Is comprehensive drug testing a more effective clinical management tool than targeted drug panels in today's rapidly evolving drug landscape?

The traditional drug testing approach for clinical monitoring and detection of exposures consists of a two-step process: an immunoassay screen followed by a confirmation by mass spectrometry coupled to either gas or liquid chromatography (GC-MS or LC-MS/MS). The confirmation typically constitutes of a focused panel detecting several pre-selected members of a certain drug class.

The major drawback of this process is that it relies on the nature of the exposure or substance use disorder to be confined to the classes of drugs tested at the screen level. Additionally, compounds that do not have good cross-reactivity with the immunoassay chosen for their class, or that are present in concentrations below the cutoff (especially important in pediatric exposures), will produce a false negative result (1). Drawbacks exist even with the confirmation step. The targeted drug panels are limited and, most importantly, static. LC-MS/MS identification typically involves multiple reaction monitoring (MRM), where precursor and product ions are monitored along with retention time. Adding compounds to a panel is a non-trivial process that requires changing the MS and LC methods. As such, confirmation panels are updated every couple of years, at best. This pace does not keep up with today’s rapidly changing landscape of drug use.

The opioid epidemic has become a polydrug epidemic (2). Patterns of use have shifted over time to polysubstance use combining drugs across different classes. Additionally, novel psychoactive substances and cutting agents are constantly mixed into the drug supply – the most recent prominent example is the recent rise of the veterinary sedative xylazine as a major contaminant in illicit drug supplies (3). The volatility of the drug supply has increased dramatically post-pandemic, with trends that vary geographically (4). Responding to the local drug supply in a timely fashion is crucial for adequate clinical response.

High-resolution mass spectrometry (HRMS) promises to enable clinical labs to deliver just that (5). HRMS instruments can be based on time-of-flight (QTOF) or orbitrap mass analyzers and offer greater specificity, untargeted data collection, and the ability to retrospectively query data. Thus, HRMS is ideal for broad spectrum drug screening via comprehensive panels and seamless expansion of said panels once NPS are reported in the area or discovered during retrospective analysis. Implementation of a HRMS method does not come without challenges, and it requires an initial investment, both financially and in staff time and training (6). So, is the clinical utility of HRMS worth the effort?

Rhode Island Hospital is a 719-bed level-1 trauma hospital with a significant outreach operation. The RIH toxicology lab implemented an LC-QTOF-based comprehensive drug screen (CDS), in urine and in serum, in July 2022. With a target turnaround time of 2-5h if the sample was received during business hours, it was implemented with the ED and ICU in mind. This replaced a GC-MS urine CDS with limited utility (10-11 tests ordered/week). In just under two years, the test volume increased by 160%. 71% of the results contained information not accessible via the classic screen-confirmation process. By the end of the second year, 49% of orders were from outpatient clinics, showing an increased adoption of the test even in clinics that traditionally relied on screens and confirmations, such as recovery centers and behavioral health clinics. A significant proportion of orders (31%) came from pediatric departments (critical care, ED, child abuse). The remaining volume was equally split between adult ED/critical care and other inpatient units. While initially not appealing to adult ED due to turnaround time, the test gained popularity once a protocol for acting on results post-discharge was implemented. Notable instances of significant clinical management impact included the identification of a cluster of bromazolam (designer benzodiazepine) exposures among teens, flagging xylazine exposures among fentanyl overdoses seemingly not responsive to naloxone, environmental exposure of infants to cocaine that were frequently under the immunoassay cutoff, and differentiation between exposure to iatrogenic vs. street fentanyl by detecting 4-ANPP, a byproduct of illegal synthesis.

While requiring a bit of a paradigm shift in terms of both staff and physician education, the implementation of an HRMS-based comprehensive drug screen has provided invaluable information both in the critical and outpatient clinic settings. Given the current complexity of the drug supply and use patterns, adopting testing strategies that are readily adaptable is essential in facing this current public health crisis and providing adequate patient care.

References

1. Moeller KE, Lee KC, Kissack JC. Urine drug screening: practical guide for clinicians. Mayo Clin Proc. 2008 Jan;83(1):66-76. doi: 10.4065/83.1.66. Erratum in: Mayo Clin Proc. 2008 Jul;83(7):851. PMID: 18174009.
2. Friedman, J, Shover, CL. Charting the fourth wave: Geographic, temporal, race/ethnicity and demographic trends in polysubstance fentanyl overdose deaths in the United States, 2010–2021. Addiction. 2023; 118(12): 2477–2485. https://doi.org/10.1111/add.16318
3. Website: FDA alerts health care professionals of risks to patients exposed to xylazine in illicit drugs. Accessed May 17, 2024. https://www.fda.gov/drugs/drug-safety-and-availability/fda-alerts-health-care-professionals-risks-patients-exposed-xylazine-illicit-drugs
4. Collins AB, Wightman RS, Macon EC, Guan Y, Shihipar A, Krieger M, Elmaleh R, Smith MC, Morales A, Badea A. Comprehensive testing and rapid dissemination of local drug supply surveillance data in Rhode Island. Int J Drug Policy. 2023; 118:104118.
5. Allen DR, McWhinney BC. Quadrupole Time-of-Flight Mass Spectrometry: A Paradigm Shift in Toxicology Screening Applications. Clin Biochem Rev. 2019 Aug;40(3):135-146. doi: 10.33176/AACB-19-00023. PMID: 31530964; PMCID: PMC6719743.
6. Strathmann FG, Lynch KL, Krotulski A, Negri P, Cichelli J, Meyer MR. Challenges of High-Resolution Mass Spectrometry for Detecting Designer Drugs. Clin Chem. 2020 Jul;66(7):868-874.