Shifting Practice in Clinical Toxicology

January 2020 - Vol. 9 No. 1 - Page #12

Drug screening remains common in clinical workups, but as drug-use trends evolve and clinical practice changes accordingly, the ways in which drug screening is performed must change as well. Just ten years ago, legally acceptable recreational marijuana use in the United States was unheard of and only a few states had ventured into medical marijuana approvals;1 the percentage of teenagers on stimulants (eg, Ritalin/methylphenidate and/or Adderall/amphetamine) for attention deficit disorder (ADD) was generally considered low;2 the terms vaping and kratom were not part of the American lexicon (the first listing of “vaping” in PubMed dates to 20113); and opioids were only approved for use in patients with pain syndromes related to terminal cancer and short-duration pain management (eg, post-operative).

Today, providers in the US are challenged on a daily basis by some or all of these potential drug exposures and their impact on patient care. Crises have been declared for both opioid abuse and vaping-related toxicity in both adults and pediatric populations;4,5 states with medical marijuana approvals abound and recreational approvals are emerging;1 ADD and ADHD diagnoses and use of prescribed stimulants are both increasing;2 and diversion is a significant issue for several drug classes and patient populations.2,6,7 The website of the National Institute on Drug Abuse (NIDA)——has expanded substantially in its provision of materials to educate all-comers about drug-use trends, addiction risk and treatment, and nationwide initiatives for intervention.

Throughout these turbulent 10 years, one element has remained constant in the realm of clinical toxicology: Given the lengthy persistence of detectable drug and/or metabolite in urine (and its general ease of collection), it remains a primary specimen of preference in hospital and clinic settings for drug screening.

When considering how societal drug-use changes and related changes in clinical practice impact the laboratory, some may argue that laboratories already provide urine drug screen tests, and the general drug classes have not drastically changed, so should not that be enough? Part of the answer to these questions is predictable, as clinical laboratories are intended to support clinical workups and care providers in the trenches, but another part of the answer is less apparent. Thus, there are multiple elements to consider when assessing test menus and offerings for clinical toxicology tests. (Note: these observations are intended for clinical hospital laboratories, not specialized toxicology and forensic testing facilities.)

Drugs, Drug Classes, and Cutoffs

The US Department of Transportation guidelines for workplace drug testing,8 released in 1975, required specific drug classes and cutoffs be used for testing newly hired employees, and that the testing be performed by certified toxicology laboratories (see TABLE 1). While intended for employees performing manual work and commercial driving services for the US DOT, these cutoffs were largely adopted by the health care and hospital laboratory sphere and remained minimally changed for decades. It was only in 2017 (with 49 CFR Part 40)9 that these guidelines were updated for health care, and laboratories started to review the new drugs within the basic classes, trends (eg, medical marijuana permits), and cutoffs.


During this same time period, manufacturers were producing FDA-approved drug screening reagents with similar cutoffs to those of the US DOT, and hospital laboratories adopted these reagents and cutoffs as alterations required laboratory-developed testing and high complexity validation work. Other drug classes had presence in clinical laboratories (eg, benzodiazepines, barbiturates) that could easily impair a transportation worker, yet no guidelines were set for these. As a result, slightly lower screening cutoffs and the lack of local confirmatory methods were status quo in the clinical setting.

Evolving Test Formats

As drug development pipelines have expanded over the past few decades, several factors have altered the ways in which providers evaluate patient care and compliance (see TABLE 2). These include incorporating new generations of classical drug groups (eg, benzodiazepines), entirely new paradigms in therapy (eg, the emergence of reuptake inhibitors for antipsychotic drugs), and expanded uses of known drug classes (eg, opioids and stimulants) in broader populations.


Traditionally, drug testing followed a screen-and-confirm workflow, with screens initially performed exclusively in laboratories (by trained technical personnel) via thin-layer chromatography approaches. This process eventually gave way to automated immunoassays that offer a much lower level of testing complexity. These in turn proliferated to point-of-care-friendly dipstick- and cup-based tests lauded for their configurability, ease-of-use, rapid result availability, and relative speed for FDA approvals. This latter feature of POC devices often renders them highly relevant and featuring the most clinically relevant cutoffs, compared to automated reagents that are not routinely resubmitted to the FDA for changes to cutoffs, improved selectivity, etc.

Confirmatory testing has evolved as well, from all tests being largely performed by gas chromatography-mass spectrometry (GC-MS), to select tests (eg, volatile panels) tested with GC-MS and remaining classes migrating to liquid chromatography-tandem mass spectrometry (LC-MS/MS). In both cases, confirmatory testing remains a high-complexity approach that requires extensive validation, quality control, and highly trained testing personnel.

In terms of specimens, urine remains the primary specimen tested most for illicit drugs in the clinical setting. However, in some settings, oral fluid testing is being used. Discussion of the utility of oral fluid testing is beyond this scope of this article, but there are other interesting summaries pertaining to urine and oral fluid testing in the pain management setting available.10

Expanding Test Menus

Known issues with older, higher-cutoff drug screening immunoassay reagents place clinical laboratories in a difficult position. While some drug testing reagents offer higher cutoffs intended for detecting toxicity and lower cutoffs intended for detection of misuse and/or compliance, very often the need for compliance checks involving individuals receiving low-dose drugs results in false-negative screening findings. These, in turn, may be sent for confirmatory testing, which may also yield false-negative results due to a lack of updates.

In addition, given the expansion of drug classes in use clinically in the modern era (eg, from classical opiates into a broader spectrum that includes semi-synthetic and synthetic opioids), basic reagents for drug classes often demonstrate poor cross-reactivity with newer compounds. For example, in an opiate drug screening reagent for an automated chemistry analyzer with a cutoff of 300 ng/mL, the calibrator is morphine. Compounds with close structural similarities cross-react relatively well: 6-acetyl morphine yields a positive screening result at 280 ng/mL, codeine at 150 ng/mL, and morphine glucuronides at approximately 300 ng/mL. However, even with this reagent—developed decades ago and transferred from one generation of analyzer to the next11—dihydrocodeine and hydrocodone only yield a positive screening results at 650 ng/mL, hydromorphone at 1400 ng/mL, oxycodone at 10,500 ng/mL. Further, buprenorphine and naloxone do not even have such information in the package insert, so cross-reactivity is essentially unknown, but time has shown that it is virtually nil. These findings are not restricted to the cited reagent; careful review of local package inserts’ limitation sections should tell a similar story.

What Does This Mean to the Clinical Laboratory?

  • It means calls to the laboratory, asking (for example) why the patient on hydrocodone had a false-negative drug screen despite adamant claims of compliance. This requires improved training and vigilance for personnel, and/or connections to expert feedback.
  • It means expanding menu offerings and drug panels to include more components. This too contributes to a call for expanded toxicology literacy at the level of the clinical laboratory.
  • It means more confirmatory testing, more service for troubleshooting when unexpected screening results arise, and more expense in testing and personnel time related to drug testing. This comes down to resources, funding (or lack thereof), and/or the emergence of more clinical mass spectrometry sections in laboratories that previously had none.

See TABLE 3 for a view of how the urine drug screening menu alone has evolved at West Virginia University (WVU), since a clinical chemist joined the faculty and took directorship of the chemistry section of the hospital laboratory.


Tying it All Together: Three Case Examples


A pediatrician prescribing Ritalin to a teenager diagnosed with ADD calls the laboratory about an unexpectedly negative urine drug screen result for amphetamines, intended as a compliance check.

Aspects to Consider

  • Ritalin/methylphenidate does not cross-react with amphetamines screening tests, even if a low cutoff is used
  • Even if the prescription is for Adderall/amphetamine, the screening cutoffs used in clinical laboratories are typically high (eg, 1000 ng/mL), more consistent with overdose/toxicity, and unlikely to be positive even if the patient is complying
  • Confirmatory amphetamine panels typically do not include methylphenidate; knowledge about testing options to accurately answer the provider’s question is key to helping the provider and the patient

Advice and Actions

The provider was coached about cross-reactivity and given a test code for a methylphenidate compliance test for use in the future. The remaining urine specimen was forwarded for the appropriate test and compliance was confirmed.


An outpatient generalist prescribing alprazolam to an elderly woman contacted the laboratory about an unexpectedly negative urine drug screening result for benzodiazepines. Confirmatory testing had already been requested and it also was unexpectedly negative. The provider suspects that the caregiver and/or family members may be diverting the medication.

Aspects to Consider

  • Upon review of the screening information, alprazolam does cross react with the screening method, and consultation with the reference laboratory confirmed that the definitive testing yielded a signal that was below the assay cutoff for positivity (and thus reported as negative).
  • Return call to the provider revealed that the dosing regimen for alprazolam was not only low-dose, but also prescribed with a frequency of every other day. This is likely to repeatedly yield false-negative urine testing results via currently available tests.
  • Inquiries with other reference laboratories demonstrated similarly-high confirmatory cutoffs, providing no explicit answers for this type of test use.

Advice and Actions

The provider was told that screening may not yield supporting positive results for patients with low-dose, less-frequent prescriptions, and that there is currently no test available to the laboratory. Plans are set to develop an in-house, mass spectrometry-based definitive testing protocol with improved cutoffs/sensitivity for similar situations, and which will not require up-front screening tests.


A local addiction group session convened, after which, cut-up films of suboxone (buprenorphine and naloxone) were found in the parking lot, suggesting possible simulated compliance in one or more of the point-of-care-based drug screens performed on the group members. The whole group was called back to clinic for screening, as soon as possible.

Aspects to Consider

  • In the clinic, cup-based screening tests were collected on all patients, all of whom were adamant about compliance and avoiding other drug use.
  • All cups yielded positive buprenorphine screens, as expected for patients on suboxone.
  • Confirmatory testing only reports for buprenorphine and norbuprenorphine, and not the naloxone component; thus, the selected confirmatory test was not actually for suboxone.
  • There were no given results for adulteration testing, if it was performed, at the reference laboratory.
  • Several patients had norbuprenorphine present at levels several-fold higher than the detected buprenorphine. This pattern represents physiological clearance of metabolized and unmetabolized buprenorphine (likely, a true compliance).
  • One patient had undetectable buprenorphine and detectable norbuprenorphine that was relatively low. This pattern also represents physiological clearance of metabolized buprenorphine (likely, a true compliance).
  • One patient had norbuprenorphine present at significantly lower concentrations (<1%) than the buprenorphine, which was greater than the measuring limit for the confirmation test. This pattern is consistent with simulated compliance (ie, “film dipping”).

Advice and Actions

The psychiatry team was educated on the aspects of a true suboxone confirmation (rather than a buprenorphine confirmation only), and which patterns were consistent with both true compliance and simulated compliance. The team decided that the patient would be counseled first about the potential for removal from the group and discontinuation of the suboxone prescription; further, the patient was placed on an increased vigilance level until consistent compliance was demonstrated for an agreed period of time.


The practice of clinical toxicology is evolving rapidly and the laboratory’s role in affecting patient outcomes is expanding apace. As providers seek advice and consultation regarding new and increasingly complex challenges, laboratory leaders must be able to apply their expertise in finding the best and most efficient solution.


  1. Timeline of State Marijuana Legalization Laws. Accessed 12.20.19.
  2. Lakhan SE, Kirchgessner A. Prescription stimulants in individuals with and without attention deficit hyperactive disorder: misuse, cognitive impact, and adverse effects. Brain Behav. 2012;2(5):661-77.
  3. McQueen A, Tower S, Sumner W. Interviews with “vapers”: implications for future research with electronic cigarettes. Nicotine Tob Res. 2011;13(9):860-7.
  4. Hooper RW 2nd, Garfield JL. An Emerging Crisis: Vaping-Associated Pulmonary Injury. Ann Intern Med. 2019. doi: 10.7326/M19-2908.
  5. Walley SC, Wilson KM, Winickoff JP, Groner J. A Public Health Crisis: Electronic Cigarettes, Vape, and JUUL. Pediatrics. 2019;143(6).
  6. Schuler MS, Dick AW, Stein BD. Heterogeneity in prescription opioid pain reliever misuse across age groups: 2015-2017 National Survey on Drug Use and Health. J Gen Intern Med. 2019. doi: 10.1007/s11606-019-05559-6.
  7. Smith RV, Havens JR, Walsh SL. Gabapentin misuse, abuse and diversion: a systematic review. Addiction. 2016;111(7):1160-74.
  8. Office of the Secretary, DOT. Procedures for transportation workplace drug and alcohol testing programs. Final rule. Federal Register. 2000;65(244):79462-579.
  9. Code of Federal Regulations. Title 49, Subtitle A, Part 40, Subpart F, §40.87. Accessed 12.20.19.
  10. Kwong TC, Magnani B, Moore C. Urine and oral fluid drug testing in support of pain management. Crit Rev Clin Lab Sci. 2017;54(6):433-45.
  11. Abbott Diagnostics Corp. Opiates urine screening package insert. Catalog 3L34-20, June 2018 version.

Danyel Tacker, PhD, DABCC, FACB, is director of clinical chemistry at West Virginia University Hospital and a member of the pathology faculty in the West Virginia University School of Medicine. Her lab sections include automated and special chemistry, mass spectrometry, and blood-gas testing. Danyel also assists with specimen processing, outreach, point-of-care, and send-out functions of the WVUH laboratory.


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