What medications can cause a false positive result for methadone?

Medications That Cause False-Positive Methadone Urine Drug Screens

Diphenhydramine (Benadryl) is the most well-documented medication causing false-positive methadone results on immunoassay urine drug screens, and quetiapine (Seroquel) and vortioxetine (Trintellix/Brintellix) have also been confirmed to cross-react with methadone testing. 1, 2, 3

Primary Offending Medications

Antihistamines

• Diphenhydramine causes false-positive methadone results on rapid immunoassay screens, specifically demonstrated with the One Step Multi-Drug, Multi-Line Screen Test Device and other competitive binding immunoassays 1, 4
• The cross-reactivity occurs with diphenhydramine itself, but notably NOT with its metabolites (nordiphenhydramine or dinordiphenhydramine) 1
• This has been confirmed through in vitro laboratory testing at concentrations of 10-100 μg/mL 1

Antipsychotics

• Quetiapine (Seroquel) produces false-positive methadone results on the COBAS Integra Methadone II test kit using KIMS (kinetic interaction of microparticles in solution) methodology 2, 4
• The structural similarity between quetiapine and methadone—both featuring a tricyclic structure with sulfur and nitrogen atoms in the middle ring—underlies this cross-reactivity 2

Antidepressants

• Vortioxetine (Trintellix/Brintellix) causes false positives specifically in the Roche KIMS Methadone II Urine immunoassay (MDN2) 3
• This is particularly problematic because vortioxetine is commonly prescribed for mood disorders, which have high prevalence in patients treated for opioid addiction 3
• A metabolite of vortioxetine shows high cross-reactivity in the MDN2 assay, meaning routine use of the drug can cause false positives even without detectable parent drug in urine 3
• Parent drug concentrations as low as 7500 ng/mL in spiking studies produced positive results 3

Critical Clinical Approach

Immediate Actions When Encountering Positive Methadone Screen

• Obtain complete medication history including all prescription medications, over-the-counter drugs (especially antihistamines), and supplements before interpreting any positive methadone result 5, 6
• Request confirmatory testing using gas chromatography-mass spectrometry (GC-MS) immediately before making any clinical decisions, as this definitively distinguishes true methadone use from false positives 5, 6, 1
• Never make consequential clinical decisions (admission, social services involvement, loss of privileges) based solely on immunoassay screening results 5, 6

Understanding Test Limitations

• Standard immunoassay drug screens are designed as presumptive tests only and are susceptible to cross-reactions that limit their specificity 5, 6
• Product information for urine drug screens may not include all cross-reacting agents, so clinicians cannot rely solely on manufacturer documentation 1
• Different immunoassay platforms may show different cross-reactivity patterns—a specimen may test positive on one platform but negative on another 3

Common Clinical Pitfalls to Avoid

• Never assume immunoassay results are definitive—these tests have known limitations in specificity and require confirmation when results are unexpected or will impact patient management 5, 6
• Avoid punitive actions such as discharging patients from practice, involving child protective services, or removing treatment privileges based solely on screening results without confirmatory testing 6, 7
• Don't overlook over-the-counter medications—diphenhydramine is widely available without prescription and patients may not consider it worth mentioning 1, 4
• Be aware that pain medications given during labor and delivery can cause false positives, so testing should ideally occur before administering any medications 5

Additional Medications Reported in Literature

While the evidence is strongest for the three medications above, the following have also been associated with false-positive methadone results in case reports:

• Verapamil 4
• Thioridazine 4

When Confirmatory Testing is Essential

• Patient denies methadone use and has no prescription for methadone 1, 2, 3
• Patient is taking any of the known cross-reacting medications listed above 1, 2, 3
• Results will affect child custody, employment, parole, or treatment privileges 5, 6
• Clinical presentation is inconsistent with methadone use 5, 6