ToxCard: UDS – Its Utilization Demands Scrutiny

Authors: Andrew Yde, MD and Ann-Jeannette Geib, MD (Department of Emergency Medicine, Carolinas Medical Center, Charlotte, NC) // Reviewed by: Cynthia Santos, MD (@CynthiaSantosMD); Alex Koyfman, MD (@EMHighAK); and Brit Long, MD (@long_brit)

Picture this: a 23-year-old female patient walks into your emergency department with the complaint of depression, crippling anxiety, and suicidal ideation with a plan. In an effort to expedite the admission process, you order a UDS for psychiatric clearance. The UDS  ultimately results positive for benzodiazepines, and you note that she is not prescribed this medication. When you ask her, she tells you that she has never taken a benzodiazepine before. The only medication she is prescribed is sertraline. Later in her emergency department course, she begins to hyperventilate and cry uncontrollably. She tells you she’s experiencing a panic attack. Your gut tells you to not give her a benzodiazepine to calm her down, because of her positive urine drug screen. You feel that she may be malingering, and you wait to see if she can be verbally deescalated. Should you trust the patient when she argues the result of the urine drug screen? Did your urine drug test help or hinder you from providing this patient with adequate care?

Introduction

• Many studies have argued against the benefit of urine drug screens (UDS) in the emergency department, and in the setting of emergent psychiatric evaluation. These studies cite high costs associated with the UDS, increased length of stay (LOS), and lack of alteration in patient management. Additionally, the interpretation of the typical UDS, an immunoassay of typical drugs of abuse, is fraught with a high potential for false positives and false negatives¹.
• The immunoassay is a bioanalytical method that uses the reaction of an antigen (analyte) with an antibody, and is used in the typical point of care UDS to determine the presence or absence of a drug in the urine. Each immunoassay tests for a specific analyte, and has a set cutoff above which a concentration of said analyte will yield a positive result. Because of either limited or cross-reactivity, immunoassays are subject to a large number of false positives and false negatives².
• A number of substances can cross-react with structurally related and unrelated compounds in the system to produce a positive result.
• False negatives occur due to a variety of reasons, including antibody interference, a high concentration cutoff for a positive result, and duration between drug dosing and the time the sample is obtained for analysis.
• Confirmatory laboratory testing, generally gas chromatography-mass spectroscopy (GC-MS) or liquid chromatography-mass spectroscopy (LC-MS), can be performed following questionable UDS results, but is expensive, and typically will not result in the time frame required for ED decision making. These tests are usually performed in reference laboratories².
• Still, certain hospital protocols require completion of a UDS in the workup of the psychiatric patient. Therefore, healthcare providers should be aware of the common false negatives and false positives in order to formulate a more clinically accurate opinion on UDS results, and apply these results to one’s clinical decision making. Knowledge of false positives and negatives on the UDS can also save patients from inappropriate elimination from employment, and prevent physicians from developing biases against patients.
• One review of 62 articles investigated five major classes of common drugs of abuse: amphetamines, tricyclic antidepressants (TCAs), benzodiazepines, cannabinoids, and opioids (both natural and synthetic). The review included articles published on 60 different common over-the-counter and prescription drugs, and their metabolites to investigate the culprits of false positive results. Structural similarities and dissimilarities between potential drugs of interference and drugs tested for on the UDS were also compared. The strongest degree of evidence was obtained by adding the drugs in question to drug free urine (DFU) at several different concentrations, and then performing the immunoassay on those samples. Other studies have employed similar methods to determine common false positive interferences, reasons for false negatives, and how the timing of drug intake and UDS acquisition can produce misleading results³.

Amphetamines/ Methamphetamine

• Used therapeutically to treat ADHD, ADD. Also a common drug of abuse, causing a sympathomimetic toxidrome. Amphetamine salts will cause positive UDS for up to three days following last use.

Substances associated with positive amphetamine screen:

• Bupropion: A retrospective chart review of 10,011 UDSs obtained in the emergency department from 2006 to 2007, bupropion prescription use was identified as the likely cause of false positive results for amphetamines on UDSs in 53 (41%) of 128 confirmed false positive tests⁴.
• DMAA: widely used in energy supplements
• Cold medications containing pseudoephedrine, phenylephrine, phenylpropanolamine (PPA)
• Labetalol
• Chlorpromazine
• Promethazine
• Ofloxacin
• MDMA, via cross-reactivity of metabolite meta-chlorophenylpiperazine (m-CPP)³

Benzodiazepines

• Benzodiazepines act on the GABA-A receptor and are used to treat anxiety, agitation, sedation, alcohol withdrawal symptoms, seizures, muscle spasm
• In the setting of toxicity or overdose, patients present with CNS depression, respiratory depression, and delirium.

Substances associated with a positive benzodiazepine screen:

• Sertraline: One study analyzed patients whose UDSs were falsely benzodiazepine positive based on subsequent negative confirmatory testing. Around 26.5% of these patients were found to have sertraline in their prescription records⁵.
• Efavirenz: The NNRTI used to treat HIV creates a metabolite known as 8-hydroxyefavirenz that can cross-react to produce a false positive for benzodiazepines on the standard UDS.

The benzodiazepine screen is also subject to false negatives. The standard UDS detects only one metabolite reliably: Oxazepam.[Figure 1] Only Chlordiazepoxide (Librium), Diazepam (Valium), and Temazepam (Restoril) are metabolized via the CYP-450 system to Oxazepam (Diazepam is metabolized first to Nordiazepam, then to Oxazepam), which is detected in the urine on the standard UDS⁷.

False Negatives Include these commonly used benzodiazepines, as they are metabolized via pathways that do not terminate in oxazepam:

• Clonazepam (Klonopin^TM)
• Lorazepam (Ativan^TM)
• Flunitrazepam (Rohypnol^TM)⁶

Opioids

Opioids are generally utilized for analgesia for moderate to severe pain, often in the acute pain, end-of-life, and post-surgical settings, but have become infamous for an ever-evolving overdose epidemic in the United States. Typical UDSs test for the natural opioids morphine and codeine (the opiates), both of which are derived from the opium poppy (​Papaver somniferum​), and are detectable within 3 to 5 days from last use. Heroin is a semisynthetic opioid, twice as potent as morphine, derived from and ultimately metabolized to morphine after intravenous injection, therefore producing positive results on standard UDSs^8,9.

False Negatives Include:

• Semisynthetic opioids such as oxycodone, hydrocodone, hydromorphone, and oxymorphone are similar enough in structure to morphine to produce positive results on a standard UDS, though they very often result in false negatives.
• Synthetic opioids such as fentanyl, methadone, and tramadol are typically missed on the standard UDS, and require the completion of a synthetic-opioid-specific immunoassay and/ or confirmatory testing to be identified in a sample. These opioids are currently driving the opioid epidemic that has cost more than 31,000 people their lives in 2018¹⁰.
• Though methadone is a synthetic opioid, some UDSs will include immunoassays specific for methadone in order to detect its presence in the urine⁸.

Substances associated with a positive opiate screen

• Household products such as poppy seeds (one poppy seed muffin or two poppy seed bagels, as identified in one study, can cause a positive for opiates on a standard hospital UDS⁸.
• Codeine, a compound standard in many cough medicines
• Diphenhydramine (Benadryl)
• Fluoroquinolone antibiotics, such as levofloxacin
• Quetiapine (atypical antipsychotic)
• Verapamil (calcium channel blocker)⁸

Cocaine

• Cocaine inhibits the reuptake of central dopamine, norepinephrine, and serotonin, resulting in a transient increase in all three neurotransmitters, inducing a feeling of euphoria and alertness. Cocaine is metabolized primarily by cholinesterases in the liver and plasma to norcocaine, ecgonine, methyl ester, and benzoylecgonine (BE). BE, an inactive metabolite, is present in the greatest concentrations, and is the substance detected by the standard UDS¹².
• It takes approximately 4 hours for BE to reach concentrations in the urine sufficient for detection by immunoassay. Therefore, a urine sample obtained less than four hours from last use can yield a false negative on the UDS for cocaine. BE is detectable on a UDS anywhere from 3 to 5 days after last use, but can be detected for up to 8 days.
• Alcohol further complicates the timing issues with cocaine detection using the standard UDS. If consumed proximate to the ingestion of alcohol, cocaine combines with ethanol in the liver to produce cocaethylene (CE). CE confers a higher risk for cardiovascular toxicity than cocaine alone. The LD50 of CE is much lower than cocaine alone, and it carries an 18 to 25 times greater risk for immediate death. CE, unlike BE, is an active metabolite, and is associated with seizures and liver damage. Its plasma half-life is 3 to 5 times greater than that of cocaine and BE. The simultaneous presence of alcohol and cocaine in the body increases the concentration of cocaine by roughly 20%.¹³

Cannabinoids

• Immunoassays detect 11-nor-delta-9-tetrahydrocannabinol-9-carboxylic acid, which is the main urinary metabolite of of THC, the biologically active compound in marijuana. Cannabinoids can produce positive results on UDS for up to 3 days after a single use. In chronic users, it is detectable in the range of 4 to 6 weeks¹.
• Substances associated with positive THC screen on standard UDS
• Efavirenz
• Ibuprofen and Naproxen have been reported in some instances
• Promethazine

***Note: Synthetic cannabinoids such as “K2” and “spice,” are not detectable on standard UDSs¹.

Conclusions

False negatives can mislead the physician, steering him or her away from the appropriate treatment pathway. False positive interferences and a low threshold for positive results on the standard UDS have tarnished many a physician-patient relationship, breeding mistrust and false impressions of patients by physicians. Look back at our female patient who presented to the emergency department and developed a panic attack. She was judged as being untruthful, because of a urine drug test that resulted positive for benzodiazepines, when, in all likelihood, her sertraline had triggered a false positive. Because of this, she was allowed to suffer through her episode of panic without the appropriate medical intervention.

Still, many mental health institutes and psychiatric inpatient services require UDSs, and UDSs continue to be useful in some settings, such as in the investigation of child abuse or neglect. With respect to interpretation of UDS results in the emergency department, the cocaine immunoassay is fairly sensitive and specific, with fewer reports of false positives and false negatives, but factors such as timing of sample acquisition can obscure interpretation. The remaining immunoassays present on the traditional UDS are made highly problematic in most scenarios by false positives and false negatives, and one should practice cautious interpretation of both positive and negative results, utilizing thorough history taking and exhaustive review of medication lists when feasible.

Ultimately, the diagnosis of most intoxications relies on a careful history that aligns with physical exam findings consistent with a toxidrome. The treatment of the poisoned patient is time-sensitive and should not wait for the acquisition of urine or the test results.

References/Further Reading:

1. Riccoboni, S. T., & Darracq, M. A. (2018, April). Does the U Stand for Useless? The Urine Drug Screen and Emergency Department Psychiatric Patients. Retrieved July 29, 2020, from https://pubmed.ncbi.nlm.nih.gov/29500048/
2. Darwish, I. A. (2006, September). Immunoassay Methods and their Applications in Pharmaceutical Analysis: Basic Methodology and Recent Advances. Retrieved July 29, 2020, from ​https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3614608/
3. Saitman, A., Park, H., & Fitzgerald, R. (2014, July 01). False-Positive Interferences of Common Urine Drug Screen Immunoassays: A Review. Retrieved July 29, 2020, from https://academic.oup.com/jat/article/38/7/387/2798054
4. Casey, E., Scott, M., Tang, S., & Mullins, M. (2011, June). Frequency of false positive amphetamine screens due to bupropion using the Syva EMIT II immunoassay. Retrieved July 29, 2020, from ​https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3724447/
5. Nasky, K., Cowan, G., & Knittel, D. (2009, July). False-Positive Urine Screening for Benzodiazepines: An Association with Sertraline?: A Two-year Retrospective Chart Analysis. Retrieved July 29, 2020, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2728940/citedby/
6. Craven, C., MS, Fileger, M., MS, FTS-ABFT, & Woster, P., PharmD. (2014, January/February). Demystifying Benzodiazepine Urine Drug Screen Results. Retrieved July 29, 2020, from https://www.practicalpainmanagement.com/treatments/addiction-medicine/drug-monitori ng-screening/demystifying-benzodiazepine-urine-drug
7. Hayes, B. D., PharmD, DABAT, FAACT, FASHP. (2019, January 10). All Benzodiazepines are Metabolized by the Liver. Retrieved July 29, 2020, from https://www.aliem.com/all-benzodiazepines-are-metabolized-by-the-liver/
8. Keary, C., MD, Wang, Y., MD, Moran, J., MD, MBA, Zayas, L., MD, & Stern, T., MD. (2012, July 26). Toxicologic testing for opiates: Understanding false-positive and false-negative test results. Retrieved July 29, 2020, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3505132/
9. College of Physicians and Surgeons of British Columbia. (2017, May). Retrieved July 29, 2020, from ​https://www.cpsbc.ca/for-physicians/college-connector/2017-V05-03/07
10. Synthetic Opioid Overdose Data. (2020, March 19). Retrieved July 29, 2020, from https://www.cdc.gov/drugoverdose/data/fentanyl.html
11. Algren, D., MD, & Christian, M., MD. (2015, May/June). Buyer Beware: Pitfalls in Toxicology Laboratory Testing. Retrieved July 29, 2020, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6170116/
12. Andrews, P. (1997). Cocaethylene toxicity. Retrieved July 29, 2020, from https://pubmed.ncbi.nlm.nih.gov/9243342/
13. Dasgupta, A. (2017, January 06). Combined alcohol and drug abuse: A potentially deadly mix. Retrieved July 29, 2020, from https://www.sciencedirect.com/science/article/pii/B978012805455000004X
14. Cotten, S., Duncan, D., Burch, E., Seashore, C., & Hammett-Stabler, C. (2012, March 22). Unexpected interference of baby wash products with a cannabinoid (THC) immunoassay. Retrieved July 29, 2020, from https://www.sciencedirect.com/science/article/pii/S0009912012001518