Every investigation has a story!

Herein, we detail the unanticipated yet fortuitous events leading to our recent Harm Reduction Journal publication, titled “Harm Reduction in the Fourth Wave of the Opioid Epidemic: A Case Series Investigation of the Effectiveness of Definitive vs Presumptive Urine Drug Testing for Opioid Use Disorder with Co-Occurring Polysubstance Use.” ¹

INTRODUCTION

Our inquiry presents the first peer-reviewed investigation to evaluate evidence-based effectiveness, medical necessity, and expense of 'smarter' drug testing²—using near-real-time mass spectrometry rather than less costly immunoassay testing to guide both clinical decision-making and harm reduction in substance use disorder patients with co-occurring polysubstance use disorder in a real-world, outpatient, buprenorphine MOUD (medication for opioid use disorder) setting.

Acknowledging that an illustration can provide an attractive alternative to a 2,500-word manuscript, we offer the following:

BACKGROUND

When we established our clinic network a decade ago, we initially adopted point-of-care immunoassay as our testing modality. Very quickly, however, we encountered two concerning trends. First, nearly two-thirds of point-of-care immunoassay samples revealed one or more substances requiring laboratory confirmation using mass spectrometry. Second, as part of the confirmation process, the laboratory using mass spectrometry to process our specimens reported finding a disturbing number of additional, unsuspected substances—which they detected as part of their routine, in-house quality assurance processes—in our test samples that a) we had not ordered, and b) represented drugs most often found in autopsies of fatal overdoses (ie, fentanyl, cocaine, amphetamine, methamphetamine, and benzodiazepines).

Although the available medical literature initially provided limited insight, we found several resources that pointed to the need for exploratory research on using point-of-care immunoassay vs laboratory/mass spectrometry technology for clinical management of substance use disorder patients.

• ASAM: A 2013 white paper introducing the concept of 'smarter' drug testing, followed in 2017 by a more detailed consensus statement on the topic.²
• Barthwell et al: Two publications (cited in manuscript), including a literature review, underscoring the importance of specifying laboratory testing as the primary methodology to minimize both false positives and false negatives.
• Five additional publications (cited in manuscript) spanning the last decade detailing the experiences of Millenium Health’s reference laboratory, which mirror our findings of significant, concerning discovery of unordered and unexpected substances detected in urine samples.
• Nora Volkow’s NIDA editorial perspective in 2023 in the New England Journal of Medicine calling for evaluation of the feasibility of expanding drug testing to include laboratory testing to facilitate harm reduction in real-world clinical settings.³

To the best of our knowledge, our investigation is the first peer-reviewed effort to address the potential for leveraging near-real-time laboratory testing to expand the realm of harm reduction for substance use disorders in a real-world, outpatient clinical setting.

INVESTIGATION

Our case series included all opioid use disorder patients, most of whom exhibited co-occurring polysubstance use, treated with buprenorphine MOUD for one year in a single outpatient clinic. Interventions entailed head-to-head, split-sample urine drug testing that compared definitive laboratory chromatography/mass spectrometry testing to less-costly presumptive point-of-care immunoassay testing, which is more susceptible to false-positive and false-negative results. Outcomes included return to use during treatment, morbidity, and mortality.

Urine Drug Testing

With regard to the superiority of laboratory mass spectrometry  vs point-of-care immunoassay , our investigation is one of the first to report effectiveness of both the incidence and clinical relevance of using MS in a real-world, community clinic setting, not merely by eliminating false positives and false negatives but also by further leveraging mass spectrometry technology to identify other high-risk substances critical to optimizing harm reduction.

Harm Reduction

Although the term “harm reduction” most often appears in the context of substance use disorders and intravenous drug use, the public health community has long used the term to characterize a broad spectrum of preventive considerations, as illustrated by the following:

In this regard, our investigation is one of the first to respond to NIDA’s exhortation³ for clinicians to contribute to the ever-expanding scope of drug testing to include both real-time immunoassay test strips and near-real-time laboratory mass spectrometry testing to facilitate harm reduction.

Although some of our findings regarding the sensitivity and specificity of presumptive testing are neither new nor unexpected, we believe that our overall findings and resulting conclusions are unique in that they are the first to be reported a) in a single cohort of OUD patients with co-occurring polysubstance use employing split-sample presumptive vs. definitive testing and b) in the context of medical decision-making based on definitive UDT to facilitate harm reduction by guiding and escalating care in near real-time.

TAKEAWAYS

Our investigation offers three takeaways of particular relevance to real-world clinical practice:

1. Although point-of-care immunoassay may suffice for population-based screening (initial detection and referral), medical decision-making (diagnosis and management) for MOUD is better served by near-real-time definitive laboratory testing.
2. Our 'smarter' drug testing experience demonstrates that using non-quantitative, near-real-time testing for MOUD patients virtually eliminates the need for point-of-care testing—which requires confirmatory laboratory testing for more than half (57.6%) of all point-of-care tests due to one or more positive presumptive findings—yet costs only $10 more per patient encounter.
3. These findings have facilitated the opportunity to integrate MOUD with harm reduction by refining 'smarter' definitive laboratory testing protocols to detect emerging and novel substances, including but not limited to kratom, xylazine, carfentanil, dexmedetomidine, tianeptine, levamisole, bromazolam, and nitazenes.

Hopefully, our exploratory findings will be serve to inform more robust additional research.

REFERENCES

1. Cales RH, Bishop CL, Huecker MR, et al. Harm reduction in the fourth wave of the opioid epidemic: A case series investigation of the effectiveness of definitive vs presumptive urine drug testing for opioid use disorder with co-occurring polysubstance use. Harm Reduct J. 22, 187 (2025). https://doi.org/10.1186/s12954-025-01335-4
2. Jarvis M, Williams J, Hurford M, et al. Appropriate use of drug testing in clinical addiction medicine. J Addict Med. 2017;11(3):163–173.
3. Volkow ND, Califf RM, Sokolowska M, Tabak LA, Compton WM. (2023). Testing for fentanyl—Urgent need for practice relevant and public health research. NEJM. 388(224):2214-2217.