Turning questions to answers in drug testing

Dr. Snozek notes that currently there are approved immunoassays for fentanyl, tramadol, hydrocodone, and oxycodone. These tend to be more readily available on automated platforms, as opposed to point-of-care screening cups. Labs that have historically relied on POC cups may want to reconsider whether that remains the best solution. And even if it is, newer cup options now offer a better mix of tests.

Given the increase labs are seeing in drug testing, it may well be time to consider moving from a POC cup to automated immunoassays. “They tend to be more customizable,” Dr. Snozek says. “You can validate the ones that are appropriate for your practice,” and not be locked into what a POC manufacturer offers.

Mass spectrometry tests are almost exclusively laboratory-developed, Dr. Snozek says, adding that more labs are finding this technology within reach. She and others are evaluating Surveys data to understand trends in that area as well. Moreover, the Critical Reviews publication highlights the challenges of using various mass spec assays. As the authors note, even with the more readily available platforms, such as standard triple quads, there remains a lack of standardization in terms of what cutoffs to use, whether to report results qualitatively or quantitatively, and what drugs and metabolites to include.

For that guidance to appear, it will require “someone to grab the opportunity by the horns and get it moving,” Dr. Snozek says. She points to how matters have unfolded in an adjacent setting: testing for drug-facilitated sexual assault. The Scientific Working Group for Forensic Toxicology, or SWGTOX, though a more forensically focused group, recognized the need for standardization for drug-facilitated sexual assault testing. “They put that guidance out there with the scientific backing behind it to say that evidence suggests this is what you need to do.”

It’s not a stretch to think of the current testing scene as the Wild West, says Dr. Delaney, in part because there’s so little guidance for clinicians.

In her own three-hospital network, recently formed, the clinical practices at the two key hospitals are vastly different, reflecting in part the variations in patient populations. “It’s tricky to meet everyone’s needs.”

She’s tried to address this by providing interpretive guidance, including on the lab test catalog website. This involves, among other things, keeping up to date with the cutoff concentrations for the immunoassays, explaining cross-reactivities, and indicating what’s included in confirmatory and broad-spectrum testing. The lab also makes it easy for providers to know whom to contact for help with interpreting urine drug screen results.

These efforts have helped somewhat, Dr. Delaney says. “It is so hard. The physician needs are different, and it’s hard to understand which guidelines they follow,” she says, given that each specialty—ED, mental health services, addiction medicine, pain management—is likely using different guidance. “There are many guidelines out there. None of them agree with each other.”

Drug testing requires another essential but often overlooked element: trust. Patients need to trust their physicians to manage test results, which means overcoming the stigmas that cling to drug use.

Fortunately, that metamorphosis is underway, says Dr. Delaney, who notes that changing guidelines from the CDC and American Society of Addiction Medicine and in a couple of Canadian guidance documents are influencing how urine drug testing is performed. “We’re shifting to a less punitive way, to a more patient-centered approach.”

In Toronto, Dr. Delaney has been immersed in harm reduction as one of the leads for the city’s Drug Checking Services.

The premise of this approach is fairly straightforward: People who use drugs go to a safe consumption site to submit a sample of the drug they used or intend to use; the sample is analyzed at her lab, which then returns results to the user along with harm reduction information.

It’s not unusual for someone to submit what they think is fentanyl, while the analysis indicates the presence of other drugs, such as xylazine. Not only is that important from a health and user perspective—“It can have significant unexpected effects on the person if they’re used to using fentanyl, and now they’re using a whole bunch of other sedatives in the mix,” says Dr. Delaney—it also provides useful insights to labs. It’s a fairly novel and underappreciated approach, she suggests, one she’ll be discussing in a talk at this month’s AACC meeting.

Dr. Delaney explains: One of the limits of urine drug testing is that most methods are either targeted (usually mass-spec confirmatory tests) or class-based (immunoassays). But because so many drugs are circulating in and out of the drug supply, unknown to the medical community, “How are we supposed to know what to test for?” she asks. The drug checking essentially works as an invaluable surveillance tool for monitoring trends in the unregulated drug supply. If a pattern of seeing xylazine mixed with fentanyl has persisted for several months—to give an example—“We might want to think about adding it to our confirmatory method.”

With more germane information, clinical treatment improves. If a patient wants to start opioid agonist therapy, for example, having an up-to-date urine drug testing menu or capabilities will allow physicians to manage the patient’s situation more thoroughly—considering the need to manage benzodiazepine withdrawal, for example, if they’ve been taking it unknowingly.

Knowledge is perhaps the best path through a forest where fully grown trees seem to spring up overnight.

“Education is so important to this,” Dr. Tacker says. “So many providers are swimming in heavy schedules, and they get just a few minutes to talk to patients. The last thing they also need to do is double major in toxicology.”

Much of the burden is falling on primary care physicians, Dr. Snozek agrees, noting that this is a group that almost never gets direct education on opioid treatments, or on buprenorphine therapy, which is now being funneled into primary care as well.

Those with less experience may be trying to incorporate drug testing because of guidelines, Dr. Snozek says. “But they haven’t been given a toolbox for how to best do it. They don’t get that information alongside the guidelines saying, Thou shalt. Should it be on all our patients? Maybe. Should it be on select patients? Maybe. It depends on the practice.”

Some studies indicate physicians may not have a clear understanding about how to interpret drug tests. Never simple to begin with, it’s only become more complicated in recent years, says Dr. Snozek. And with the growing use of mass spec, which entails a host of new metabolites, physicians are understandably confused.

Dr. Snozek would like to see organizations such as the CAP step in with additional help, given the lack of training in medical school and residency. Pathologists can directly target educational gaps by making sure their own laboratory staff are trained. There is, she says, room for improvement. “I’ve had the experience where bench staff don’t necessarily have training in interpreting drug tests, either.” For those who lack such knowledge, she says it should be easier to turn to the CAP and other professional organizations for help. Bench techs either need to improve their understanding of drug testing issues, or recognize their own lack of understanding, she says. In the latter case, “It’s not part of your day-to-day job—no big deal. But make sure you have an escalating path to somebody who is trained in it, who can help [answer] those questions.”

Dr. Delaney likewise has found it useful to educate clinical colleagues about the limitations of urine drug testing, both on immunoassays and mass-spectrometry–based or confirmatory testing.

Immunoassays are limited to a select number of drug classes, she notes. The opioid drug class can identify a number of opiates with varying cross-reactivities; the same holds true for the benzodiazepine screen. What’s important to understand is that some of these class-based methods can’t identify drugs like xylazine or emerging novel psychoactive substances. With most institutions using immunoassay-based testing at least as a screen, it’s likely many drugs will be missed.

Moreover, fentanyl requires its own specific immunoassay. “A lot of providers still don’t know that,” Dr. Delaney says, which explains why they’ll order an opiate screen and assume a negative result means the patient is not using fentanyl. This happens even among her ED colleagues, she says.

That lack of understanding remains surprising to Dr. Delaney. Even in more specialized areas, such as addiction medicine, there remain generous opportunities to help clinicians interpret test results. And overall, she’s found, physician confidence in interpreting urine drug screen results “is very low,” despite the resources she and others in the lab have provided. In a survey she did at her own institution, Dr. Delaney asked her clinical colleagues whom they’d turn to for drug testing guidance. Only a small percentage said they’d contact laboratory personnel. “A lot of them said they’d just talk to their colleagues, peer-to-peer”—another surprising (and doubtless unsettling) response.

Nor are mass spectrometry/confirmatory tests beyond reproach, which means providers have to be educated about those limitations as well, Dr. Delaney continues. Most of them are targeted. If a physician orders a confirmatory opioid test but is also looking to investigate potential fentanyl exposure, it needs to be part of the test menu—a point not always appreciated. “You can only look for what you tell it to look for.”

Dr. Tacker had her own surprises involving confirmatory testing and so-called simulated compliance. (This is when a person diverts a drug they’re supposed to be taking, for any number of reasons. “It happens,” says Dr. Tacker. “There’s no judgment there.”)

The laboratory addressed that by adding simulated compliance comments to results for a handful of drugs, including oxycodone and methadone. Mass spectrometry can detect that pattern, since it looks not only for the original compound but also for the metabolite—evidence that a drug such as buprenorphine has been converted to norbuprenorphine, for example. If a result shows exceedingly high quantities of the former, but less than one percent of the latter, the lab flags it as abnormal and adds “potential simulated compliance” to the results.

When the lab first encountered it, “It shook us up,” she says. “The tech would be sitting there wondering, Why do I have no metabolite? Is there something wrong with my method?”

This gave the lab another opening to educate its clinical colleagues, says Dr. Tacker. If providers receive only the numbers, they might not think about simulated compliance. “But if we can detect, they can have a different conversation with the patient.”

Like any good conversation, those around drug testing rely on careful listening, says Dr. Tacker, who notes that the needs of every department vary. The emergency department does not routinely do confirmatory testing; it would only slow them down, she says. Instead, if a patient has been admitted and has a positive result from the ED, the lab provides confirmatory toxicology testing for those services, if needed.

The WVU system is also rolling out pediatric toxicology services at its children’s hospital, which opened last October. It’s a field that places far different demands on the laboratory. In addition, psychiatric medicine is enmeshed with multiple departments, and the lab is adjusting to guidelines for drug testing in obstetrics, palliative care, and oncology. In some cases there are hybrid groups—behavioral medicine specialists who work with oncologists in palliative care clinics to manage pain control.

“Every hospital situation might be a little different,” Dr. Tacker says. But every conversation can start with the same questions: What do you need? What can the lab do? What can we do together?

If it’s not clear by now, Dr. Tacker is a big believer in talking to clinical colleagues. Perhaps the most common question she gets has to do with false-positives: Is the patient really taking the drug in question, or is there something else going on (like the aforementioned prior surgery)? The stakes are high, particularly as it gets to the heart of patient-physician trust.

Occasionally she’ll field questions about why a patient who’s taking Ritalin has a negative amphetamine screen. She pauses, then explains: That drug is not an amphetamine.

Another example involves fentanyl screening, a test the lab added a few years ago. It had the lowest cutoff of any drug in the urine panel: 1 ng/mL. (By comparison, THC is 50 ng/mL; buprenorphine, 5 ng/mL; cocaine, 150 ng/mL; and MDMA, around 500 ng/mL.) With that wide scope of cutoffs, there could be cross-reactions with fentanyl that might result in a false-positive.

“We saw a rash of positives in the ED,” Dr. Tacker recalls. The clinicians doubted the results and wondered if the test was too sensitive, given that patients who had supposedly taken the drug entered the ED walking and talking.

Dr. Tacker went back to her trusty reports, looking at the raw data for positive fentanyl results.

Her explanation: “We get a number, but it’s not actually the number.” She noticed that the positive results that led to the ED’s questions were extremely close to the cutoff—1 ng/mL, 1.1 ng/mL. “Low, low positives.” she says. “And I reliably found antihistamines in the patient’s chart when they presented in the emergency department.” Spotting the cross-reaction cleared up the mystery.

She also encountered a disconcerting number of positives for fentanyl in OB patients being treated for hypertension with labetalol, which also cross-reacts with the fentanyl screen. The question from clinicians was swift and direct: What is going on? It turns out the beta blocker was going on.

These experiences led the lab to add a comment to its results, noting the labetalol or antihistamines may trigger low-level false-positives and suggesting confirmation if clinically indicated.

“We can do certain things with outreach,” Dr. Tacker concludes. “For us, that’s been lots and lots of conversations about cutoffs and cross-reactivity.”

Some patients may take lower-than-prescribed doses of a drug, for any number of reasons. For example, they might think a medication that has a low dose to begin with can be taken as needed, rather than prescribed. They may think they’re being compliant—I’m taking this when I need it—but they take so little of it, so infrequently, it won’t show up in sufficient volume to trigger a positive screen or positive confirmation.

That means more conversations with providers about the nuances of cutoffs, Dr. Tacker says, and how patients might be unintentionally diverting. “Lots and lots of questions about that.”

Dr. Tacker remains upbeat as she surveys the staggering challenges. “If people see the potential to partner up with clinicians and to turn this into a positive thing, then it gives me hope for our profession.”

She had her own learning curve. “The first thing I learned was you have to set aside your biases. And you have to learn from providers that the stigma doesn’t help. If you see this as an illness that is treatable, then people can benefit from intervention.” Just like any illness, she adds, “they don’t want this one. You learn so much more when you push your bias aside and listen to providers and their stories and help with the casework,” Dr. Tacker says.

She continues: “That’s a big part of this—just removing the stigma. We don’t damn people who have heart disease quite as much as the person who has a substance use disorder. We don’t go after people who have gout—we don’t call them bad people because they like chicken and beef and wine.”

Setting aside stigmas should be simple for labs, she says, if they ask questions of themselves as well as their clinical colleagues. “What is the data in front of me? What can I contribute to this team’s knowledge? And how can I help them through their clinic day?”

Karen Titus is CAP TODAY contributing editor and co-managing editor.