What drugs are likely to interfere with urine drug screens?
Introduction
Abuse and misuse of prescription and illicit drugs is a growing concern, with 11.7% of the U.S. population over 12 years of age reporting illicit drug use in 2018, an increase from 7.9% in 2004.1,2 Drug testing is frequently used in clinical setings to identify substance-use disorders, confirm medication adherence, or identify overdoses. Drug tests are also performed in the workplace to identify illicit substance abuse. Drug testing can be performed using various biologic specimens, including urine, saliva, hair, sweat, nails, meconium, and blood. Urine is most commonly used due to its ease of collection. Additionally, drugs can be detected in the urine for a longer duration compared to blood or serum, and the concentration is typically higher. Both parent and metabolite compounds can be detected in the urine.
When collecting a urine sample, several factors should be recorded to ensure accurate collection and avoid false-negative results, including temperature, pH, specific gravity, and creatinine.2 These factors should be considered when evaluating results to rule out adulterated samples. The temperature of urine should be between 90 to 100 degrees Fahrenheit measured within 4 minutes of collection; the pH should be consistent with the range of 4.5 to 8; the specific gravity should be between 1.002 and 1.030; and the creatinine should be greater than 20 mg/dL. Certain medications, foods, and disease states may cause valid outliers; however, a pH <3 or >11 or a specific gravity <1.002 or >1.030 increases the suspicion for adulteration.
Methods for urine drug testing
There are 2 main methods for urine drug testing, screening and confirmatory.2 Immunoassay testing is primarily used for initial screening. Immunoassay testing can be performed in a laboratory or in an office using point of care testing. Results are relatively rapid, and the test can screen for a wide variety of drug metabolites. The 3 most common types of immunoassay testing include enzyme-multipled immunoassay technique, enzyme-linked immunosorbent assay (ELISA), and fluorescence polarization immunoassay. Immunoassay technology uses antibodies to detect drug metabolites. However, antibodies may detect drug metabolites with similar structure and characteristcis, leading to false-positive results. For this reason, immunoassay testing should be considered preliminary and presumptive.
Confirmatory testing should be considered following a presumptive positive screening test.2 The decision to perform a confirmatory test should take into consideration the patient’s history, clinical judgement, and the potential impact on patient care. Confirmatory tests are more timely and costly and are performed by highly trained laboratory personnel. Gas chromatography/mass spectrometry (GC-MS) is the gold standard for confirmatory testing. This test is more specific than immunoassay testing, as it detects drugs by molecular structure. Additionally, GC-MS quantifies the amount of drug present in a sample. Liquid chromatography/tandem mass spectrometry (LC-MS/MS) is an alternative to GC-MS and may be more time efficient.
Quantification of urine drug levels
Drug concentration level thresholds are used in reporting of positive and negative reports for urine drug testing.2 If a test detects a concentration above the threshold, it is reported as positive, and vice versa for negative results. Cutoff values were developed to mitigate false-positive results, especially in the workplace. The use of cutoff values may be particularly useful in ruling out false-positives due to passive inhalation of substances. The U.S. Department of Health and Human Services (DHHS) standardized these cutoff values for drug testing in the workplace (Table 1).3,4 A negative test result using these values does not represent the absence of drug use, and false-negatives can occur.2 Lower thresholds may be used in clinical settings, as the cutoff values defined by the DHHS are higher and intended for the workplace. For example, testing for medication adherence would necessitate lower thresholds. The DHHS cutoff values were developed for adults, and lower thresholds should be used for infants. Infants tend to have more dilute urine, which reaches adult osmolarity around the age of 2 years. In 1998, the DHHS increased the cutoff for opiates from 300 ng/mL to 2000 ng/mL to avoid false positive tests from poppy seed ingestion, as well as routine prescription drug use. Synthetic and semisynthetic opioids historically have not been included as part of federal workplace drug testing; however, in 2017 the U.S. DHHS released cutoffs for hydrocodone/hydromorphone and oxycodone/oxymorphone for additional testing.5
| Table 1. U.S. DHHS drug testing cuttoff values for adults in the workplace.4,5 | |||
|---|---|---|---|
| Initial test (immunoassay) | Confirmatory test (GC-MS) |
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| Analyte | Cutoff concentration | Analyte | Test cutoff |
| Marijuana metabolites | 50 ng/mL | THCA | 15 ng/mL |
| Cocaine metabolites | 150 ng/mL | Benzoylecgonine | 100 ng/mL |
| Codeine/Morphinea | 2000 ng/mL | Codeine | 2000 ng/mL |
| Morphine | 2000 ng/mL | ||
| Hydrocodone/hydromorphone | 300 ng/mL | Hydrocodone | 100 ng/mL |
| Hydromorphone | 100 ng/mL | ||
| Oxycodone/oxymorphone | 100 ng/mL | Oxycodone | 100 ng/mL |
| Oxymorphone | 100 ng/mL | ||
| 6-Acetylmorphine | 10 ng/mL | 6-Acetylmorphine | 10 ng/mL |
| PCP | 25 ng/mL | PCP | 25 ng/mL |
| Amphetamine/ Methamphetamineb | 500 ng/mL | Amphetamine | 250 ng/mL |
| Methamphetaminec | 250 ng/mL | ||
| MDMA | 500 ng/mL | MDMA | 250 ng/mL |
| MDA | 250 ng/mL |
||
| MDEA | 250 mg/mL |
||
| aMorphine is the target analyte for codeine/morphine testing. bMethamphetamine is the target analyte for amphetamine/methamphetamine testing. cSpecimen must also contain amphetamine at a concentration greater than or equal to 100 ng/mL. Abbreviations: DHHS=Department of Health and Human Services; GC-MS=gas chromatography-mass spectrometrey; MDA=methylenedioxyamphetamine; MDEA=methylenedioxyethylamphetamine; MDMA=methylenedioxymethamphetamine; PCP=phencyclidine; THCA=delta-9-tetrahydrocannabinol-9-carboxylic acid. |
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Drug detection times
Each drug varies in the amount of time it can be detected in the urine (Table 2).2 The detection time is primarily based on half-life and the presence of drug metabolites. Additional factors such as drug interactions, dose and frequency intervals, chronic versus occasional use, and time of last ingestion can all affect the detection window. Patient variability in body mass, urine pH and concentration, and renal and hepatic function can also affect the detection window.
| Table 2. Length of time drugs can be detected in the urine.2 | ||||
|---|---|---|---|---|
| Drug/drug class | Detection time | Drug/drug class (continued) | Detection time |
|
| Alcohol | 7 to 12 hours | Marijuana Single use Moderate use (4x/week) Daily use Long-term heavy smoker | 3 days 5 to 7 days 10 to 15 days >30 days |
|
| Amphetamine | 48 hours | |||
| Methamphetamine | 48 hours | |||
| Barbiturates Short-acting Long-acting | 24 hours 3 weeks |
|||
| Benzodiazepines Short-acting Long-acting | 3 days 30 days | Opiates Codeine Heroin (morphine) Hydromorphone Methadone Morphine Oxycodone | 48 hours 48 hours 2 to 4 days 3 days 48 to 72 hours 2 to 4 days |
|
| Cannabinoids, synthetic Single use Chronic use | 72 hours >72 hours |
|||
| Cocaine metabolites | 2 to 4 days | PCP (Phencyclidine) | 8 days |
|
False-positive results
Due to the potential for cross-reactivity associated with immunoassay urine drug screens, several prescription and non-prescription drugs have been reported to cause false-positive results.2,6 In addition to medications, several other substances have been associated with false-positives, such as baby wash products, supplements, and food. False-positive drug screens are commonly documented in case reports. Various immunoassay drug tests are available on the market, and each test uses a proprietary antibody technology, leading to differences in false-positive results between tests.7 Furthermore, immunoassays may be reformulated to correct for false-positive, which may not be adequately reflected in published literature. For example, an immunoassay for cannabinoids that resulted in a false-positive from ibuprofen was corrected over 20 years ago. Ibuprofen is still frequently reported in resources as a possible cause for false-positive cannabinoid immunoassays. Table 3 lists substances that may cause false-positive results on immunoassay urine drug screens; however, this list may not include all potential substances.2, 8-10 Positive immunoassay urine drug screens should be considered presumptive, and confirmed with GC-MS to rule out false-positives.
Barbiturate tests are generally reliable, and false-positives and -negatives are rare.5 Similarly, immunoassays for cocaine are sensitive and specific. In general passive inhalation of crack cocaine does not cause a false-positive; however, it has been reported in cases of chronic exposure.
| Table 3. Substances that may cause false-positives on immunoassay urine drug screens.2, 8-10 | |
|---|---|
| Drug/drug class | Interfering medication |
| Amphetamine | Amantadine, aripiprazole, atomoxetine, brompheniramine, bupropion, chlorpromazine, desipramine, DMAA, ephedrine, fluoxetine, labetalol, metformin, ofloxacin, phentermine, phenylephrine, phenylpropanolamine, promethazine, pseudoephedrine, ranitidine, selegiline, thioridazine, trazodone, nonprescription nasal antihistamine/decongestant inhalation |
| Barbiturates | Ibuprofen, naproxen |
| Benzodiazepines | Efavirenz, oxaprozin, sertraline |
| Buprenorphine | Amisulpride, sulpride, tramadol |
| Cannabinoid | Baby wash products, dronabinol, efavirenz, ibuprofen, lamotrigine (on screenings for synthetic cannabinoids), naproxen, niflumic acid, proton pump inhibitors |
| Cocainea | Coca leaf tea |
| LSD | Ambroxol, amitriptyline, benzphetamine, bupropion, buspirone, cephradine, chlorpromazine, desipramine, diltiazem, doxepin, fentanyl, fluoxetine, haloperidol, imipramine, labetalol, metoclopramide, prochlorperazine, risperidone, sertraline, thioridazine, trazadone, verapamil, ergonovine, lysergol, brompheniramine, imipramine, methylphenidate, fentanyl, sertraline |
| Methadone | Diphenhydramine, doxylamine, chlorpromazine, clomipramine, doxylamine, quetiapine, thioridazine, verapamil |
| Opiates | Amisulpride and sulpride, codeine, dextromethorphan, diphenhydramine, dihydrocodeine, morphine, methadone, morphine-3-glucuronide, creatinine, dihydrocodeine, levofloxacine, ofloxacine, morphine, naloxone, ofloxacin, petanzocine, psychotropic drugs, quetiapine, rifampicin, tapentadol, tramadol, verapamil, quinolones, quinine |
| PCP | Dextromethorphan, diphenhydramine, doxylamine, ibuprofen, imipramine, ketamine, lamotrigine, MDPV, meperidine, thioridazine, tramadol, venlafaxine |
| TCAsb | Cyclobenzaprine, quetiapine |
| aAmoxicillin has been reported to cause false-positives in review articles and various internet sources; however, data is lacking to confirm this cross-reactivity. bFalse-positives in the serum have been reported for carbamazepine, cyproheptadine, diphenhydramine, and hydroxyzine. Abbreviations: DMAA=dimethylamylamine (an energy supplement); LSD=lysergic acid diethylamide; MDPV=3,4-methylenedioxypyrovalerone (synthetic cathinone in bath salts); PCP=phencyclidine; TCA=tricyclic antidepressant |
|
False-negative results
In addition to false-positive results, there are several notable limitations of immunoassay urine screens that can lead to false-negative results.6 Enzyme immunoassays used for amphetamines have low sensitivity to certain drugs commonly used in the “rave scene”, such as 3,4-methylenedioxyamphetamine (MDA) and 3,4-methylenedioxyamphetamine (MDMA), and they are unable to detect phenethylamine-based “bath salts”. Benzodiazepines also are regulary missed on enzyme immunoassay screens. Benzodiazepine use may result in low concentration levels that are not detected on screening, which is common for clonazepam. Additionally, many enzyme immunoassays are designed to detect nordiazepam or oxazepam, metabolites of diazepam, chlordiazepoxide, and clorazepate.11 Therefore, lorazepam and clonazepam are not reliably detected by immunoassay, and GC-MS should be utilized if detection of these agents is desired. Many positive phencyclidine (PCP) tests are due to cross-reactivity; given that it is no longer commonly abused in the U.S., with the exception of select regions, clinical presentation should be used to guide management without the use of an immunoassay drug screen.6 Immunoassays for tetrahydrocannabinol (THC) are not able to detect newer synthetic cannabinoids. Opiate immunoassays detect morphine and codeine, the major metabolites of heroin and a common contaminant acetylcodeine, respectively.11 Therefore, they do not reliably detect semisynthetic and synthetic opioids. Additionally, it is important to note which opioids are included on an institution’s standard screening, as certain opioids may require an additional order or GC-MS.
Summary
While urine drug screening using immunoassay is convenient, the test is associated with multiple limitations. An understanding of these limitations is necessary to identify false-positive and false-negative results. Additionally, a thorough medication history should be obtained to anticipate false-positive results. In addition to medications, certain body washes, foods, and supplements have been associated with false-positives, which may be difficult to identify. Positive results on urine immunoassay screening should be considered presumptive, and confirmatory testing with GC-MS should be considered to confirm the findings.
References
- Illicit drug use. Centers for Disease Control and Prevention (CDC). Updated March 1, 2021. Accessed April 8, 2021. https://www.cdc.gov/nchs/fastats/drug-use-illicit.htm
- 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(5):774-796. doi: 10.1016/j.mayocp.2016.12.007
- Drug-free workplace guidelines and resources. Substance Abuse and Mental Health Services Administration (SAMHSA). Updated March 15, 2021. Accessed April 8, 2021. https://www.samhsa.gov/workplace/resources
- Analytes and their cutoffs. Substance Abuse and Mental Health Services Administration (SAMHSA). Analytes. November 25, 2008. Accessed April 8, 2021. https://www.samhsa.gov/sites/default/files/workplace/2010GuidelinesAnalytesCutoffs.pdf
- Mandatory guidelines for federal workplace drug testing programs. Substance Abuse and Mental Health Services Administration (SAMHSA). January 23, 2017. Accessed April 8, 2021. https://www.federalregister.gov/documents/2017/01/23/2017-00979/mandatory-guidelines-for-federal-workplace-drug-testing-programs
- Nelson ZJ, Stellpflug SJ, Engebretsen KM. What can a urine drug screening immunoassay really tell us? J Pharm Pract. 2016; 29(5):516-26. doi: 10.1177/0897190015579611
- Grunbaum AM, Rainey PM. Laboratory principles. In: Nelson LS, Howland M, Lewin NA, Smith SW, Goldfrank LR, Hoffman RS, eds. Goldfrank’s Toxicologic Emergencies. 11th ed. McGraw-Hill; 2019: chap 7. Accessed April 8, 2021. https://accesspharmacy.mhmedical.com/content.aspx?sectionid=210267566&bookid=2569#216818178
- Saitman A, Park HD, Fitzgerald RL. False-positive interferences of common urine drug screen immunoassays: a review. J Anal Toxicol. 2014;38(7):387-369. doi: 10.1093/jat/bku075
- Brahm NC, Yeager LL, Fox MD, Farmer KC, Palmer TA. Commonly prescribed medications and potential false-positive urine drug screens. Am J Health Syst Pharm. 2010;67(16):1344-1350. doi: 10.2146/ajhp090477
- Standridge JB, Adams SM, Zotos. Urine drug screening: a valuable office procedure. Am Fam Physician. 2010;81(5):635-640.
- Cupp M. PL Detail-Document, urine drug testing. Pharmacist’s Letter/Prescriber’s Letter. March 2014.
Prepared by:
Amanda Gerberich, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy
May 2021
The information presented is current as April 5, 2021. This information is intended as an educational piece and should not be used as the sole source for clinical decision making.