TOXCard: Urine Drug Screens

Author: Kathleen Yip, MD (Harbor-UCLA Medical Center) // Edited by: David Tanen, MD (Harbor-UCLA Medical Center), Cynthia Santos, MD (Rutgers New Jersey Medical School), Alex Koyfman, MD (@EMHighAK, UTSW / Parkland Memorial Hospital), and Brit Long, MD (@long_brit)

Case: A 56-year-old female with a history of bipolar disorder and polysubstance abuse presents with worsening altered mental status of unknown timeframe. Paramedics found her at her residence with drug paraphernalia nearby, and you have treated her for amphetamine use multiple times in the last year. Family members tell you that she has been using dextromethorphan and pseudoephedrine recently for viral-like symptoms. Vitals are heart rate 122, respiratory rate 18, blood pressure 154/92, oxygen saturation 95%, and temperature 38.2C. Exam reveals a middle-aged woman who appears her stated age, diaphoretic, and somewhat agitated; she attempts to grab objects in the air while appearing confused. Her first test, a urine drug screen, comes back positive for amphetamines, opiates/opioids, and phencyclidine. Remaining studies are pending.

Questions:

• Why do urine drug screens (UDS)?
• What are the methods for UDS testing?
• Which drugs are tested? What are the limitations?

Background:

• Commonly used in the workplace, military, sports, and criminal or legal contexts.
• Also ordered in health care settings for confirmation of known or suspected use.
  • May be useful in altered pediatric patients with no other known etiology.
  • May be useful in trauma patients for substance abuse counseling.
  • ACEP clinical policy states that urine drug screening should not be performed in alert, awake and cooperative adult patients presenting with acute psychiatric symptoms, as it does not affect ED management. (1)
• Most urine drug screens include the five drugs required by federal workplace guidelines: amphetamines, cocaine, marijuana, opiates, and phencyclidine (PCP). (2)
  • Other drugs such as benzodiazepines and tricyclic antidepressants (TCAs) may also be included.
• Tests need to be carefully interpreted since many can be falsely positive (or negative), and results have adverse implications for personal reputations, job offers, participation in sports, convictions, and most importantly, appropriate medical treatment. (2)

Methods of drug testing

• While blood, hair, saliva, and other specimens can be obtained for drug testing, urine is most commonly obtained for drug screening, as it is inexpensive and quick with a relatively high concentration of tested drugs and their metabolites. (2,3)
• Immunoassay
  • Most common method for drug testing.
  • Uses antibodies to detect the presence of a drug or its metabolites.
  • Results should be considered “presumptive” until confirmed.
• Gas chromatography-mass spectrometry (GC-MS)
  • Considered the gold standard for confirmatory testing, with a sensitivity and specificity of 99%. (2,3)
  • Time consuming, costly, and not readily available in most hospitals.

Limitations of urine drug screens

• Properties of Drugs
  •  Structural analogs
    • Many drugs share similar chemical structures with one another, which may cause false positives. For example, TCAs and certain antihistamine agents have 3-ringed structures, which result in cross-reactivity.
• Pharmacokinetics
  • Generally, most drugs become undetectable in the urine after about 72 hours (Table 1).
    • Exceptions include long-term or daily use of marijuana, long-acting benzodiazepines, and PCP.
  • Drugs that have high lipid solubility may lead to slow elimination of the drug from the body, causing a positive result when the last true use was in the distant past.
  • Urine drug screens may detect the metabolites, rather than the parent compound.
    • Opiate drug screens detect for the presence of morphine, which can be metabolized from heroin and codeine.
    • Fentanyl and its metabolites are structurally different from morphine, thus causing a negative urine drug screen.
• Patient characteristics
  • Adulteration
    • Dilution by drinking excessive water.
    • Common household items, such as bleach and over the counter eye drops, can be added directly to evade detection.
    • A variety of chemicals are also available for purchase online.
    • Substitution with a clean urine sample.
    • Advice can be found on drug-forum websites. 
  • Drugs themselves are also dependent on an individual’s genetics, metabolism, frequency, dosage, etc.

• Drug cutoff levels 
  • Within the workplace only, levels that define a positive result are set by the Department of Health and Human Services (DHHS). 
    • For some substances, cutoff levels are raised to avoid false positives. For example, poppy seeds can cause a false positive opiate screen if the level is set low enough.
  • Cutoff levels for a positive result may vary from clinical setting to the workplace; as a result, false negative results are often possible. (4,5)
• Specimen Validity
  • Appearance
  • Temperature (90-100F)
  • pH testing (pH 3-11)
  • Specific gravity (> 1.003)
  • Creatinine (> 20 ppm)
• Urine concentration
  • Urine is most concentrated in the morning and is best suited for urine drug screens.
  • Infants and toddlers produce less concentrated urine compared to adults, which can potentially lead to more frequent false negative screens.

Tested Drugs in Immune Assays 

• Amphetamines
  • This is one of the most difficult to interpret tests; many medications (e.g. OTC cold preps, herbals) are structurally similar to amphetamines, which causes a false positive due to cross reactivity.(2)
• Benzodiazepines
  • High false negative rate (25-30%), especially with lorazepam, clonazepam, flunitrazepam, alprazolam
  • While not many medications cause false positives for benzodiazepines, a positive urine drug screen does not establish a single, recent use of the drug.
  • Benzodiazepines that have long half-lives (e.g diazepam) can be detected in the urine up to 30 days after use. (2)
• Cannabinoids
  • Tetrahydrocannabinol (THC) is highly lipophilic, leading to extensive storage in the lipid compartments of the body. Consequently, there is also slow elimination in urine.
  • Urine drug screens may be positive for cannabinoids up to a week after a single use (or significantly longer if chronic use).
  • Passive inhalation of marijuana is not likely to cause a positive screen. (6)
  • Synthetic cannabinoids (e.g. K2, spice) will not result in a positive screen. (7)
• Cocaine
  • False positives are uncommon with cocaine due to high accuracy and low cross reactivity. (2)
• Opiates and opioids
  • Recall that an opiate is naturally-derived (e.g. heroin, morphine, codeine) while an opioid is partially- or fully-synthetic (e.g. hydrocodone, oxycodone, fentanyl).
  • The term “opioid” is commonly used to refer to drugs derived from opium; in other words, all opiates are opioids but the reverse is not true. (8)
  • Urine drug screens will usually detect heroin, morphine, and codeine.
  • Synthetic opioids such as fentanyl and oxycodone are often not detected. (9)
• Phencyclidine (PCP)
  • PCP abuse declined in the 1980s and 1990s, but has been on the upswing in the last two decades. (10)
  • False positives (e.g. dextromethorphan, ketamine, diphenhydramine, bupropion, venlafaxine) are also likely due to structural similarities causing cross reactivity.
• Tricyclic antidepressants
  • As mentioned earlier, TCAs have a 3-ringed structure that is also found in many other compounds (e.g. cyclobenzaprine, carbamazepine, diphenhydramine, hydroxyzine, quetiapine) which can cause false positives. (2)

Table 1 References: 2, 11, 12

Take home points

• Use careful judgment before ordering a urine drug screen.
• Urine drug screens test for the presence of specific compounds; if it is not present (such as in synthetic opioids), this will cause a false negative result.
• Many drugs may trigger a false positive test due to cross reactivity with the assay.
• Though results are affected by many factors, a drug’s duration of detectability is roughly 2-3 days.
• Urine drug screens can be helpful if interpreted correctly in appropriate clinical settings.
• Be wary of making clinical decisions based solely on positive drug screens.

Case conclusion:

Recalling that her over the counter medications can trigger a false positive urine drug screen, you continue searching for a cause. Though her mild hyperthermia, tachycardia, and altered mental status may be explained by illicit drug use, you also consider sepsis and begin providing her with fluids and antibiotics. Notably, her white blood cell count comes back at 28,300 cells per cubic millimeter of blood, and a chest x-ray shows a right lobar pneumonia. You administer antibiotics and admit her to the medicine service with cultures pending, pleased that you did not fall into the trap of premature closure.

References/Further Reading:

1. Nazarian DJ, Broder JS, Thiessen MEW, Wilson MP, Zun LS, Brown MD. Clinical Policy: Critical Issues in the Diagnosis and Management of the Adult Psychiatric Patient in the Emergency Department. Ann Emerg Med 2017;69:480-98.
2. Moeller KE, Lee KC, Kissack JC. Urine drug screening: practical guide for clinicians. Mayo Clin Proc 2008;83:66-76.
3. Moeller KE, Kissack JC, Atayee RS, Lee KC. Clinical Interpretation of Urine Drug Tests: What Clinicians Need to Know About Urine Drug Screens. Mayo Clin Proc 2017;92:774-96.
4. Mandatory Guidelines for Federal Workplace Drug Testing Programs. 2017. (Accessed at https://www.samhsa.gov/sites/default/files/workplace/frn_vol_82_7920_.pdf.)
5. Luzzi VI, Saunders AN, Koenig JW, et al. Analytic performance of immunoassays for drugs of abuse below established cutoff values. Clin Chem 2004;50:717-22.
6. Perez-Reyes M, Di Guiseppi S, Mason AP, Davis KH. Passive inhalation of marihuana smoke and urinary excretion of cannabinoids. Clin Pharmacol Ther 1983;34:36-41.
7. Spaderna M, Addy PH, D’Souza DC. Spicing things up: synthetic cannabinoids. Psychopharmacology (Berl) 2013;228:525-40.
8. Ogura T, Egan TD. Opioid Agonists and Antagonists. In: Hemmings HC, Egan TD. eds. Pharmacology and Physiology for Anesthesia: Foundations and Clinical Application, 1e. Philadelphia, PA: Saunders Elsevier; 2013
9. Reisfield GM, Bertholf RL. “Practical guide” to urine drug screening clarified. Mayo Clin Proc 2008;83:848-9; author reply 9.
10. Bush DM. Emergency Department Visits Involving Phencyclidine (PCP). 2013:1-8.
11. Rengarajan A, Mullins ME. How often do false-positive phencyclidine urine screens occur with use of common medications? Clin Toxicol (Phila) 2013;51:493-6.
12. Standridge JB, Adams SM, Zotos AP. Urine drug screening: a valuable office procedure. Am Fam Physician 2010;81:635-40.