Urine drug tests: How to make the most of them Effective use of UDTs requires carefully interpreting the results, and modifying treatment accordingly Xiaofan Li, MD, PhD rine drug tests (UDTs) are useful clinical tools for assessing and Staff Psychiatrist Sioux Falls Veterans Health Care System monitoring the risk of misuse, abuse, and diversion when pre- Assistant Professor scribing controlled substances, or for monitoring abstinence University of South Dakota Sanford School of Medicine U in patients with substance use disorders (SUDs). However, UDTs have Sioux Falls, South Dakota been underutilized, and have been used without systematic documenta- Stephanie Moore, MS tion of reasons and results.1,2 In addition, many clinicians may lack the Toxicologist Richard L. Roudebush VA Medical Center knowledge needed to effectively interpret test results.3,4 Although the Indianapolis, Indiana reported use of UDTs is much higher among clinicians who are mem- Chloe Olson, MD bers of American Society of Addiction Medicine (ASAM), there is still a PGY-4 Psychiatry Resident need for improved education.5 University of South Dakota Sanford School of Medicine Sioux Falls, South Dakota The appropriate use of UDTs strengthens the therapeutic relationship and promotes healthy behaviors and patients’ recovery. On the other hand, incorrect interpretation of test results may lead to missing poten- tial aberrant behaviors, or inappropriate consequences for patients, such Disclosures The authors report no financial relationships with any as discontinuing necessary medications or discharging them from care companies whose products are mentioned in this article, secondary to a perceived violation of a treatment contract due to unex- or with manufacturers of competing products. pected positive or negative drug screening results.6 In this article, we review the basic concepts of UDTs and provide an algorithm to deter- mine when to order these tests, how to interpret the results, and how to modify treatment accordingly. Urine drug tests 101 Urine drug tests include rapid urine drug screening (UDS) and con- firmatory tests. Urine drug screenings are usually based on various types of immunoassays. They are fast, sensitive, and cost-effective. Because immunoassays are antibody-mediated, they have significant Current Psychiatry BRUCE MARION Vol. 18, No. 8 11 false-positive and false-negative rates due initiating any controlled substance for to cross-reactivity and sensitivity of anti- pain therapy.12,13 They also suggest random bodies.7 For example, antibodies used in drug testing at least once or twice a year immunoassays to detect opioids are essen- for low-risk patients, and more frequent tially morphine antibodies, and are not able screening for high-risk patients, such as to detect semisynthetic opioids or synthetic those with a history of addiction.12,13 For opioids (except hydrocodone).7 However, example, for patients with opioid use dis- Urine immunoassays specifically developed to order who participate in a methadone pro- drug tests detect oxycodone, buprenorphine, fen- gram, weekly UDTs are mandated for the tanyl, and methadone are available. On the first 90 days, and at least 8 UDTs a year are other hand, antibodies can cross-react with required after that. molecules unrelated to proto-medicines or However, UDTs carry significant stigma drug metabolites, but with similar antigenic due to their association with SUDs. Talking determinants. For example, amphetamine with patients from the start of treatment immunoassays have high false-positive helps to reduce this stigma, and makes it rates with many different classes of medica- easier to have further discussions when Clinical Point tions or substances.7 patients have unexpected results during For patients with Urine drug tests based on mass spec- treatment. For example, clinicians can trometry, gas chromatography/mass explain to patients that monitoring UDTs SUDs, clinicians can spectrometry (GC/MS), and liquid chro- when prescribing controlled substances explain that using matography/mass spectrometry (LC/MS) is similar to monitoring thyroid function UDTs to monitor their are gold standards to confirm toxicology with lithium use because treatment with abstinence is similar results. They are highly sensitive and spe- a controlled substance carries an inher- cific, with accurate quantitative measure- ent risk of misuse, abuse, and diversion. to monitoring HbA in 1c ment. However, they are more expensive For patients with SUDs, clinicians can patients with diabetes than UDS and usually need to be sent to a explain that using UDTs to monitor laboratory with capacity to perform GC/ their abstinence is similar to monitor- MS or LC/MS, with a turnaround time of ing HbA1c for glucose control in patients up to 1 week.8 In clinical practice, we usu- with diabetes. ally start with UDS tests and order confir- matory tests when needed. Factors that can affect UDT results In addition to knowing when to order When to order UDTs in outpatient UDT, it is critical to know how to interpret psychiatry the results of UDS and follow up with con- On December 12, 2013, the ASAM released firmatory tests when needed. Other than a white paper that suggests the use of drug the limitations of the tests, the following testing as a primary prevention, diagnostic, factors could contribute to unexpected and monitoring tool in the management of UDT results: addiction or drug misuse and its application • the drug itself, including its half-life, in a wide variety of medical settings.9 Many metabolic pathways, and potential interac- clinicians use treatment contracts when pre- tions with other medications scribing controlled substances as a part of a • how patients take their medications, risk-mitigation strategy, and these contracts including dose, frequency, and pattern of often include the use of UDTs. Urine drug drug use Discuss this article at tests provide objective evidence to support • all the medications that patients are www.facebook.com/ or negate self-report, because many people taking, including prescription, over-the- MDedgePsychiatry may underreport their use.10 The literature counter, and herbal and supplemental has shown significant “abnormal” urine test preparations results, ranging from 9% to 53%, in patients • when the last dose of a prescribed receiving chronic opioid therapy.2,11 controlled substance was taken. Always The CDC and the American Academy ask when the patient’s last dose was taken Current Psychiatry 12 August 2019 of Pain Medicine recommend UDS before before you consider ordering a UDT. continued Figure 1 Metabolic pathways of commonly used benzodiazepinesa Diazepam CYP3A4/ CYP3A4 CYP2C19 Temazepam Nordiazepam Chlordiazepoxide CYP3A4/ CYP3A4 CYP2C19 2-hydroxyethyl- Flurazepam flurazepam Oxazepam Demoxepam Norchlordiazepoxide CYP3A4 1-hydroxymidazolam α-hydroxy-alprazolam Alprazolam CYP3A4/ Midazolam CYP3A5 Glucuronidation 4-hydroxymidazolam CYP3A4/ α-hydroxy-triazolam Triazolam CYP3A5 CYP3A4 Clonazepam 7-aminoclomazepam Urinary excretion Lorazepam aDrugs in bold are commonly used benzodiazepines CYP: cytochrome P450 Source: Reference 14 Figure 2 Metabolic pathways of commonly used opioidsa Poppy seeds Heroin 6-monoacetylmorphine Oxycodone Codeine CYP2D6 Morphine Prodrug <2.5% CYP3A4 CYP2D6 <11% CYP3A4 Norhydrocodone Noroxycodone Oxymorphone Norcodeine Normorphine CYP2D6 Hydromorphone Hydrocodone Noroxymorphone 6-oxymorphol 6-hydromorphol Dihydrocodeine CYP3A4 Fentanyl Norfentanyl Glucuronidation CYP3A4 Norbuprenorphine Buprenophine CYP3A4/CYP2B6 Methadone EDDP CYP2B6/CYP3A4 Normeperidine Meperidine CYP2C19 CYP3A4 Tramadol O-desmethyl-tramadol Urinary excretion Prodrug CYP2D6 Norpethidine aDashed lines indicate minor pathways. Drugs in bold are commonly used opioids CYP: cytochrome P450; EDDP: 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine Source: Reference 15 Table Commonly seen false positives and false negatives in urine drug screens Other drugs Detecting drugs/ detected in the Potential Potential Immunoassays metabolites same class false positivea false negativea Amphetamineb Amphetamine Dextroamphetamine, Bupropion, None known lisdexamphetamine trazodone, Urine desipramine, drug tests doxepin, labetalol, metformin, promethazine, ephedrine, pseudoephedrine, phentermine, atomoxetine, ranitidine Benzodiazepines Diazepam Oxazepam, Sertraline, Clonazepam Clinical Point temazepam, oxaprozin, flurazepam, efavirenz For patients taking chlordiazepoxide, midazolam (±), medications that are triazolam (±), undetectable by UDS, lorazepam(±), alprazolam(±) consider ordering Buprenorphine Buprenorphine Morphine, None known confirmatory tests at methadone, least once to ensure codeine, compliance tramadol Cocaine Benzoylecgonine None None known Marijuana 9-carboxy-THC Efavirenz, Nabilone, synthetic ibuprofen, and designer naproxen, cannabinoids dronabinol (spice, K2) Methadone Methadone Antipsychotics None known (quetiapine, thioridazine, chlorpromazine), verapamil, diphenhydramine Opioids Morphine Codeine, heroin, Quinolones, Oxycodone/ hydrocodone/ naltrexone, oxymorphone, hydromorphone (±) diphenhydramine, fentanyl, rifampicin methadone, buprenorphine, tramadol, meperidine Oxycodone Oxycodone None known None known Phencyclidine Phencyclidine Venlafaxine, None known lamotrigine, ibuprofen, dextromethorphan, bath salt, tramadol, zolpidem aThe potential false positives and false negatives listed do not indicate that the drug(s) will show or not show every time for every patient in every immunoassay bMethylphenidate