What drugs are likely to interfere with urine drug screens?
Urine drug screens (UDS) are a frequent practice used to detect common drugs of abuse. On-site drug screening is performed for a variety of medical, professional, and legal reasons. A few scenarios in which screening may be done are listed below:1
Reasons for urine drug screening1
• Preemployment
• Suspicion of drug abuse (e.g., unexplained negligence/impairment/behavior)
• Random testing outlined in employment contract
• Military service
• Sports participation
• Legal/criminal (e.g., postaccident, parole)
• Drug-therapy compliance monitoring
• Drug abuse rehabilitation monitoring
• Postmortem investigation
Screening Methods
Urine drug screens are generally performed using either immunoassays or gas chromatography-mass spectrometry (GC-MS).2 Immunoassay UDS contain specific antibodies against common drugs of abuse and their metabolites. The immunoassay is the most commonly used UDS because it is inexpensive and rapid. Five different immunoassays are available: cloned enzyme donor immunoassay, enzyme-multiplied immunoassay (EMIT), fluorescence polarization immunoassay (FPIA), and immunoturbidimetic assay radioimmunoassay (RIA). The substances most commonly tested by a typical immunoassay include amphetamines, cannabinoid metabolites, cocaine metabolites, opiate metabolites, and phencyclidine (PCP). Expanded immunoassays are available to test for tricyclic antidepressants, barbiturates, methadone, alcohol, and benzodiazepines and may be beneficial when use of these substances is suspected. One major problem with immunoassays is a false-positive result. Therefore, a more specific confirmatory test, such as GC-MS, is needed to confirm a positive finding with an immunoassay. GC-MS is more accurate than an immunoassay, but it is more expensive and time consuming.1 GC-MS breaks down drug molecules into ionized fragments and identifies substances based on mass-to-charge ratio using a mass spectrometer.
Although blood, hair, nails, or saliva can be used, most screening is done using urine samples.2 Ease of collection, higher drug concentrations, and longer durations of detection are primary reasons for using urine samples for drug screening. Table 1 lists common drugs of abuse and their duration of detection in the urine.
Table 1. Length of time drugs of abuse can be detected in the urine.1,2
Drug/drug class Detection time Drug/drug class Detection time
Alcohol 7 to 12 hours Marijuana
Amphetamine 48 hours Single use 3 days
Methamphetamine 48 hours Moderate use (4x/week) 5 to 7 days
Barbiturates Daily use 10 to 15 days
Short-acting 24 hours Long-term heavy smoker >30 days
Long-acting 3 weeks Opiates
Benzodiazepine Codeine 48 hours
Short-acting 3 days Heroin (morphine) 2 to 4 days
Long-acting 30 days Hydromorphone 2 to 4 days
Cocaine metabolites 2 to 4 days Methadone 3 days Morphine 48 to 72 hours Oxycodone 2 to 4 days Propoxyphene 6 to 48 hours Phencyclidine 8 days
Collection Methods and Criteria
Proper urine collection methods must be used to avoid false-negative results. Urine should be collected in a tamper-evident container under supervision if necessary.1 Criteria for legitimate urine samples include:
• A volume of 30 mL or more
• Temperature between 32▫C and 38▫C
• pH of 4.5 to 8.5
• Nitrates 1.002 and 20 mg/dL
Urine samples with characteristics outside of these ranges, or with a cloudy or dark appearance, may be adulterated in some manner, either diluted or substituted.
Urine Drug Test Results
The United States Department of Health and Human Services (DHHS) sets the threshold for drug concentrations for detection by UDS.2 Drug concentrations in the urine below this level are reported as negative. Table 2 contains a list of these values. However, despite standardization, inaccurate results can occur.
Table 2. Standard threshold levels for screening and confirmatory tests 1,3
Drug/drug class Immunoassay screena (ng/mL) GC/MS confirmationa (ng/mL)
Amphetamine and methamphetamine 1000 500
Barbiturates 300 200
Benzodiazepines 300 200
Cocaine metabolite (benzoylecgonine) 300 150
Marijuana metabolites (delta-9-tetrahydrocannabinol-9-carboxylic acid) 50 15
Methadone 300 200
Opiates (codeine and morphine) 2,000 2,000
Phencyclidine 25 25
Propoxyphene 300 200 a Standard cutoff levels; alternate cutoff levels may be available.
Abbreviation: GC-MS, Gas chromatography-mass spectrometry.
False-Negative Results
False negatives are uncommon but can occur as a result of low drug concentrations in the urine, tampering, and in other situations. Possible reasons for false-negative results include: 1,2
• Dilute urine (excess fluid intake, diuretic use, pediatric sample)
• Infrequent drug use
• Prolonged time since last use
• Recent ingestion
• Insufficient quantity ingested
• Metabolic factors
• Inappropriate test used
• Elevated urine lactate
• Tampering o Tetrahydrozoline (eye drops) o Bleach o Vinegar o Soap o Ammonia o Lemon juice o Drain cleaner o Table salt o Various chemicals (glutaraldehyde, sodium or potassium nitrate, pyridinium chlorochromate, and peroxide/peroxidase)
Understanding the UDS and ordering the appropriate test can prevent false-negative results. Results from an immunoassay or a GC-MS can be deceiving, as these tests may not be able to detect every drug in a particular drug class.2 This particularly pertains to the opiate and amphetamine/methamphetamine immunoassays. For example, a test for opiates will detect morphine and drugs that are metabolized to morphine, such as codeine and heroin. Heroin itself can only be detected for up to 8 hours after use. After 8 hours, only the morphine metabolite of heroin will be detected in the urine by immunoassay or by GC-MS. Other opiates such as fentanyl, oxycodone, methadone, hydrocodone, buprenorphine, and tramadol will not be detected and require an expanded immunoassay panel for detection.1 The amphetamine/ methamphetamine immunoassay can detect racemic compounds (dextroamphetamine, methamphetamine) and illicit analogues (methylenedioxyethylamphetamine, methylenedioxyamphetamine, and methylenedioxymethylamphetamine [MDMA]). This assay, however, has a low sensitivity for MDMA and a more specific test should be performed if MDMA is suspected.
False-Positive Results
Although immunoassays are very sensitive to the presence of drugs and drug metabolites, specificity and accuracy varies depending on the assay used and the substance for detection.2 This limitation may result in false-positives from substances cross-reacting with the immunoassay. Positive results seen on immunoassay need to be confirmed using the more accurate GC-MS, the forensic standard. The DHHS detection limits reduce false-positive results, but do not eliminate them. In 1998, the cut-off for opiates was raised from 300 ng/mL to 2000 ng/mL to avoid false positives from poppy seed ingestion. However, these more stringent requirements can lead to false-negatives and many laboratories continue to use the lower value for detection. For example, detectable levels of cannabinoids after ingestion of hemp-containing foods with immunoassay have been reported. Levels of cannabinoids in these samples, however, were not detectable with GC-MS. Passive marijuana or cocaine smoke inhalation has never been documented to achieve detectable urine concentrations in adults, however, passive cocaine smoke inhalation has achieved detectable levels in pediatric cases.
GC-MS is very accurate; however, it is not without problems in drug detection.2 As mentioned earlier, heroin and hydrocodone are metabolized into morphine and hydromorphone respectively, and GC-MS may identify the metabolites rather than the parent compound. Selegiline is metabolized to l-amphetamine and l-methamphetamine, isomers without central nervous system stimulation. Neither immunoassay nor GC-MS can differentiate between the l and d isomers and a positive result for amphetamines will be found; an alternative test, chiral chromatography, may be needed.
Many prescription and nonprescription substances have been reported to cross-react with immunoassays and cause false-positives.2 Most have only been documented in case reports. Table 3 lists substances reported to cause false-positive results using immunoassay. This list may not include all potential substances. The frequency of false-positives varies, depending on the specificity of immunoassay used and the substance under detection. Immunoassay results for cannabinoid and cocaine metabolites are associated with very few false-positives while immunoassay results for amphetamines and opiates are associated with a higher number of false-positives.1
Table 3. Substances that may cause false-positives on immunoassay urine drug screens.1-7
Drug/drug class Interfering drug Drug/drug class Interfering drug
Amphetamine and Amantadine Cocaine Amoxicillin methamphetamine Brompheniramine Coca leaf teas Bupropion Tonic water Chlorpromazine Methadone Chlorpromazine Desipramine Clomipramine Desoxyephedrine Diphenhydramine Ephedrine Doxylamine Fluoxetine Ibuprofen Isometheptene Quetiapine Isoxsuprine Thioridazine Labetalol Verapamil Phentermine Opiates Dextromethorphan Phenylephrine Diphenhydramine Phenylpropanolamine Fluoroquinolonesa Promethazine Poppy seeds and oil Pseudoephedrine Rifampin Ranitidine Quinine Selegiline Phencyclidine Dextroamphetamine Thioridazine Dextromethorphan Trazodone Diphenhydramine Trimethobenzamide Doxylamine Trimipramine Ibuprofen Vicks inhalerb Imipramine
Barbiturates Ibuprofen Ketamine Naproxen Meperidine
Benzodiazepines Oxaprozin Thioridazine Sertraline Tramadol
Cannabinoids Dronabinol Venlafaxine Efavirenz Tricyclic Carbamazepine Hemp-containing foods antidepressants Cyclobenzaprine Ibuprofen Cyproheptadine Ketoprofen Diphenhydramine Naproxen Hydroxyzine Piroxicam Quetiapine Promethazine Lyseric acid Amitriptyline Proton pump inhibitorsc diethylamine (LSD) Dicyclomine Sulindac Ergotamine Tolmetin Promethazine Sumatriptan a Ciprofloxacin, levofloxacin, and ofloxacin. b Vicks inhaler due to l-methamphetamine content interfered with older immunoassays; interference has not been seen with new enzyme multiplied immunoassay tests (EMIT). c Pantoprazole.
Summary
The strengths and limitations of UDS need to be fully understood in order to perform the correct screen and also to correctly interpret the results. All positive results on immunoassay are presumptive until confirmed using GC-MS. An extensive medication history including prescription, nonprescription, and herbal medications should be obtained from the patient. Medication histories are important in order to anticipate false-positives as well as differentiate between drugs used for legitimate medical purposes and drugs of abuse.
References
1. Standridge JB, Adams SM, Zotos AP. Urine drug screen: a valuable office procedure. Am Fam Physician. 2010;81(5):635-640.
2. Moeller KE, Lee KC, Kissack JC. Urine drug screening: practical guide for clinicians. Mayo Clin Proc. 2008;83(1):66-76.
3. Quest Diagnostics. Standard urine testing for drug and alcohol abuse. www.questdiagnostics.com/employersolutions/standard_urine_testing_es.html
Accessed Nov 11, 2010.
4. Vincent EC, Zebelman A, Goodwin C. What common substances can cause false positives on urine drug screens for drugs of abuse? J Fam Pract. 2006;55(10):893-894, 897.
5. 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.
6. Holtorf K. Ur-ine Trouble. Scottsdale, AZ: Vandalay Press; 1998.
7. Woelfel JA. Drug abuse urine tests: false-positive results. Pharmacist's Letter/Prescriber's Letter. 2005;21(3):210314.
Prepared by: Krista Williams, PharmD