Let’s Talk About Drug Testing

SPECIAL REPORT: SUBSTANCE USE

Case Example 1

“Michael,” a 45-year-old man, presents to the emergency department (ED) with chest pain. At some point, his urine is collected and a drug test is ordered, which returns a positive result for amphetamines. Michael denies using any substances and does not understand why the test was ordered. The team tells him he must have used amphetamines, and so they are contacting the psychiatry department and/or the addiction medicine team for his substance use disorder (SUD). Michael feels angry, confused, and judged by the ED staff.

The Most Misused Test in Medicine?

Drug screenings are one of the most ordered tests in medicine. Unfortunately, they are also one of the most misinterpreted and arguably misordered tests as well.¹ There are multiple reasons for this. During medical school and residency, little education is provided regarding ordering them or their interpretation. Drug screenings are also one of the few tests where it is important to understand how the testing was done. In comparison, this is not a concern when ordering and interpreting a basic metabolic panel (BMP). Additionally, tests such as the BMP do not result in stigma. Maybe some patients with diabetes worry when their doctor orders a hemoglobin A_1C test, but they are not worried about being removed from the clinic because of the result. The stigma and the consequences surrounding drug screenings can result in disruption of the patient-clinician relationship and ultimately lead to negative patient outcomes, which is why the question of when and whether they should be ordered is a subject of much controversy.²

It is not as simple as just ordering a drug test; you need to understand how the testing is done to accurately interpret it. Most urine drug screenings (UDSs) are immunoassays, such as an enzyme multiplied immunoassay technique (EMIT).³ Whether it is an EMIT or not, what is important is understanding the limitations of immunoassays. They are generally cheap and easy to do (think of the drug tests sold at the local pharmacy), but they have significant limitations.^4,5 Immunoassays generally target a specific part of a chemical structure. As such, they can detect members of a family of drugs but not every member of the family (false-negative results); it also means that they may detect similar substances that are not members of that class (false-positive results). Immunoassays are also based on a cutoff, which can be adjusted as needed.³ For instance, raising the cutoff is why poppy seeds should not cause a positive opiate screening result, although if the threshold were lowered, they could.

Circling back to Michael’s case, the typical UDS will not pick up many of the designer amphetamines (eg, many of the synthetic cathinones or bath salts) but can attain a positive result if someone has recently taken pseudoephedrine or bupropion.^6,7 If a clinician is unsure about cross-reactivity or a cutoff,⁸ they can either contact the laboratory director or look at the package insert to properly understand them and correctly interpret the test.

Chromatography and Spectrometry Testing

The definitive or confirmatory test to determine whether the UDS result was a true positive or negative is generally a form of spectrometry and chromatography, such as gas chromatography/mass spectrometry (GC/MS).³ In this form of testing, there is a separation phase (chromatography) and an identification phase (spectrometry).^9,10

Spectrometry matches the chemical structure to a known library of structures to identify the molecule (directed testing), although some laboratories offer undirected testing. Although chromatography and spectrometry are considered the definitive test or gold standard, they also have limitations. They are more complex and expensive to perform than an immunoassay.¹⁰ If your substance is not in the testing library, it will not be identified. They also use a cutoff, just like immunoassay testing. If the concentration is below the cutoff, it will have a negative result, even if the substance is present at a low concentration. This threshold can be increased or decreased, depending on the purpose of the testing.

Case Example 2

“Jenny,” a 32-year-old woman, is in treatment for her opioid use disorder. The initial drug test has a positive result for fentanyl, and Jenny is started on methadone. However, 20 days later, her test result is still positive, and Jenny is inappropriately removed from treatment because the clinician does not understand how to interpret the chromatography/spectrometry results (never mind that she should not be removed from treatment even for a truly positive test result). The clinician assumes the result is still positive due to continued use when there is an alternative explanation: The test detected both fentanyl and its metabolite norfentanyl. The repeat testing no longer detected any fentanyl but had a positive result for a very low concentration of norfentanyl, although still above the threshold. This explains why the test result is still positive, even though Jenny has been adherent to her methadone treatment and is not using other opioids.

When to Test

Most clinicians have also seen long lists of substances that cross-react in a UDS, causing false-positive results; however, these lists generally lack the appropriate nuance to be useful. Many times, they are a long list of anything that has ever been reported.³ Unfortunately, they do not convey the likelihood of this happening nor reflect that this may have occurred with outdated technology or medications no longer used. For example, a patient of mine had a false-positive result for cocaine due to levomilnacipran. Although we could never reproduce this again, either in the patient or a laboratory, my fellow published it as an abstract,¹¹ which may be cited on one of these lists. Additionally, nonsteroidal anti-inflammatory drugs (NSAIDS) are listed as a cause of false-positive cannabinoid results. However, the likelihood of this occurring on modern technology with modern NSAIDS is very unlikely.^8,12

The take-home message may be that confirmatory testing should always be ordered. However, confirmatory testing, such as GC/MS, is expensive and technically complex and takes longer to achieve a result.¹⁰ Although a urine immunoassay can be obtained in clinic in minutes, confirmatory testing generally has to be sent off and can take days to return. It is also more expensive than an immunoassay, potentially leading to unnecessary costs to the patient and system. For instance, if the patient admits to drug use or the result will not affect care, there is no reason to order confirmatory testing. Many health care systems have removed reflex confirmatory testing to save money, especially for results unlikely to change acute care. However, there is a negative consequence to this as well: Patients’ records may contain unconfirmed positive drug screening results. As results in electronic medical records are easily aggregated and viewed by clinicians across health systems, this may affect future care. For instance, we have received consultations from the transplant service about potential transplant recipients who had unconfirmed positive test results, potentially affecting their ability to be listed. Given the limitations of testing, this could easily occur at other health care institutions.¹³

Instead, clinicians should consider whether the testing or cadence of testing is necessary prior to ordering it. Although testing may be useful in a patient’s psychiatric or addiction management, a drug test cannot diagnose a SUD. If ordered, it should be used in a holistic manner, with validated screening tools to properly diagnose the patient with a SUD.¹⁴ As alluded to in case example 1, clinicians may equate a positive drug test result with the patient having a SUD, which is incorrect. Drug testing should also not be used to remove the patient from care, as in case example 2, a concern leading to some of the stigma surrounding these tests. Again, an endocrinologist would not remove a patient from the clinic if their hemoglobin A_1C level increased; they would modify their treatment plan. If ordered, the other consideration is how the test is collected. Observed testing might prevent adulteration, but it is awkward and stigmatizing and may negatively affect the patient-clinician relationship.¹⁵ An alternative, if observed testing is needed, is oral testing. It still has limitations but at least does not include the same stigma as observed urine testing.

Concluding Thoughts

Drug testing is a commonly ordered diagnostic test. Unfortunately, it is often misinterpreted or ordered inappropriately, potentially leading to multiple negative consequences for the patient or negatively affecting the patient-clinician relationship. Prior to ordering testing, clinicians should consider whether the testing is necessary, how it will affect care, and whether they understand the limitations of the testing methodology. Understanding these limitations can be challenging, especially with the evolving world of substance use and testing. As such, knowing the resources that are available to assist with their interpretation is important to consider prior to ordering any tests.

Dr Schwarz is an emergency physician, medical toxicologist, and addiction medicine physician at UCLA in Los Angeles, California. He is also the medical toxicology fellowship director.

References

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5. Melanson SEF, Lee-Lewandrowski E, Griggs DA, Long WH, Flood JG. Reduced interference by phenothiazines in amphetamine drug of abuse immunoassays. Arch Pathol Lab Med. 2006;130(12):1834-1838.

6. Nixon AL, Long WH, Puopolo PR, Flood JG. Bupropion metabolites produce false-positive urine amphetamine results. Clin Chem. 1995;41(6 pt 1):955-956.

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10. Yuan C, Chen D, Wang S. Drug confirmation by mass spectrometry: identification criteria and complicating factors. Clin Chim Acta. 2015;438:119-125.

11. NACCT abstracts 2016. Clin Toxicol (Phila). 2016;54(8):659-811.

12. Rollins DE, Jennison TA, Jones G. Investigation of interference by nonsteroidal anti-inflammatory drugs in urine tests for abused drugs. Clin Chem. 1990;36(4):602-606.

13. Snozek CLH, Corey RL, Buras MR, Johnson-Davis KL. False-positive serum cocaine screening results in patients undergoing evaluation for renal transplant. J Anal Toxicol. 2019;43(7):587-590.

14. Jarvis M, Williams J, Hurford M, et al. Appropriate use of drug testing in clinical addiction medicine. J Addict Med. 2017;11(3):163-173.

15. Strike C, Rufo C. Embarrassing, degrading, or beneficial: patient and staff perspectives on urine drug testing in methadone maintenance treatment. J Subst Use. 2010;15(5):303-312.