Toxicology

I Ordered the Urine Drug Screen, Now What? An Overview on Testing, Interference, and Utility of UDS in the ED

A 36-year-old woman presents to the ED with chief complaints of altered mental status, cough, fever, and runny nose.

Her vitals are: BP 104/62; pulse 120; respiratory rate 28; SpO2 96% on room air; and temperature 100.5°F. Her friend at bedside notes the patient has been taking acetaminophen cold and flu, pseudoephedrine, diphenhydramine, ibuprofen, and dextromethorphan to treat her current acute symptoms. The patient has a history of asthma and frequent marijuana use. Differential diagnosis includes a polypharmacy overdose such as acetaminophen or diphenhydramine, illicit drug intoxication, viral encephalopathy, and electrolyte abnormality. You decide to order a head CT, CBC, CMP, TSH with reflex T4, EKG, aspirin and acetaminophen levels, Flu/COVID/RSV swab, and a urine drug screen (UDS).

Introduction
The UDS is a frequently ordered test in the emergency department as well as in inpatient services, psychiatry, pain medicine, and outpatient clinics. Nearly 30 million ED visits per year are associated with some form of drug use.1

In non-emergency medicine settings, these drug screens can be used to evaluate pharmacologic diversion, medication compliance, and the possibility of recent or current intoxicants.

In the ED, the UDS allows the emergency physician to ascertain the nature of a patient’s current or recent toxicity, which can assist in the narrowing of a differential diagnosis. For example, the UDS may play a role in determining if a chest pain patient is suffering from an acute occlusive myocardial infarction or amphetamine-induced vasospasm, or if an unresponsive patient may have a substance-related cause for their obtundation.

Despite the ubiquitous nature of these tests — which are widely used as screening and diagnostic tools within medicine as well as in the sports industry and business sectors — many healthcare providers are skeptical to trust the results for a variety of reasons. To best understand the utility (or possible lack thereof) of the UDS, it is important to analyze how the test is actually performed.

The Science Behind the Test
Although hair, fingernails, toenails, and saliva can be used to detect the presence of drugs, hospitals most commonly employ the use of blood or urine assays. These assays take the form of an immunoassay or gas chromatography combined with mass spectrometry (GS-MS).2 The latter is considered the gold standard of detection and has the capability to detect innumerable substances if the column used is calibrated appropriately.

Not all hospitals have access to GS-MS due to the cost and maintenance of the instrument or a lack of qualified personnel.2 Regardless, it is the urine immunoassay that most emergency physicians are familiar with ordering. Immunoassays utilize pre-made antibodies to a particular substance of interest (e.g., cocaine metabolite) and the presence or absence of a color-producing enzyme as a surrogate method of detecting the presence of the substance. This is a qualitative process that generally answers the binary question of “drug or no drug” without providing details such as last time used or quantity.2

Unfortunately, immunoassays can be ripe with error. The antibodies may bind substances with a similar structure to the target of interest despite not actually being the drug in question, or in contrast, they may miss drugs because of chemical modifications or lack of a common metabolic pathway.2 Due to this cross reactivity of compounds with the immunoassay, confirmatory testing is required to ensure that the result is not a false positive.2

Herein lies the big controversy with the UDS: Can we trust it? Do the results matter?

The Literature
Most emergency departments use two separate types of drug screens: a narrow or five-panel screen, and an expanded panel screen. Typically, the five-panel screen evaluates for the presence of amphetamines, benzodiazepines, opiates, cocaine, and cannabinoids.3 The expanded panel includes tricyclics, fentanyl, barbiturates, methadone, and phencyclidine (PCP), in addition to the five-panel substrates.3 These tests are independent of specific urine tests that exist such as a urine fentanyl screen.

It is important to note that the UDS components vary from hospital to hospital.

In Table 1, we detail some common substrates and the intricacies around their testing.

Table 1. Substance detection time and common false positives and negatives.4,7,8,9,10 

Substance

(Tested Metabolite)

Detection start

Detection end

False positives

False negatives

Amphetamines

(-amphetamine)

4-6h

2-3d

Pseudoephedrine (Sudafed), phenylephrine, amantadine, atomoxetine, bupropion, chloroquine, metformin, ranitidine, chlorpromazine, trazodone, promethazine, hemp-containing foods, proton pump inhibitors

MDA, MDMA

Benzodiazepines (oxazepam)

2-7h

Most 3-5d

Diazepam - 10-30d

Coca tea, some forms of yerba mate, sertraline

Clonazepam, lorazepam, alprazolam, midazolam, 

Phencyclidine

4-6h

7-14d

Dextromethorphan, venlafaxine, ibuprofen, thioridazine, diphenhydramine, tramadol, ketamine, lamotrigine, zolpidem

None

Opiates

(morphine)

2-6h

1-3d

 

Levofloxacin, ofloxacin, imipramine, naltrexone, rifampin, dextromethorphan

Oxycodone, hydrocodone, tramadol, methadone, buprenorphine - synthetic opioids

Cocaine

(benzoylecgonine)

2-6h

12h, possibly 2-4d

Coca leaves in tea drinks

None

Cannabinoids

(11-carboxy-delta9-tetrahydrocannabinol)

1-3h

3-30d depending on chronicity of use

Promethazine, NSAIDs, pantoprazole

Synthetic/designer cannabinoids

Tricyclics

8-12h

2-7d

Cyclobenzaprine, quetiapine, carbamazepine, cyproheptadine, hydroxyzine, cetirizine, diphenhydramine

None

Barbiturates

2-4h

Short-acting up to 24h, long-acting up to 3 weeks

Ibuprofen, naproxen

Sodium thiopental

Positive results in the UDS can be affected by many external factors including patient body mass, short-term versus long-term use of the drug, pH of the urine, and last ingestion time.4 There are several common drugs that do not have any false negatives found in the literature. These include PCP, TCAs, cocaine, and LSD. Thus, if a patient admits to ingesting these drugs and tests negative, the level in their urine is likely below the cut-off value. In addition, patients can adulterate their urine through the addition of substances such as Visine drops, which frequently can cause false negatives.4

In a retrospective analysis of more than 8000 urine samples, Johnson-Davis and colleagues showed that there is a significant false positive rate depending on the immunoassay used for urine screening. With amphetamines, there were up to 14% false positives, and with opiates, a 34% false positive rate. With other drugs of abuse, the false positive rate was significantly lower, with 0.4% for benzodiazepines and 0.9% false positive for THC.5

Urine drug screens also fail to mirror emergency physician clinical gestalt. In a small single-center study, Gilfillan and colleagues used urine drug screening results and physician notes to determine if clinician suspicion was correct. In this study, 35 patients were suspected of drug use but only 14 tested positive, showing clinicians to be correct only 40% of the time. Of 58 patients the clinicians did not suspect, 18 — or 31% — tested positive.6 This study did not use any confirmatory testing. It is certainly possible that clinician gestalt was inaccurate, but given the overwhelming data of UDS inaccuracies, it is likely that many of these drug screens had false positives or false negatives.

Discussion
With possible false positives and false negatives, emergency physicians must be cautious in using the UDS to inform and guide care in the ED. The UDS is severely limited given the wide variation in false positive and lack of sensitivity in identifying drugs of a particular class (e.g., benzodiazepines or opioids) as detailed in Table 1.4,7,8,9,10

Of significant clinical importance recently is the ability to detect the presence of opioids. As the opioid epidemic continues, EDs everywhere have been plagued by street adulterants contaminated with fentanyl and analogs, none of which screen positive on a UDS given they are not metabolized through morphine like heroin. Additionally, emergency physicians must consider many other common sources of intoxication and overdose that are not typically included on urine drug screens, such as ketamine, mescaline, gamma-hydroxybutyrate (GHB), and synthetic cannabinoids.2Providing care to a trauma activation or sexual assault victim may require testing outside the UDS in specific circumstances, such as drug-facilitated sexual assault.

Many psychiatric patients are required to have a UDS result for placement to ensure that possible drug withdrawals or concomitant substance-use counseling can be included during their hospitalization. Multiple studies performed within the United States and abroad have found that there is no significant change in patient disposition, clinical outcome, or length of stay in a psychiatric facility based on the results of a urine drug screen.11,12,13 Kagel evaluated the UDS in an otherwise healthy group of 682 patients at a U.S. military hospital; the study found no positive UDS, and patients had no change in disposition or care.11

Another study in a single-center ED in a state psychiatric hospital in Israel found no change in disposition of patients based on the UDS. Drug use as high as 20-30% was predicted, but only 9% positivity was found. The study determined that UDS use for psychiatric patients should be more focused on those suspected of drug-induced psychosis.12

And yet another study by Schiller and colleagues at a large urban psychiatric emergency center divided 392 patients into a usual care group and a mandatory urine drug screen group. Schiller determined that when left to clinician gestalt versus testing of all psychiatric patients with urine drug screening, there was no change in disposition or treatment length between the mandatory screen versus the usual care group.13

Others argue the drug test can significantly improve accuracy of diagnosis and thus inform treatment after disposition. One study by Szuster and colleagues found a one-third increase in substance-induced organic mental disorders when a urine drug screen was used for confirmation of drug use instead of a questionnaire or direct patient inquiry.14Elangovan supported this finding through a high rate (26%) of cocaine use in the tested psychiatric patient population at a single center, but a low rate of admission of use (13%) in the tested population at a psychiatric facility.15

Many overdoses involve multiple medications. If the patient’s clinical presentation does not match the UDS, consider the presence of coingestants and non-tested ingestions, and ensure the patient’s medication list has been thoroughly reviewed for possible confounding agents.

Physicians should also remember that the effects of most of these substances wear off long before they are no longer detected in the urine. Be careful of anchoring bias, especially if a patient is forthcoming about when they ingested the drugs they tested positive for on a UDS.7

The UDS transcends bedside clinical care to the far reaches of healthcare policy. In the age of value-based care, physicians are rewarded for providing the highest quality care at the lowest cost.16 As the Centers for Medicare & Medicaid Services (CMS) continues to expand the notion of value-based care, it is reasonable to think that ordering a test that rarely changes management or disposition may not be reimbursed. Testing that is not reimbursed or not indicated by CMS may lead to a withholding of physician incentive payments.

Summary
For emergency physicians, the urine drug screen offers a practical way to assess possible causes of altered mental status for obtunded patients and may aid our psychiatry colleagues in psychiatric placement. It may also serve a role in confirming potential substances taken in overdose (e.g., tricyclics and benzodiazepines). However, given the risk of false negatives, clinicians should rely on additional laboratory studies and physical examination to guide clinical management. Numerous studies have shown that the UDS does not impact changes in disposition or management. The urine drug screen is not a foolproof diagnostic test. However, it is another tool in the toolbox of the emergency physician. Because of its potential flaws, it should not be used out of context or in isolation.

Case Conclusion
The UDS returns positive for amphetamines, PCP, THC, and TCA. The patient’s friend at bedside is adamant the patient could not have ingested any of these medications and that she had not taken anything other than what was originallylisted. The patient’s symptoms also do not seem to match this array of drug ingestion. You consider that several of these results are likely false positives. You request that the lab performs confirmatory testing. In the meantime, the patient is treated for multi-med ingestion with normal saline and benzodiazepines, and is closely monitored in the ICU. The confirmatory testing returns positive only for THC and negative for amphetamines, PCP, and TCA. Given the patient’s co-ingestions, she likely tested positive for these additional substances due to her aggressive treatment of her cold symptoms, leading to her altered mental status.

Take-Home Points

  • The UDS is an imperfect screening test and has been shown to minimally impart any change in clinical management or disposition, so use with caution.
  • When in doubt, order confirmatory testing. See what is available in-house at your hospital and what requires a sendout assay.
  • Understand which adulterants are tested for in your institution-specific panels.
  • Obtain careful history of recent medication use, both prescribed and over-the-counter.

Tips

  • The addition of glucuronidase to the UDS increases the sensitivity of benzodiazepine detection as it cleaves off the large glucuronide moiety which interferes with analysis of medications not metabolized through an oxazepam intermediate.17
  • Delta 8 THC, the “legal” hemp derivative sweeping the country, leads to a positive test on the UDS for cannabinoids, given the overwhelming structural similarity.18

References

  1. Bhalla A. Bedside point of care toxicology screens in the ED: Utility and pitfalls. Int J Crit Illn Inj Sci. 2014;4(3):257-260. doi:10.4103/2229-5151.141476
  2. Nelson ZJ, Stellpflug SJ, Engebretsen KM. What Can a Urine Drug Screening Immunoassay Really Tell Us? Journal of Pharmacy Practice. 2016;29(5):516-526. doi:10.1177/0897190015579611
  3. Hoffman RJ, Traub SJ, Ganetsky M. Testing for drugs of abuse (DOAs). UpToDate. https://www.uptodate.com/contents/testing-for-drugs-of-abuse-doas#H192794310. Accessed August 1, 2022. 
  4. Moeller KE, Lee KC, Kissack JC. Urine Drug Screening: Practical Guide for Clinicians. Mayo Clinic Proceedings. 2008;83(1):66-76. doi:10.4065/83.1.66 
  5. Johnson-Davis KL, Sadler AJ, Genzen JR. A retrospective analysis of urine drugs of abuse immunoassay true positive rates at a National Reference Laboratory. Journal of Analytical Toxicology. 2015;40(2):97-107. doi:10.1093/jat/bkv133 
  6. Gilfillan S, Claassen CA, Orsulak P, et al. A comparison of psychotic and nonpsychotic substance users in the psychiatric emergency room. Psychiatric Services. 1998;49(6):825-828. doi:10.1176/ps.49.6.825 
  7. Stellpflug SJ, Cole JB, Greller HA. Urine Drug Screens in the Emergency Department: The Best Test May Be No Test at All. J Emerg Nurs. 2020;46(6):923-931. doi:10.1016/j.jen.2020.06.003
  8. Saitman A, Park HD, Fitzgerald RL. False-positive interferences of common urine drug screen immunoassays: A Review. Journal of Analytical Toxicology. 2014;38(7):387-396. doi:10.1093/jat/bku075 
  9. Moeller KE, Kissack JC, Atayee RS, Lee KC. Clinical interpretation of urine drug tests. Mayo Clinic Proceedings. 2017;92(5):774-796. doi:10.1016/j.mayocp.2016.12.007 
  10. Drugs of abuse home use test. U.S. Food and Drug Administration. https://www.fda.gov/medical-devices/drugs-abuse-tests/drugs-abuse-home-use-test. Published September 27, 2018. Accessed July 30, 2022. 
  11. Kagel KE, Smith M, Latyshenko IV, Mitchell C, Kagel A. Effects of mandatory screening labs in directing the disposition of the apparently healthy psychiatric patient in the emergency department. US Army Med Dep J. 2017;(2-17):18-24.
  12. Margolis A, Rosca P, Kurs R, Sznitman SR, Grinshpoon A. Routine Drug Screening for Patients in the Emergency Department of a State Psychiatric Hospital: A Naturalistic Cohort Study. J Dual Diagn. 2016;12(3-4):218-226. doi:10.1080/15504263.2016.1252075
  13. Schiller MJ, Shumway M, Batki SL. Utility of routine drug screening in a psychiatric emergency setting. Psychiatr Serv. 2000;51(4):474-478. doi:10.1176/appi.ps.51.4.474
  14. Elangovan N, Berman S, Meinzer A, Gianelli P, Miller H, Longmore W. Substance abuse among patients presenting at an inner-city psychiatric emergency room. Hospital and Community Psychiatry. 1993;44(8):782-784. doi:10.1176/ps.44.8.782 
  15. Szuster RR, Schanbacher BL, McCann SC. Characteristics of psychiatric emergency room patients with alcohol- or drug-induced disorders. Psychiatric Services. 1990;41(12):1342-1345. doi:10.1176/ps.41.12.1342 
  16. What is value-based healthcare? Innovations in Care Delivery. https://catalyst.nejm.org/doi/full/10.1056/CAT.17.0558. Published 2017. Accessed August 1, 2022.
  17. Johnson-Davis KL. Opiate & Benzodiazepine Confirmations: To Hydrolyze or Not to Hydrolyze is the Question. J Appl Lab Med. 2018;2(4):564-572. doi:10.1373/jalm.2016.022947
  18. Helander A, Johansson M, Andersson A, Villén T. Analytical and medico‐legal problems linked to the presence of delta‐8‐tetrahydrocannabinol (Delta‐8‐THC): Results from urine drug testing in Sweden. Drug Testing and Analysis. 2021;14(2):371-376. doi:10.1002/dta.3190

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