguish prescribed medications like sertraline from benzodiazepines, even when immunoassay screens are positive 3
• LC-MS/MS has detection limits typically less than 1 ng/mL and can detect all classes of medications or their metabolites 1

Common Medications Causing False Positives

Amphetamine/Methamphetamine Screens

• Bupropion is the most frequent cause of false positive amphetamine screens, accounting for 41% of unconfirmed positive results in one study 4
• Pseudoephedrine (in over-the-counter cold medications) causes false positive amphetamine results 2, 5
• Trazodone (via its metabolite m-CPP) causes false positive amphetamine/methamphetamine results 6
• Metoprolol can cause false positives for both amphetamine and MDMA at therapeutic concentrations 7

Opiate Screens

• Fluoroquinolone antibiotics cross-react with opiate immunoassay screens 5
• Poppy seed ingestion causes false positives for morphine and codeine on both screening and confirmatory tests 2
• Standard immunoassays may not detect semisynthetic opioids like oxycodone, and hydromorphone (a metabolite of hydrocodone) can be confused with actual hydromorphone use 1

Other Drug Classes

• Sertraline causes false-positive benzodiazepine screens due to lack of specificity; GC-MS will distinguish sertraline from actual benzodiazepines 3
• Ziprasidone and risperidone may cause false positive fentanyl results 8
• Carbamazepine causes false-positive tricyclic antidepressant results 9
• Dextromethorphan (cough suppressant) can cause false positives 2

Critical Clinical Approach

Before Testing

• Obtain complete medication history including all prescription medications, over-the-counter drugs, and supplements before interpreting any positive drug test 2, 5
• Document this medication list on the laboratory request form 1

When Results Are Positive

• Discuss unexpected results with the local laboratory or toxicologist before making clinical decisions 1, 5
• Request confirmatory GC-MS testing when results are unexpected or will impact patient management 2, 5
• Never make consequential clinical decisions (such as discharging patients from care, child custody implications, or legal actions) based solely on immunoassay results without confirmation 5, 6

Interpreting Confirmatory Results

• If GC-MS is negative after a positive immunoassay, the initial screening was a false positive 5
• If GC-MS confirms the presence of a prescribed medication (like amphetamine salts for ADHD), this represents appropriate medication use, though testing cannot distinguish between appropriate use and misuse 5
• Metabolite patterns can provide additional information—for example, hydromorphone is a metabolite of hydrocodone, and oxymorphone is a metabolite of oxycodone 1

Important Pitfalls to Avoid

• Never assume immunoassay results are definitive—they are screening tests only with known limitations 1, 2
• Do not dismiss patients from care based on urine drug test results, as this constitutes patient abandonment 1
• Recognize that timing of medication use relative to testing affects detection windows 1
• Be aware that standard panels often don't include commonly abused substances like fentanyl, buprenorphine, MDMA, or ketamine 2
• Pain medications given during delivery can cause false positives, so testing should occur before administering such medications when possible 2