This paper was submitted as part of Dr. Gold's application for ACOFP Fellowship. ACOFP Fellowship recognizes exceptional national, state, and local service through teaching, authorship, research, or professional leadership. Visit the ACOFP Fellows page to learn more about fellowship and apply.

Urine drug screen (UDS) testing in the clinical setting is rapidly growing, yet can be a confusing tool in POCT (point of care testing) in outpatient settings. Understanding the limitations of the tests is crucial to their proper use. UDS is used in many platforms, including but not limited to clinical, employment, educational, legal settings, and especially with compliance to medical therapy. POCT with urine is easy to collect, readily available and affordable, and interpretation via colorimetric testing produces rapid results. It does not require much training and can be performed by clinicians and nonclinicians alike. However, results may be misinterpreted, leading to confusion on the meaning of the particular test. Understanding how to interpret POCT UDS, including understanding cutoff values, detection times, and false positive results, is important in the current clinical landscape. Unexpected results should have confirmatory tests performed from a reference lab.

POCT testing came about with lateral flow technology utilizing assay strips, adding cassettes and, later, cups. But this needed pipetting. Single test strips are architecturally similar to a urine dipstick, where each strip is used for the detection of a single analyte test. Multiplexed detection systems perform simultaneous tests from a limited sample volume and reduce diagnosis time. Presently we have specimen collection cups with the test strips incorporated directly into their walls, which eliminates any handling or pipetting of urine specimens. Test results are now available in minutes.

In the clinical setting offices utilize POCT UDS due to the ease of testing, testing consistency, compliance to medical adherence to pharmacologic regimens in the treatment in substance abuse disorders or pain management, detection of illicit drugs, and preemployment physicals. UDS are a useful tool for the medical necessity of monitoring of patients who are receiving opioid therapy, benzodiazepine therapy or stimulant medications. Currently available POCT tests include amphetamines, barbiturates, benzodiazepines, cocaine, codeine, heroin, marijuana, methamphetamines, opiates, oxycodone, phenocyclidine. Recently added tests include methadone, bupropion, fentanyl, cocaine, MDMA (3,4-Methylenedioxy methamphetamine; ecstasy), ethylglucoronide, Kraton, marijuana, and K2 synthetic cannabinoid.

Immunoassay tests are qualitative tests that use antibodies to detect drugs at a molecular level. They are the most common method for the initial screening process. A sample of urine is added to a solution containing antibodies or immunoglobulins which in turn bind to target analytes. By this interaction with specific structures the immunoglobulins signal the presence of certain compounds. Structurally related compounds may result in a positive finding. In fact, immunoassay tests can detect several related chemical compounds and metabolites that share common chemical structural characteristics.

Each colorimetric test has its own specificity and sensitivity with predetermined cut off ranges of ng/ml. Cut off levels have been established by the Department of Health and Human Services to provide testing subjects the benefit of doubt in the event small amounts of drug metabolites are detected in a subject’s system due to circumstances such as medication or passive inhalation (1, 3, 4, 5).

Testing is more than a positive or negative response, as there can be an invalid response as well. Test kits include temperature and pH for validity, and some offer specific gravity for adulterants. Normal temperatures can be 90-100 degrees F, but are typically 96-99 degrees F within 4 minutes of urination; same as body temperature. The normal pH is between 4.5-8; usually near 7 neutral. Specific gravity 1.002-1.020; the measure of the concentration of dissolved particles in the urine. So, SG <1.001 essentially water and >1.02 think of lemonade.

False negatives can occur when urine drug concentrations are below the threshold level of the particular test. Dilute urine, the duration of time between ingestion and of the drug and time tested, and the quantity of drug ingested may affect the occurrence of false negatives. Patients may attempt to hide a potential positive utilizing adulterants.

Adulteration or dilutions should be suspect if pH is less than 3 or greater than 11. Or if SG less than 1.002 or greater than 1.030. Noting time of last use of medication as cutoff values vary from test to test. Methods of tampering include dilution with water, substituting a sample, or extraneous agents added in order to disguise the presence of an illicit product. Items such as ammonia- interferes with PCP; bleach; goldenseal herbal diuretic- decreases sensitivity to THC and amphetamines; potassium nitrate interferes with THC; peroxidase- interferes with THC and opioids; gluteraldehyde; pyridium – oxidizing agent; acetic acid- interferes with THC; Visine eye drops (Benzalkonium chloride) - decrease sensitivity to THC (2, 5).

Other false negatives may occur if the UDS is unable to detect a particular agent as the drug is present below the cut off level and not detected. Basic UDS for benzodiazepines are designed to test for the breakdown metabolites of oxazepam and nordazepam (metabolite of diazepam and chlorodiazepoxide). Thus not all benzodiazepams will be detected as they follow a different metabolic pathway. Specific tests are required for alprazolam, clonazepam, and lorazepam.

Methylphenidate products do not cross-react with amphetamines and will produce negative result. Oxycodone, buprenorphine and tramadol follow separate pathways other than codeine. Also fentanyl has no metabolites (2,4,12).

Many medications may lead to false positive results on POCT due to cross reactivity with the immunoassay, often due to similar structures of the parent medication or one of its metabolites to the tested drug. Metabolism of drugs further into active and inactive metabolites may lead to more than one positive result. In nonregulated expanded drug panels, it is always important to check the immunoassay cross reactivity table. Likewise, oxycodone may also not be positive on opiate assays. Depending on what is being tested, each has its own assay.

Some potential agents that may cause false positive include:

Amphetamines: amantadine, bupropion, chlorpromazine, MDMA, Vicks inhaler l-methamphetamine, methylphenidate, phenylephrine, promethazine, chlorpromazine, pseudoephedrine, ranitidine, selegline, thioridazine, trazodone, bupropion, quinolones, labetalol, metformin

THC: dronabinol, hemp containing products, pantoprazole, tolmetin, ibuprofen, naproxen, Cannabidiol (CBD) may contain up to 0.3% (THC) Delta-9-tetrahydrocannabinol

Opioids: dextromethorphan, poppyseeds, quinine, quinolones, rifampin, verapamil, diphenhydramine, doxylamine [quetiapine can cause false positives for methadone, tricyclics and ketamine]

Phencyclidine: dextromethorphan, diphenhydramine, doxylamine, ibuprofen, imipramine, ketamine, meperidine, mesoridazine, thioridazine, tramadol, venlafaxine, tramadol

BZD: sertraline, tolmetin, naproxen, etodolac, fenofibrate, oxaprozin

LSD: sertraline, risperidone, haloperidol

Methadone: quetiapine (1,3,5,9,11,12)

Unintentional exposures and ingestion: The l-isomer of methamphetamine is marketed over the counter as a nasal decongestant. It is also a metabolite of selegiline, a MAOI used in Parkinson's treatment. L-isomer affects the body peripherally and d-isomer affects the body centrally. So use caution if someone uses Vicks vapor inhaler for decongestion.

Good ole poppy seeds. How many are needed to produce a false positive result? Poppy contains no opiates, but the poppy seeds become contaminated by opiates contained in the milky extract of the seed that covers them. Usually not an issue, as the cut off is set high, but a military screening test is considered absolute and can lead to dire consequences. Studies have show that casual ingestion will not cause a positive test result, as the cut off levels are below threshold (3,5).

Other potentials for false positives include H2 blockers and heroin. Though ranitidine has the potential for false positive for amphetamines, not all H2 blockers do. Furthermore, pantoprazole may cause false positives for THC; other PPIs do not. So choosing a therapeutic medication appropriately may minimize a false positive. Heroin breaks down into morphine and hydromorphone such is the cause of cross false positives. Codeine breaks down into hydrocodone and hydromorphone and so one needs to be considerate of these positive findings (2, 4, 12).

The length of time a product is maintained in the urinary system or its window of detection further plays a role in detection.

  • Amphetamine: 3 days;
  • Barbiturates 1-3 days short acting and 3 weeks long acting;
  • Benzodiazepines 3 days short acting and 4 weeks long acting; THC 3 days short acting and 30 days long acting, 6-12 weeks heavy use;
  • Cocaine 3-5 days;
  • Codeine 1-2 days;
  • Fentanyl 2-3 days;
  • Heroin 3 days;
  • Dilaudid 1-2 days;
  • Methadone 3-4 days;
  • Oxycodone 1-3 days;
  • Oxymorphone 1-4 days;
  • PCP 1-10 days;
  • Tramadol 2-4 days;
  • Zolpidem 1-5 days.

This is dependent on last time used and quantity used. ( 1, 2, 3, 5)

In conclusion, it is important to understand the principles of laboratory methods and interpretation of urine drug screening. The simplicity of use and access to rapid results have increased demand for and use of immunoassays. However, these assays are not perfect. UDS POCT is a fast reliable test with 98% sensitivity. Specificity is dependent on cut off ranges but is over 90%.

Results of immunoassays are always considered presumptive. A positive or negative result does not necessarily include or exclude drugs of abuse or compliance with medical therapy. Be it for legal, forensic, medical, or preemployment situations consider to screen and confirm if needed through a reference lab. Follow up assay at a reference lab is required for confirmation of tests if so inclined. These may include tests from serum, sweat, saliva, and hair.

Bibliography

  1. Algren, D. Adam and Christian, R. Michael. "Buyer beware: Pitfalls in Toxicology Laboratory testing" Missouri Medicine 2015 May-June 112 (3) 206-210
  2. Kale, Neelma. "Urine Drug Tests: Ordering and Interpretation" American Family Physician 2019;99 (1) 33-39
  3. Moeller, Karen et al. "Clinical Interpretation of Urine Drug Tests What Clinicians Need to Know about Urine Drug Screens" Mayo Clinical Proceedings 2017 May 92 (5) 774-796
  4. Rongwei, Lei et al. "Clinical and Emerging trends in point of care urinalysis test" Expert Review Molecular Diagnostics 2020 Jan 20(1) 69-84
  5. Shults , Theodore. Medical Review Officer Handbook: Comprehensive resource for the Substance Abuse Testing Process 10th edition 2014
  6. Baden, LR et al. Quinolones and false positive urine screening for opiates by immunoassay technology" JAMA 2001
  7. Reisfield "Can eating poppy seeds affect drug tests results? An addiction and pain medicine specialist explains" University of Florida Health Feb 28 2023
  8. Bertholf, RL , Sharma, R. Reinsfeld GM. " Predictive values of positive drug screening results in an urban outpatient population" Journal Anals of Toxicology 2016;40(9) 726-731
  9. Ferguson, McKenzie C. " How common are false positive amphetamines urine screens?" Practical Pain Management 2015;15(1)
  10. Woelfel, J.A. "Drug abuse urine tests: false positive results" Prescribers Letter 2005;21 2103
  11. Moeller, Karen et al "Urine drug screening; a practical guise for clinicians" Mayo Clinical Proceeding Jan 2008 83(1): 66-76
  12. Schwebach, Alyson and Ball, Jennifer "Urine Drug Screening: Minimizing False Positive and False Negatives to Optimize Patient Care" US Pharmacist 2016;41(8); 26-30
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