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OBJECTIVES
- 1.State the differences of the most common urine drug screening testing modalities: immunoassay and gas chromatography/mass spectrometry.
- 2.Describe common causes of false-positive and false-negative urine drug testing results and the detection window of specific medications.
- 3.Identify common caveats when interpreting urine drug testing result.
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OVERVIEW OF URINE DRUG SCREENING
Urine drug screening (UDS) is a laboratory test frequently used to screen for drugs of abuse, monitor for medication compliance, evaluate for suspected drug intoxication or overdose, and in office-based pain contracts (
Kale, 2019
; Standridge, Adams and Zotos, 2010
). In children and adolescents, UDS may be used to prevent substance use, evaluate for suspected drug use or intoxication, or as part of substance abuse treatment (Levy et al., 2014
). When using UDS as a tool to make clinical decisions about high-risk medications, it is important to understand the differences between UDS testing modalities, common causes of false-positive or false-negative results, and the detection window of specific medications. There are two commonly used types of UDS available: immunoassay and gas chromatography/mass spectrometry (GC-MS; Kale, 2019
).Immunoassays are the most frequently used initial UDS modality because they are simple to use, easy to automate, and provide rapid results. Immunoassays are a qualitative test that identifies the presence of substances above a set threshold through antibody complex that binds with a drug, metabolite, or class of compounds (
Jarvis et al., 2017
). Immunoassays allow for point of care testing and are typically used as the initial UDS because of their low cost, rapid results, and convenience. Because of poor specificity and the risk of false-positive results, positive immunoassay results should be considered presumptive and followed by GC-MS for confirmation (Kale, 2019
; Standridge, Adams and Zotos, 2010
). GC-MS is a laboratory-based test that separates medications on the basis of polarity to detect substances (Standridge, Adams and Zotos, 2010
). Although GC-MS is more costly and time-consuming, it provides higher sensitivity and specificity (Jarvis et al., 2019; Kale, 2019
; Schwebach and Ball, 2013
).UDS requires cutoff values to be met to be considered positive. Results lower than the established cutoff are reported as negative, but it does not necessarily mean that the substance was not present. Therefore, a negative result indicates the concentration was lower than the established cutoff. When evaluating a UDS, it is also important to consider time because of the ingestion and window of detection. After a substance is used, it takes approximately 2 hr to become detectable in the urine (
Jarvis et al., 2017
). This factor is crucial for patients who present acutely ill after recent suspected ingestion. Although it would still be indicated to obtain a UDS, the test results must be interpreted cautiously.The window of detection is the amount of time a substance can be detected in the urine and still produce a positive result. To evaluate the detection window, clinicians should consider both drug and patient characteristics. Drug characteristics that affect the detection window include half-life, metabolites, drug interactions, dosing interval, low versus high dose, chronic versus occasional use, and time of last ingestion. Patient-specific factors include body mass, pH of the urine, urine concentration, and renal or liver impairment (
Moeller, Lee and Kissack, 2008
). Table 1 lists the window of detection in the urine for drugs routinely screened for in UDS. The Department of Health and Human Services has standardized cutoff values for use in the workplace; however, institutions may use lower values in practice. Clinicians should confirm cutoff values with their institution's laboratory before the interpretation of results.TABLE 1Window of detection in the urine
| Substance | Time |
|---|---|
| Amphetamines | 2–3 days |
| Benzodiazepines | |
| Short-acting | 3–5 days |
| Long-acting | 30 days |
| Cocaine | 2–4 days |
| Marijuana | |
| Single-use | 2 days |
| Moderate use (3 times/week) | 2 weeks |
| Daily use/Long-term heavy use | 4–6 weeks |
| Opioids | |
| Buprenorphine | 11 days |
| Codeine | 1–2 days |
| Fentanyl | 2–3 days |
| Heroin | 1–2 days |
| Hydromorphone | 1–2 days |
| Methadone | 3–4 days |
| Morphine | 3 days |
| Oxycodone | 1–3 days |
| Tramadol | 2–4 days |
Note.
Levy et al., 2014
).WHEN TO SCREEN FOR DRUGS OF ABUSE IN CHILDREN AND ADOLESCENTS
The American Society of Addiction Medicine (ASAM) and American Academy of Pediatrics (AAP) does not recommend routine UDS by clinicians in the absence of suspicion for substance use (
Jarvis et al., 2017
; Levy et al., 2014
). Neither group supports home UDS by parents because of the risk of misinterpretation and limited evidence that home UDS reduces adolescent drug use (Jarvis et al., 2017
; Levy et al., 2014
). The ASAM and AAP recommend screening children and adolescents for emergent clinical care, assessment of behavioral or mental health symptoms, in substance abuse programs, or as a deterrent for use in the juvenile probation system (Levy et al., 2014
). UDS is useful for clinicians to identify potential toxins in patients who present with altered mental status. The AAP recommends obtaining a UDS if there is a concern for accidental or intentional ingestion, unexplained seizures, syncope, arrhythmias, or the presence of toxidromes (Levy et al., 2014
). The ASAM identifies those with a known history of substance use or trauma, in treatment for mental health disorders, or declining academic performance as a high-risk population that may benefit from early detection of substance use (Levy et al., 2014
). High-risk patients suspected of having recent or ongoing drug use (by parent or clinician) should be screened by clinicians, particularly if the patient also presents with fatigue, moodiness, or school failure (Levy et al., 2014
). Screening may not be necessary if a patient is honest about substance use history, though it may provide added value. If a child or adolescent denies substance use but shows concerning signs/symptoms of substance use, screening should still be performed.CAVEATS WHEN INTERPRETING TEST RESULTS
Accurate interpretation of UDS is crucial as misinterpretation may lead to adverse consequences, such as criminal charges, loss of a job, loss of trust from health care professionals, or discontinuation of chronic pain contracts. In children and adolescents, misinterpretation may result in mistrust or tension from parents. To decrease the likelihood of inaccurate interpretation, health care professionals performing these tests should be familiar with common causes of false-positive results (Table 2) or negative results and signs of adulteration. Before performing UDS, providers should obtain a list of all prescription, over-the-counter, and herbal medications to fully assess UDS results (
Schwebach and Ball, 2013
).TABLE 2Medications commonly causing false-positive results on immunoassay
| Medications | Amphetamine/Methamphetamine | Benzodiazepines | Cannabinoid | Methadone | Opioids |
|---|---|---|---|---|---|
| Over-the-counter products | |||||
| Brompheniramine | X | ||||
| Dextromethorphan | X | ||||
| Diphenhydramine | X | ||||
| Doxylamine | X | X | |||
| Ibuprofen | X | ||||
| Naproxen | X | ||||
| Pantoprazole | X | ||||
| Pseudoephedrine | X | ||||
| Ranitidine | X | ||||
| Vicks nasal inhaler | X | ||||
| Antidepressants/antipsychotics | |||||
| Bupropion | X | ||||
| Chlorpromazine | X | X | |||
| Desipramine | X | ||||
| Doxepin | X | ||||
| Fluoxetine | X | ||||
| Quetiapine | X | ||||
| Sertraline | X | ||||
| Trazodone | X | ||||
| Other agents | |||||
| Efavirenz | X | X | |||
| Ephedrine | X | ||||
| Fluoroquinolones | X | ||||
| Labetalol | X | ||||
| Metformin | X | ||||
| Methylphenidate | X | ||||
| Promethazine | X | ||||
| Quinolones | X | ||||
| Selegiline | X | ||||
| Verapamil | X |
Note.
Brahm et al., 2010
; Levy et al., 2014
); Moeller, Lee and Kissack, 2008
); Moeller, Kissack, Atayee and Lee, 2017
).Adulterating, substituting, and diluting urine is commonly done to avoid detection of drug use (
Moeller, Lee and Kissack, 2008
). It is critical that clinicians evaluate all urine samples’ color, appearance, pH, and specific gravity to screen for signs of adulteration. Patients may intentionally adulterate their urine by adding vinegar, soap, bleach, drain cleaner, eye drops, salt, ammonia, or products containing peroxide (Schwebach and Ball, 2013
). Changes in urine pH, specific gravity, or appearance should prompt further investigation for adulteration (Schwebach and Ball, 2013
). Patients may also drink excessive amounts of water (2–4 quarts) in an attempt to dilute urine drug concentrations and decrease the likelihood of detection (Schwebach and Ball, 2013
). Normal urine specimens should range from pale yellow to clear and should be collected early in the morning to provide the most concentrated urine, with temperature ranges from 32°C to 38°C (Moeller, Lee and Kissack, 2008
). The temperature of urine samples should promptly be measured and recorded after collection to screen for urine substitution. Urine pH normally ranges from 4.5 to 8 throughout the day. Specimen adulteration should be suspected if the urine pH is < 3 or > 11, or if the specific gravity is < 1.002 or > 1.020 (Moeller, Lee and Kissack, 2008
).Medications with similar chemical structures may lead to a cross-reactivity on immunoassays, resulting in a false-positive result (
Schwebach and Ball, 2013
). The occurrence of false-positive results is influenced by the sensitivity and specificity of the immunoassay being used. Minimizing the use of medications that commonly cause false-positive test results may be useful in patients who require frequent UDS but should be carefully weighed against the efficacy, cost, and adverse effect profile of the alternative treatment (Schwebach and Ball, 2013
). In addition, patients may adulterate their urine with prescribed medications by “pill dipping” or “pill shaving.” A patient who diverts medications may save a small amount to “dip” or “shave” into the urine, leading to a false-positive presumptive test. This issue can be problematic when the parent compound is tested for in the urine, making clinicians unable to differentiate adulteration versus compliance. When the parent compound is not excreted in the urine, adulteration should be suspected.False-negative results may occur when urine drug concentrations are below the cutoff. This result can be because of the quantity of drug ingested, the time between ingestion and UDS performed, or urine adulteration. Another risk for false-negative results is poor cross-reactivity of medications within the immunoassay. Metabolites of parent drugs are commonly used for the detection of benzodiazepines and opioids. Patients may be prescribed medications of the same class that do not follow the specific metabolic pathway tested by the immunoassay, causing higher rates of false-negative results (
Schwebach and Ball, 2013
).REVIEW OF MAJOR MEDICATION CLASSES
Amphetamines
Amphetamine immunoassays detect amphetamines, amphetamine isomers, methamphetamine, and other amine-containing compounds (
Moeller, Kissack, Atayee and Lee, 2017
). Immunoassays for amphetamines will return positive after amphetamine, dexamphetamine, and lisdexamfetamine use. Methylphenidate does not cross-react with amphetamines on immunoassay, so testing should be completed with GC-MS (Breindahl and Hindersson, 2012
). Unfortunately, immunoassays for amphetamines commonly result in false positives because of a high rate of cross-reacting medications. Medications commonly linked to false-positive results include bupropion, phenothiazines, tricyclic antidepressants, trazodone, pseudoephedrine, ephedrine, ranitidine, and ofloxacin (Nomier and Al-Huseini, 2004
), and labetalol (Moeller, Kissack, Atayee and Lee, 2017
). In addition, dimethylamylamine, a widely used energy supplement, causes false-positive amphetamine screens (Vorce, Holler, Cawrse and Magluilo, 2011
). Structural similarities are the most common reason for false positives (Moeller, Lee and Kissack, 2008
). Vicks nasal inhaler contains an isomer of methamphetamine (l-methamphetamine) that does not cause euphoric effects, leading to potential cross-reactivity on immunoassay (Moeller, Lee and Kissack, 2008
). Selegiline metabolism also produces l-amphetamine and l-methamphetamine, contributing to false-positive UDS results (Moeller, Kissack, Atayee and Lee, 2017
).Benzodiazepines
Given the widespread use of benzodiazepines for anxiety and sedation, a thorough history should be obtained before testing. UDS for benzodiazepines frequently results in false-negative results given the inability of the immunoassay to detect conjugated benzodiazepine metabolites and high cutoff values (
Moeller, Kissack, Atayee and Lee, 2017
). Immunoassays for benzodiazepines detect the free metabolites oxazepam and nordiazepam, which are metabolites of chlordiazepoxide, temazepam, diazepam, and clorazepate (Moeller, Kissack, Atayee and Lee, 2017
). Benzodiazepines that follow alternative metabolic pathways, such as lorazepam, clonazepam, and alprazolam, have poor cross-reactivity rendering them unable to be detected on UDS (Schwebach and Ball, 2013
). False-positive results have been reported in patients taking efavirenz and sertraline; therefore, confirmatory GC-MS should be performed in patients with unexplained immunoassay results who report taking these two medications. (Blank et al., 2009
; Nasky, Cowan and Knittel, 2009
).Cannabinoids
Cannabis, also known as marijuana, refers to any part of the cannabis plant (
Moeller, Kissack, Atayee and Lee, 2017
). Cannabinoids are a subset of chemicals found within the cannabis plant, with delta-9- tetrahydrocannabinol (THC) being primarily responsible for marijuana's psychoactive properties (Moeller, Lee and Kissack, 2008
). Estimating THC's window of detection after marijuana use is complex, as it is influenced by the route of administration, potency of marijuana, frequency of use, body mass, and one's metabolic rate (Moeller, Kissack, Atayee and Lee, 2017
). Chronic users can test positive for over 30 days after cessation, whereas a single-use may only be detectable in the urine up to 3 days (Moeller, Kissack, Atayee and Lee, 2017
). Cannabinoids are available in clinical practice as dronabinol and nabilone for the treatment of chemotherapy-induced vomiting and anorexia in patients with AIDS. Dronabinol is a synthetic THC, which will result in a true-positive result on UDS. Nabilone is a synthetic cannabinoid that is similar to THC. Nabilone follows a different metabolic pathway resulting in negative UDS (Moeller, Kissack, Atayee and Lee, 2017
). Nonsteroidal anti-inflammatory drugs, pantoprazole, and efavirenz have been reported to cross-react with THC on immunoassay (Moeller, Lee and Kissack, 2008
). Confirmatory GC-MS should be performed in patients with unexplained immunoassay results who report using nonsteroidal anti-inflammatory drugs, pantoprazole, or efavirenz.Cocaine
UDS for cocaine detects the main metabolite of cocaine, benzoylecgonine (
Moeller, Lee and Kissack, 2008
). Cross-reactivity rarely exists with cocaine and its metabolites, making the risk of false-positive results relatively nonexistent (Moeller, Kissack, Atayee and Lee, 2017
). Cocaine is available for use in clinical practice as a topical anesthetic in otolaryngology and ophthalmic procedures, which can produce a true-positive UDS result (Moeller, Kissack, Atayee and Lee, 2017
).Opioids
When performing UDS for any reason, it is important to understand that UDS may not detect all opioids. To accurately interpret UDS for opioids, it is critical to understand opioid metabolism. Most immunoassays screen for morphine, codeine, and norcodeine; therefore, morphine, heroin, and codeine use can easily be detected (
Schwebach and Ball, 2013
). Morphine is metabolized to 3-morphine-glucuronide and 6-morphine-glucuronide (Moeller, Kissack, Atayee and Lee, 2017
). Codeine is metabolized in the body to morphine, norcodeine, hydrocodone, and hydromorphone. Codeine, morphine, and norcodeine can be detected in the urine after codeine ingestion; however, hydromorphone and hydrocodone typically are not (Schwebach and Ball, 2013
).Heroin is a semisynthetic derivative of morphine. Heroin is rapidly metabolized to 6-monoacetylmorphine (6-MAM), which is then metabolized to morphine (
Moeller, Lee and Kissack, 2008
). 6-MAM is a specific metabolite to heroin only, making a positive result definitive for heroin use. However, 6-MAM only has approximately an 8-hr detection window in the urine after heroin use, after which only the morphine metabolite will be detected (Moeller, Kissack, Atayee and Lee, 2017
). Oxycodone is a semisynthetic opioid excreted as oxycodone, oxycodone conjugates, oxymorphone, and noroxycodone, none of which are typically tested for on UDS. Fentanyl lacks metabolites and is usually not detected on UDS (Moeller, Lee and Kissack, 2008
). Methadone, a long-acting opioid, is excreted unchanged in the urine and as the metabolite 2-ethylidene-1,5- dimethyl-3,3-diphenylpyrrolidine. UDS uses the parent compound to detect methadone use, making interpretation problematic if a patient adulterates their urine by pill dipping. Confirmatory testing for ethylidene-1,5- dimethyl-3,3-diphenylpyrrolidine presence by GC-MS is necessary if adulteration is suspected. Buprenorphine and methadone are used to treat patients with substance abuse disorders. A few clinically significant false-positive results have been reported with these two medications. The buprenorphine assay is subject to cross-reactivity from the synthetic opioid tramadol (Shaikh et al., 2008
). Quetiapine use has been reported to cause a false-positive methadone screening test (Cherwinski, Petti and Jekelis, 2007
).MAINTAINING PATIENT CONFIDENTIALITY IN CHILDREN AND ADOLESCENTS
The ASAM and the AAP recommend that adolescents are involved in their care and that clinicians obtain informed consent before performing UDS (
Jarvis et al., 2017
). If a patient presents acutely ill and in imminent danger, UDS should be performed before obtaining consent. The clinician and adolescent should have an open discussion regarding privacy and clarify permission to share results with a parent or guardian (Jarvis et al., 2017
). If the patient does not want UDS results shared, the clinician must respect the adolescents’ wishes but should also encourage them to share the results with their parent/guardian. Although there are scenarios in which clinicians can maintain patient confidentiality, this is not always the case. If a clinician suspects the substance use puts the patient in imminent danger, there are legal and ethical implications, and the clinician may need to disclose information to a parent or guardian (Jarvis et al., 2017
). If substance use is suspected and the adolescent refuses the screening, the refusal should be documented, and the adolescent should be referred to an addiction or mental health specialist (Levy et al., 2014
).POSITIVE RESULTS
If an immunoassay is the initial UDS modality and the positive result is unexpected, confirmatory GC-MS should be performed. The clinician should also attempt to have an honest discussion with the patient regarding the test results, in hopes that the patient may provide additional information, such as substances that were not detected on the panel (
Levy et al., 2014
). If a true-positive result is confirmed and matches the adolescent's reporting, the clinician should begin developing a treatment plan. A treatment plan may include abstinence, ongoing testing, and/or referral to a treatment center (Levy et al., 2014
). In most states, adolescents can consent to substance abuse treatment without a parent or guardian (Levy et al., 2014
). If the patient denies substance use despite the positive result and no alternative explanation exists, results should still be discussed with the adolescent. Repeat drug testing may be valuable if suspicion remains high for substance abuse.CONCLUSION
When using UDS as a tool to make clinical decisions about high-risk medications, it is important to understand the differences between UDS testing modalities (immunoassay vs. GC-MS), common causes of false-positive or false-negative results, and the detection window of specific medications. Remember that drug interferences may vary on the basis of the immunoassay used and that new drug interferences are discovered annually. If ever in doubt, if there is a possible drug interference with an immunoassay, call the laboratory that performed the test and ask about known drug interferences. Send a confirmatory GC-MS test before making any decisions about the patient if there is no known interference with any of the patient's medications.
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Biography
Logan Johnson Doriety, Post Graduate Year - 2 Pharmacist Resident, Department of Pharmacy, New Hanover Regional Medical Center, Wilmington, NC.
Elizabeth Anne Farrington, Clinical Pharmacist, Pediatrics, Department of Pharmacy, New Hanover Regional Medical Center, Wilmington, NC.
Article info
Footnotes
Conflicts of interest: None to report.
Identification
Copyright
Copyright © 2020 by the National Association of Pediatric Nurse Practitioners. Published by Elsevier Inc. All rights reserved.
