Urine Drug Screening Nuances: 5 Pearls Segment

Core IM Podcast

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Time Stamps

• 03:01 PEARL 1: Basics to Urine Drug Screen (UDS)
• 08:03 PEARL 2: Types of urine drug tests, and what are immunoassays (IA)?
• 18:44 PEARL 3: What are gas chromatography/mass spectrometry (GC/MS)-based tests?
• 26:51 PEARL 4: How do you address unexpected test results on a UDS?
• 30:29 PEARL 5: Throwback to “5 Pearls on Stigma in Opioid Use Disorder” episode

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Show Notes

• What are the basics to a urine drug screen (UDS)?
  • Why do we need to obtain a UDS?
    • Verify adherence to opioid use disorder (OUD) treatment
      • It should never be done for punitive measures and should only be done to help with a patient’s OUD treatment
    • Assess for drug-drug interactions and unintended exposures to ensure safety
      • Use of gabapentin and opioids together is linked to an increased risk for opioid overdose deaths due to respiratory depression
      • Testing can be helpful if patients are unaware of the composition of the substance(s) they are using (e.g., detection of unintended fentanyl exposure)
    • Screen for substance use (e.g., detection of illicit amphetamine use)
      • This allows providers to discuss substance use and offer treatment
  • How often should we obtain a UDS?
    • Most societies recommend serial testing
      • However, according to the American Society of Addiction Medicine, “No universal standard exists in clinical drug testing for addiction identification, diagnosis, treatment, medication monitoring, or recovery.”
    • The frequency of testing is variable, but most providers agree on obtaining more frequent drug screens at the beginning of treatment and decreasing the frequency as treatment continues
    • Regular UDS may not change outcomes like deaths from overdose or provide mortality benefit
  • How do we discuss drug testing with our patients?
    • Try a straightforward approach with compassion and provide education on why a UDS is being obtained
• What are the different types of urine drug tests, and what are immunoassays?
  • The two main types of tests are immunoassay-based tests (IA) and mass chromatography/mass spectrometry-based tests (GC/MS)
  • Immunoassay-based tests
    • Indication: Often first-line and referred to as the typical “UDS panel”
    • Mechanism: Uses antibodies to detect select drugs and metabolites to provide qualitative results
    • Advantages:
      • Readily accessible as point-of care testing at most institutions with quick turnaround time of 24-48 hours for results
      • Relatively cheap but prices vary based on insurance
    • Disadvantages:
      • Lower specificity
      • Can detect non-synthetic opiates (e.g., morphine and codeine)
      • Cannot detect semisynthetic or synthetic opioids (e.g., methadone, buprenorphine, oxycodone, oxymorphine, and fentanyl)
      • Can also misidentify drugs with similar structures (e.g., amphetamine and methamphetamine)
• What is the difference between opioids and opiates?
  • Opiates refer to natural alkaloids (e.g., morphine and codeine)
  • Opioids refer to semisynthetic and synthetic (e.g., methadone, buprenorphine, oxycodone, oxymorphine, and fentanyl)
• Is there a “standard” UDS panel?
  • There is no a “standard” or “universal” UDS panel
  • Most will include marijuana, cocaine, opiates, amphetamines, and phencyclidine. Additional tests may be ordered separately
    • Know what UDS your institution offers!
• What are some common causes of false-positive results on a UDS?
  • Since it can detect compounds of structural similarity, there is a risk of false-positive results
    • However, cocaine = cocaine!
      • A positive result on a UDS has a high probability of being a true positive

• What are some common causes for false-negative results on a UDS?
  • False-negative results can occur when a drug or metabolite is present at such low levels that it is not detected
  • Can also occur if the UDS is not designed to test for a certain metabolite
    • For example, the IA UDS is not designed to detect clonazepam or methylphenidate.
  • Primary care providers should NOT use a UDS to test for adherence of either drugs
  • If there are any unclear test results, you should consult your local toxicologist!
• What are gas chromatography/mass spectrometry (GS/MS)-based tests?
  • Gas chromatography/mass spectrometry-based tests
  • Indication:
    • Used as confirmatory testing for positive results on immunoassays to test for single specific drugs or medication classes
  • Mechanism:
    • Uses a gas or liquid carrier medium to separate the urine sample’s compounds to provide quantitative results
  • Advantages:
    • Higher specificity with lower risk for false-positive results
  • Disadvantages:
    • Often a send-out test since it is not readily available at all institutions and may take days for results
    • Relatively more expensive; could have separate cost for each drug tested
• What is the difference between panel and reflex testing?
  • A panel test would be your typical IA-based UDS panel
  • Some institutions automatically do reflex testing with GC/MS for confirmatory testing if there is a positive result on the UDS
• What is the difference between buprenorphine and norbuprenorphine, and why is it important?
  • Buprenorphine is a partial μ-receptor agonist vs. norbuprenorphine is an active metabolite of buprenorphine and a full μ-receptor agonist with an increased risk of respiratory depression
  • An IA-based UDS will not differentiate between buprenorphine and norbuprenorphine. However, GC/MS confirmatory testing can distinguish the two
  • If there is a high ratio of buprenorphine to norbuprenorphine on GC/MS
    • Could indicate medication spiking to simulate adherence in those on OUD treatment
    • Occurs when a patient dips their urine with their own treatment medication
• When should we suspect UDS tampering?
  • If tampering is suspected, then the urine specimen obtained is considered presumptively positive and another urine specimen should be obtained
• Findings that suggest adulterated, diluted, or substituted UDS
  • General:
    • Temperature < 90 or > 100 degrees Fahrenheit
    • Unusual appearance (e.g., particles floating in specimen) or smell
  • Adulterated:
    • Nitrite > 5.0 mg/dL
    • Urine pH < 3 or > 11
  • Diluted:
    • Urine creatinine concentration > 2.0 mg/dL but < 20 mg/dL
    • Specific gravity > 1.001 but < 1.003
  • Substituted:
    • Urine creatinine < 2.0 mg/dL
    • Spec gravity < 1.001 or > 1.020
• Can you make a diagnosis of substance use disorder based on the results of drug tests?
  • The UDS is helpful as a screening tool for substance use, but you should not rely on the UDS to make a diagnosis of substance use disorder.
  • You should make these diagnoses based on drug-related behaviors and the DSM-5 criteria
• How do you address unexpected test results on a UDS?
  • How do you discuss positive test results?
    • Always try to come from a non-judgemental stance and address it like any other chronic medical condition
    • What should you do if the patient denies substance use?
      • Review your patient’s home medications, including prescribed and non-prescribed ones (e.g., herbal products), for potential causes of false positive results
  • What does a negative test result mean?
    • Could indicate that the patient is not taking the drug or the drug could be metabolized so rapidly that the metabolites are not detected
      • The window of detection varies for each drug

• Throwback to “5 Pearls on Stigma in Opioid Use Disorder” Episode
  • How can you avoid stigmatizing language when discussing substance use and results of a UDS?
    • Refer to the results of a UDS as “positive” or “negative” instead of “dirty” or “clean”, which carries a negative connotation
  • What are some strategies for harm reduction?
    • Harm reduction is an approach to empower patients with substance use disorder to make choices to live healthier and provide resources for risk reduction
    • Some harm reduction strategies include the following:
      • Provide access to test strips for fentanyl and xylazine
      • Provide access to naloxone
      • Provide access to clean needles by connecting patients to syringe exchange programs
      • Provide access to helplines
        • Consider listening to This American Life’s episode called “The Call” about helplines
        • Helplines are open 24/7, free, and confidential to patients and their families
        • National helplines:
          • Substance Abuse and Mental Health Services Administration
          • Never Use Alone

Transcript

Dr. Michael Incze: The other thing that I stress is that urine drug testing is not the only thing or even the most important thing that we pay attention to when we consider how someone’s doing with substance use disorder treatment. I think I place a lot more value on things like functional gains, improved self-efficacy, safety and whole person health, which is one reason I just love substance use disorder treatment in primary care. Urine drug screening is one piece of the puzzle, but by no means does it define our treatment success. And definitely it doesn’t define the patient.

Dr. Marty Fried: Who you just heard was Dr. Michael Incza, a primary care and addiction medicine physician at the University of Utah. This is Dr. Marty Fried, a primary care and addiction medicine physician, at THE Ohio State University Medical Center. This is the Core IM 5 Pearls podcast bringing you high-yield evidence-based pearls. Today we are diving deep into urine drug testing. And I am so excited to be joined again by Dr. Tina Phan, FORMER med peds resident from University of Tennessee Health Science Center! Tina, welcome back!

Dr. Tina Phan: Thanks Marty – yeah, by the time this episode is out, I’ll be officially done with residency and off to start my career as an adult hospitalist at University of Pennsylvania!

Dr. Marty Fried: Whoop whoop! So excited for you and super excited to get into urine drug screening.

Dr. Tina Phan: I’m super pumped too. So this is a topic that can seem simple – like it’s either positive or it’s negative – but it’s a little more complicated than that. There are a lot of nuances here that made us think it’s worth diving into with a dedicated 5 pearls episode. And heads up – we’ll sometimes be shortening urine drug screening to U-D-S.

Dr. Marty Fried: If you’re into the whole brevity thing. Alright Tina, let’s get into the topics we’ll be covering today

Dr. Tina Phan: Pearl 1 – Approaching urine drug screening with patients

Dr. Marty Fried: Why, when and how often should we screen for drug use, and how should we discuss drug testing with our patients?

Dr. Tina Phan: Pearl 2 – The immunoassay

Dr. Marty Fried: What is an immunoassay drug screen, and what are some sources for common false positives and false negatives?

Dr. Tina Phan: Pearl 3 – The gas chromatography / mass spectrometry, also known as GC/MS

Dr. Marty Fried: What is a GC/MS drug test and how should we interpret those results?

Dr. Tina Phan: Pearl 4 – Discussing results of drug screening

Dr. Marty Fried: How can we preserve the patient-doctor relationship while discussing unexpected results of urine drug screening?

Dr. Tina Phan: Pearl 5 – Throwback to “5 Pearls on Stigma in Opioid Use Disorder”

Dr. Marty Fried: What are some ways that we can reduce harm in describing the results of urine drug screening and what can we offer if our patient has returned to using drugs?

Pearl 1

Dr. Tina Phan: All right Marty, we’ve got a lot to cover, so let’s get started!

Dr. Marty Fried: For sure, Tina first question – What are some reasons to ask patients to submit urine drug screens?

Dr. Tina Phan: That’s a great starting point and super important question Marty. Sometimes we ask for urine drug testing not because we want to, but because we have to.

Dr. Michael Incze: You do have to sort of be aware of local laws and institutional policies, and so you don’t run afoul of them because that’s not going to help anybody. And B, so you can work to change them.

Dr. Marty Fried: Yes – we need to be aware of local requirements, but this is also an opportunity to influence those policies. Sometimes we send urine drug screens reflexively and without centering the patient and their goals in the decision. The lesson for me here is to try and avoid the automatic UDS without a thoughtful approach.

Dr. Tina Phan: And outside of “because we have to” – Dr. Incze did bring up some good reasons why we should test and how he frames it to his patients. In fact, the American Society of Addiction Medicine, or ASAM, published consensus recommendations that offer several reasons why we should test too.

Dr. Michael Incze: I frame it is the same reason that we would check a blood pressure in somebody with hypertension or an A1C and someone with diabetes not as like a gotcha kind of test or not because we don’t think that they’re trying really hard and adhering to all of the elements that we recommend for treatment. Just we want to see if our treatment is working. I stress that urine drug testing only is going to be used to add to their treatment, and the results of a urine drug test should be used to augment the treatment we offer to folks not to take it away or to deny folks treatment.

Dr. Marty Fried: Right, never use drug screening to punish – it’s a tool to support recovery, and sometimes the UDS can be a powerful motivator if the patient’s goal is to remain abstinent from drugs.

Dr. Tina Phan: Exactly! Another reason why a UDS can be so beneficial is to assess for possible drug-drug interactions or unintended exposures.

Dr. Michael Incze: If a patient is taking other medications that could potentially put them in harm’s way, especially if they have a return to use stuff like gabapentin or prescribed benzodiazepines or prescription stimulants. I do just, again for patient safety reasons, recommend more frequent testing in those circumstances.

Dr. Marty Fried: Yeah so this is a super important tenet of harm reduction. If our patients return to use we want them to be as safe as possible, and there is a growing appreciation for the presence of gabapentin in opioid overdose deaths, suggesting that there could be greater risk of respiratory depression for patients using both classes of medications.

Dr. Tina Phan: And maybe we aren’t the ones prescribing gabapentin or a benzodiazepine. But we can use the drug screen here to counsel patients to be extra careful – like doubling down on a recommendation not to use alone.

Dr. Marty Fried And there’s a similar point to be made here with prescription and illicit amphetamine use – if we find methamphetamine in the urine of a patient who we are prescribing stimulants to we might have to adjust treatment plan because taking those together can be dangerous.

Dr. Michael Incze: And I really think one of the primary reasons I recommend urine drug screening is because the illicit drug supply right now is just so poisoned and adulterated with all kinds of things that I just frame it like you deserve to know what you’re putting in your body and this is one test that can help with that.

Dr. Marty Fried Yeah the current state of the world is that we have a ubiquitously poisoned drug supply. I’ve had patients discover fentanyl in their urine when that was not what they were seeking to take and that was tremendously motivating to them to check their supply with fentanyl test strips. And I’ve even had patients commit to abstinence after discovering unintended fentanyl metabolites in their urine.

Dr. Tina Phan: Wow. Last question for this pearl about general approaches to urine drug screening – are there any guidelines about how frequently we should do urine drug screens?

Dr. Marty Fried The ASAM guidelines acknowledge that there is no evidence-based schedule. In general – more frequent testing upfront for patients early in treatment for substance use disorders and less frequent as they continue on.

Dr. Michael Incze: For patients who are really stable, I might check once a year.

Dr. Marty Fried: And this is one of those situations where your state or institution might have regulations that drive testing frequency, so another plug to familiarize yourself with those policies. Tina – what are your learning points from the first pearl?

Dr. Tina Phan: Yeah, so what I’m hoping that people take away is that a UDS can help providers verify adherence to treatment for opioid use disorder and assess for drug-drug interactions and unintentional exposures, with fentanyl being the scariest and unfortunately the most common one. My biggest takeaway though is that a UDS should never be used against a patient for punitive measures. It should only be used to help guide treatment! And lastly, we just need to be honest with our patients about frequency and goals of testing – a little compassion upfront can prevent our patients from feeling alienated later on.

Pearl 2

Dr. Marty Fried: So now let’s talk about the test itself. Tina, what are the categories here for urine drug screening?

Dr. Tina Phan: Ok Marty, get ready for this organic chemistry throwback. There are two main types of urine drug tests – immunoassays as the typical first line tests, and confirmatory tests, which use gas chromatography with mass spectrometry. Bet you thought those days were behind you.

Dr. Marty Fried: Oh you bet I did Tina, as I try to suppress o-chem nightmares let’s get a bit granular here – how do we know if the urine drug screens that we are ordering are immunoassay or the confirmatory tests?

Dr. Tina Phan: So your routine urine drug screen, or UDS panel, is typically going to be the immunoassay tests that we’ll talk about in this pearl. The gas chromatography/mass spectrometry tests are usually labeled as “confirmation” and typically sent for single specific drugs, single medications or medication classes like benzodiazepine confirmation.

Dr. Marty Fried: Right, in our shop there is a 10-drug panel that includes immunoassays for 10 commonly encountered medications and drugs. We can order confirmatory tests for each of those which are labeled a confirmation test.

Dr. Tina Phan: Perfect. So what exactly do we mean when we say immunoassay?

Dr. Heather Stieglitz: So the immunoassay based methods are going to be the more common testing that you might be used to. So these are available in most hospital laboratories. They’re also available at the point of care if you’ve ever seen the urine drug screening cups. And the way that those work are, we have these antibodies, they’re raised to detect a certain drug within a drug class. The disadvantage of immunoassays is that they really don’t have single drug level of specificity. They generally react with structurally similar compounds within a drug class.

Dr. Tina Phan: That was Dr. Heather Stieglitz, a clinical analytical toxicologist at the Ohio State University. So immunoassay-based testing uses antibodies to detect drugs or drug classes. This offers the upside of being relatively cheap and available for point-of-care testing, but at the cost of reduced specificity since it might also detect other compounds of structural similarity to the substance that you’re interested in.

Dr. Marty Fried: A crucial point here is that immunoassays are qualitative – “yes or no” vs the confirmatory mass spec which is quantitative and can tell you “how much” of that substance is present.

Dr. Tina Phan: Yeah, that’s a really good point. And here’s a quick word about drug panels.

Dr. Heather Stieglitz: So there really is no standard urine drug screen panel, especially when it comes to clinical toxicology. The decision for what drug classes to include on a urine drug screen is really a decision that’s made up at each individual lab, at each individual hospital.

Dr. Marty Fried: Ok so the lesson here is that we should be aware about what is in our shop’s standard drug screen panel, as these are probably built in house in response to local needs.

Dr. Tina Phan: Alright, now let’s talk about the limitations of immunoassays.

Dr. Michael Incze: Probably the most common thing that primary care physicians should know is that most immunoassay based tests don’t detect synthetic or most semisynthetic opioids, and that is especially true for fentanyl. So your urine drug screen could be negative for opiates if somebody was just exclusively using fentanyl.

Dr. Marty Fried: What Dr. Incze is referring to here is the difference between an opiate and an opioid. Opiates are naturally occurring substances derived from the poppy plant that include codeine, hydrocodone, morphine. In contrast, opioids are synthetic or semisynthetic substances like fentanyl and oxycodone. So if your UDS only includes opiates your patient might be exposed to scary stuff like fentanyl and we’d never know.

Dr. Tina Phan: And we know that the difference between opioids and opiates can be confusing, so check out our infographic about this and how it relates to UDS testing.

Dr. Marty Fried: And this brings up another good point about immunoassays – the interpretation can be super challenging.

Dr. Heather Stieglitz: The biggest disadvantage, with immunoassays is their specificity. So their antibodies, they’re raised to detect a certain drug within a drug class, but in actuality, they actually can cross-react and detect many different compounds within that same drug class that just have structural similarity. They have really great specificity when you’re asking them to differentiate between big molecules like differentiate between different proteins or peptides. But they aren’t quite as good when you’re asking them to differentiate between subtle changes of small molecules like changes in different functional groups.

Dr. Tina Phan: OK, and just to drive this point home, I’m going to torture you with O-chem again…what is the difference between bupropion and amphetamine?

Dr. Marty Fried: This sounds like a joke with a cheap punchline…, I don’t know…Chuck Norris?

Dr. Tina Phan: What! No! The difference between bupropion and amphetamine is actually pretty similar. It’s only a chloride atom, a ketone group and a bundle of methyl groups… it’s like basically the same thing.

Dr. Marty Fried: I feel like we’re going to have to show a picture of these o-chem goobers in the show notes…

Dr. Tina Phan: Oh for sure. But the moral of the story here is that given how subtle the molecular difference is between amphetamine and bupropion, it shouldn’t be too surprising when the immunoassay we sent looks like our patient on bupropion is taking unprescribed Adderall, an amphetamine. This is a super common false positive on immunoassays!

Dr. Marty Fried: Any other common false positives come up in our discussions with the experts?

Dr. Tina Phan: Another common one is sertraline. It will sometimes cross-react with benzodiazepine assays, and there are a whole host of other common sources of false positives that we’ll link to in our show notes. Also check out the infographic about what they might show up as on a UDS.

Dr. Marty Fried: What about false negatives? Any particularly important situations where a medication we would expect to see might not actually show up in the drug screen?

Dr. Michael Incze: One of the ones that comes up most commonly just with colleagues asking me about, for example, is the false negative that many typical amino assay based screening tests and primary care have for clonazepam. So they’ll be totally freaked out that they’re prescribing clonazepam to this person, which is already making them nervous, A PCP and then the test negative and they’re like, what? I can’t believe it. But almost always that’s a shortcoming of the test.

Dr. Marty Fried: I can see a lot of docs getting tripped up about the perceived absence of clonazepam in their patient’s urine, I mean already they are a little freaked about about prescribing benzos and then BAM – no drug – you’re out… without understanding the limitations of the test.

Dr. Heather Stieglitz: So the various benzodiazepine screens have antibodies that are raised to detect different types of benzodiazepines in the assay that we use. In my lab, the antibodies raised to detect lormmetazepam, And while it does cross-react fairly well with clonazepam, clonazepam isn’t actually the compound that is present in high concentrations in urine of a patients taking clonazepam. You’re going to find more of its major metabolite 7-amino-clonazepam. Now 7-amino-clonazepam does not show substantial cross reactivity in the assay. If you’re using the benzodiazepine screen to try to assess compliance with taking clonazepam, that’s another situation where it’s going to appear unreliable or you’re going to get more false negatives again, because the assay just doesn’t show substantial cross reactivity to that particular metabolite.

Dr. Tina Phan: Exactly! And methylphenidate is another one that we should be careful about.

Dr. Heather Stieglitz: The amphetamine screen is designed to detect amphetamine and methamphetamine. That’s what the antibodies are raised to detect. It has some cross your activity to MDMA or MDA, and so it can detect other structurally related stimulants, but it doesn’t detect all stimulants. So methylphenidate for example, generally a lot of amphetamine screens don’t have great cross reactivity to methylphenidate. So if that’s what you’re asking the amphetamines assay to detect, then you’re going to probably find that assay to be fairly unreliable because it just wasn’t, that assay was not designed to detect methylphenidate.

Dr. Marty Fried: OK – so clonazepam and methylphenidate are medications that fairly reliably won’t show up in our immunoassay drug screens… I’m feeling like I should be second-guessing everything at this point. Are there any situations where a result on the immunoassay is pretty solid, like, high probability that a positive result is actually a positive result?

Dr. Heather Stieglitz: Cocaine is my favorite immunoassay. That is because it’s very, very specific. So the antibody in the immunoassay for cocaine is raised to detect benzoylecgonine, which is a major metabolite of cocaine. And I have personally never seen an immunoassay positive results that we did not confirm by a mass spectrometry based assay, the presence of benzoylecgonine.

Dr. Marty Fried: Hallelujah! An immunoassay that I can trust.

Dr. Tina Phan: And just to clarify those terms – benzoylecgonine (ben-zoy-lek-guh-neen) is the urinary metabolite of cocaine, and the immunoassay for benzoylecgonine is suuuuper specific.

Dr. Marty Fried: Benzoylcgnoine, 7-amino-clonazepam – they just rolls off the tongue. Like who becomes an organic chemist… honestly? Tina – lets summarize this section.

Dr. Tina Phan: For sure! So the take-home point for this pearl is to understand the difference between the two major categories of drug screens – immunoassays, which use antibodies that are quick and cheap but might be positive for substances outside of what you’re looking for, and gas chromatography/mass spectrometry tests which have single drug specificity and are typically used for confirmation. It’s important to know what’s on the drug panel at your local institution, and if it’s only testing for opiates, make sure you’re checking for important opioids like fentanyl, oxycodone, methadone or buprenorphine.

Dr. Marty Fried: And there are some really important common sources of false positives with immunoassays – like how bupropion may result in an immunoassay positive for amphetamines. And a few important false negatives, like perceived absence of clonazepam or methylphenidate on most immunoassays. Cocaine is cocaine, and if you see that on an immunoassay you probably don’t need the confirmatory test.

Pearl 3

Dr. Tina Phan: Alright Marty – let’s move on to important points about the confirmatory testing assays – Gas chromatography and mass spectrometry. From here on out, we’ll use the shorthand GC/MS.

Dr. Heather Stieglitz: The other large grouping of toxicology tests are chromatography based methods. Chromatography generally paired with some kind of mass spectrometry detection. The main advantage of this type of testing is that it is highly specific. Chromatography, mass spectrometry based methods have single drug layer specificity. So for example, you can differentiate between morphine and codeine. The disadvantages of the chromatography based methods is that they’re much more complex. These are only available in specialized toxicology laboratories.

Dr. Marty Fried: So the TL;DR of this section is that the confirmatory testing using GC/MS is highly specific for single drugs or drug metabolites, so there are relatively few “false positives” at the cost of, well, cost. And maybe time, if it’s a sendout test at your lab.

Dr. Tina Phan: And just to torture you a little bit more here Marty – how the GC and MS work together is clinically important. Chromatography allows for the separation of the specimen into component parts with mass spec identifying those parts. Mass spectrometry also allows for the quantitative measurement of the concentration of a specific substance.

Dr. Marty Fried: So unlike using an antibody from the immunoassay tests to see what sticks, the chromatography isolates various metabolites from the sample and mass spec identifies and counts them… basically.

Dr. Tina Phan: Okay, but I have a question – How do we figure out which test to order?

Dr. Heather Stieglitz: I will warn you that if you have an unexpected result and that unexpected result is from an immunoassay, I’m probably going to tell you the same thing. And that is order a confirmation test.

Dr. Marty Fried: Tina, I am considering myself warned… JK I email Heather all the time and she’s wonderful.

Dr. Tina Phan: Hah, she’s really kind and knowledgeable. Basically, Dr. Stieglitz is emphasizing that the ambiguities that come up with immunoassays are significantly reduced when you follow that up with a confirmatory GC/MS.

Dr. Marty Fried: For sure. One thing that came up as we were talking about how to figure out which test to order is that sometimes you don’t actually have to decide at all to get a confirmatory GC/MS test – it might happen automatically.

Dr. Tina Phan: Right! So these are called reflex assays. The lab will automatically send confirmatory GC/MS assays on all positive immunoassay test results within a UDS panel.

Dr. Marty Fried: These can be helpful because we just heard Dr. Stieglitz tell us that if there are any questions about an immunoassay we should get the confirmatory GC/MS, and the reflex assay will do that automatically. Like, every time. That is the both the blessing and the curse of the reflex assay.

Dr. Tina Phan: Blessing because it happens automatically, curse because we might not need actually need that confirmatory GC/MS every time.

Dr. Marty Fried: The ASAM guidelines on urine drug screens recommend that testing be tailored to the clinical situation and we should selectively confirm positive tests.

Dr. Tina Phan: So for example, if you and your patient have already discussed their fentanyl relapse and the immunoassay shows fentanyl, we probably don’t need the confirmatory GC/MS that a reflex test would order automatically.

Dr. Marty Fried: Exactly. Our job is to pick the times when we are definitely going to want the confirmation and either order the reflex test or wait until the immunoassay comes back and see if you can order the confirmatory GC/MS on the sample that has already been collected.

Dr. Tina Phan: Yeah, our last point about interpreting GC/MS requires a bit of knowledge about urinary metabolites for opioids.

Dr. Marty Fried: So for many of the urinary metabolites of opioids, you’ll see a lot of “nor” in front of the medication name. Like noroxycodone, norfentanyl, and norbuprenorphine. That “nor” signifies that it’s a metabolite of the medication, and when it appears in the result of a quantitative mass spectrometry test, you can be fairly confident that the medication was taken, metabolized, and passed in urine. And that is a unique feature of GC/MS tests, not immunoassays.

Dr. Tina Phan: So immunoassays will tell us yes or no for any particular medication or drug, but GC/MS will tell us what specific metabolite is present in the urine. This is a pretty important point when trying to figure out if a patient has been tampering with their drug screen.

Dr. Heather Stieglitz: So if you have, say, an immunoassay screen for buprenorphine and it just elicits a positive for buprenorphine, you can’t really differentiate is that urine test positive because the patient actually took buprenorphine or because they just added buprenorphine directly to the urine. However, if you get a mass spectrometry based confirmation test and you can measure the quantitative concentrations of buprenorphine and nor buprenorphine, then you can look at those quantitative results. And if you see really, really, really high concentrations of buprenorphine and very low or undetectable amounts of no buprenorphine, that’s a situation that’s suggestive of the patient directly adding buprenorphine to their urine as opposed to physiologically taking it.

Dr. Tina Phan: DIABOLICAL!

Dr. Marty Fried: So the pattern you are looking for to confirm a positive buprenorphine screen is a GC/MS that has a high level of urine norbuprenorphine, indicating the metabolized compound is present in high concentrations and a relatively lower concentration of unmetabolized buprenorphine.

Dr. Tina Phan: I meannn, I’m just so impressed by the ingenuity…

Dr. Marty Fried: Hah – listen, our experts didn’t indicate that this happens often, but recognizing when this does happen is important because it represents an opportunity to check in with our patient about how things are going.

Dr. Tina Phan: Totally. We’ll talk about how to address urine drug screen results in the next pearl, but first, we should probably be clear about the limitations of a UDS in terms of what it can tell us about our patients.

Dr. Michael Incze: A urine drug screen cannot diagnose a substance use disorder, right? There are diagnostic criteria for a substance use disorder and urine drug screening is not one of ’em. And so I think you have to be really careful in how you interpret that and not to use that as a diagnostic tool, but rather a screening tool for substance use.

Dr. Marty Fried: This is huge! A lot of docs and most trainees can identify a substance use disorder as a pattern of compulsive drug use that affects various elements of someone’s life. But we should stop for a moment to realize that the result of a urine drug test is not found anywhere in the DSM criteria for the diagnosis of any substance use disorder.

Dr. Tina Phan: Exactly. So drug tests screen for substance use, not substance use disorders – there are tons of validated screeners out there for opioid use disorder and alcohol use disorder and others – and we couldn’t find a single screener that includes results of urine drug tests. So these screen for substance use, and that’s something we shouldn’t forget.

Dr. Marty Fried: Totally Tina, so to summarize what I’m taking away from this pearl is that the first step to interpreting an unexpected result is to check the confirmatory GC/MS test. Remember that the pattern of opioid metabolites matter. If you patient is taking a medication that contains buprenorphine we expect to see a high ratio of norbuprenorphine to buprenorphine in the urine – if that ratio is flipped and we see more bupe and low or absent norbupe then we should be seriously considering medication spiking and would want to check in with our patient.

Pearl 4

Dr. Marty Fried: So Tina, at this point hopefully we’ve clarified some ambiguities around urine drug screen interpretation, but I feel like that’s actually not the hardest part of this test. I’ve been talking about the results of urine drug screen with patients for a long time, and I still worry that I might mess up all the trust and rapport that I’ve built with patients when I have to address a urine drug screen that has some positives that we didn’t expect.

Dr. Tina Phan: You know Marty, I think it’s safe to say that you’re probably not the only one who feels that way. It’s tempting to fixate on that “bad news” discussion, but Dr. Incze actually has a super pragmatic way to talk about drug screens.

Dr. Michael Incze: I put that on my agenda for the visit, but I don’t start with it. Usually I just start it like I would any other primary care visit? How have things been going? Address whatever other concerns that person has, other health things that we’re working on. And then eventually I kind of circle around to the substance use disorder and as a part of that, I address the urine drug screen and usually I just say it and then let there be a little bit of silence like, Hey, urine drug testing was positive for benzodiazepines this time and I wasn’t expecting that. And then just wait. And then one of two things will happen. The patient will, most typically in my experience at least, and especially if you’ve developed a good rapport with this person over time will either tell you, Hey, this is what’s been going on and that can open a new door into augmenting treatment and et cetera. Or they’ll say, absolutely I did not use that substance. And then I think in that case it’s really worth it to take a minute to think about the shortcomings of the urine drug test and the possibility that there could be a false positive or a false negative.

Dr. Tina Phan: I loveee this. It seems like the best method is to come from a non-judgmental stance and just tackle it like any other primary care issue.

Dr. Michael Incze: I do think that clarifying someone’s goals around substance use is a really important part of substance use disorder treatment. Maybe people don’t completely desire a hundred percent abstinence. I have patients that are like that. They’re like, look, I’m going to continue to use every now and again because it helps with this or because I like it or because of whatever reason. And I think you have to align your goals with them.

Dr. Marty Fried: This is great. I love checking in about goals of abstinence in the setting of ongoing drug use because it affirms that I’m here for the patient no matter what, and for those folks who really do want to avoid drugs or alcohol it brings out some amazing change talk that I can amplify with some reflective statements.

Dr. Tina Phan: Hmm – so is that you being a motivational interviewing wizard there, Marty?

Dr. Marty Fried: I am by no means an MI wizard, but there are times when it is for sure helpful, and this is one of them!

Dr. Michael Incze: And I think just helping to clarify goals and if the goal is not to stop using immediately to make sure that you just turn the harm reduction up to 11, and then if someone’s goal is to stop using, then just to help get them started back on treatment for that.

Dr. Tina Phan: Okay. Dialing harm reduction up to 11? I love that, and we’ll highlight more on that in the final pearl. But first, Marty, tell us what you’re taking away from this section.

Dr. Marty Fried: So yeah this pearl is all about normalizing the discussion around an unexpectedly positive urine drug screen test. We don’t have to start the conversation with finger-wagging. Try to find a way to start the conversation with your patient about something other than their positive test. And use positive drug screens as a chance to check in about recovery goals – because we are here for our patients regardless if they want to use or abstain.

Pearl 5

Dr. Tina Phan: Okay. So let’s finish this episode with a throwback to our 5 Pearls on Stigma in Opioid Use Disorder podcast. One of the biggest takeaways I had from this was all the different ways we can avoid stigmatizing language when we’re discussing results of a urine drug screen.

Dr. Marty Fried: For sure – I still remember the story that Dr. Wakeman told in that episode about her friend who was asked how long they have been “clean” for – and the person’s response was that they had been bathing since they were a child and in recovery for at least 5 years. It was a good reminder for me that this really has nothing to do with hygiene.

Dr. Tina Phan: Exactly – so let’s refer to urine drug screens as either “positive” or “negative” instead of “dirty” or “clean”.

Dr. Marty Fried: And we just heard Dr. Incze mention to crank up the harm reduction for patients whose goal is not to stop using drugs immediately. Tina, can you remind us about some of the harm reduction strategies that came up in the Stigma episode?

Dr. Tina Phan: Yeah, so this was a learning point for me – a few ways we can help with risk reduction include providing access to test strips for both fentanyl and xylazine, connecting patients to syringe exchange programs, and of course making sure that they have narcan nearby.

Dr. Marty Fried: Yeah discussing injection practices with our patients can be really informative. This is a situation where hygiene matters so talk about washing hands before injection or cleaning the skin over an injection site.

Dr. Tina Phan: And if your patient is using alone without someone nearby, there are more and more hotlines nowadays. You can call to share your location and someone will stay on the phone to activate emergency services if help is needed.

Dr. Marty Fried: If you want to hear an amazing story about one of those programs check out a This American Life episode titled “The Call” – about one of those programs called the Never Use Alone hotline.

Dr. Tina Phan: I’ll definitely have to check that out now, Marty. So this is a wrap for this episode. If you found it helpful, please share this with your colleagues and give it a rating on Apple podcasts or whatever podcast app you use!

Dr. Marty Fried: Thank you to our peer reviewers ***. Huge thanks to *** for the audio editing and *** for the accompanying graphics. Opinions expressed are our own and do not represent the opinions of any affiliated institution. See you later!

Dr. Tina Phan: Bye!

References

• Mattson CL, Chowdhury F, Gilson TP. Notes from the Field: Trends in Gabapentin Detection and Involvement in Drug Overdose Deaths – 23 States and the District of Columbia, 2019-2020. MMWR Morb Mortal Wkly Rep. 2022 May 13;71(19):664-666.
• American Society of Addiction Medicine. The ASAM Appropriate Use of Drug Testing In Clinical Addition Medicine.
• McNeil SE, Chen RJ, Cogburn M. Drug Testing. [Updated 2023 Jul 29]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-.
• American Society of Family Medicine. Urine Drug Screen: Ordering and Interpreting.
• Waters RC, Perez M. How do I interpret and use quantitative buprenorphine and norbuprenorphine urine levels? Cleve Clin J Med. 2022 Oct 3;89(10):557-560.
• Raouf M, Bettinger JJ, Fudin J. A Practical Guide to Urine Drug Monitoring. Fed Pract. 2018 Apr;35(4):38-44.
• Substance Abuse and Mental Health Services Administration. Harm Reduction.
• This American Life. The Call. September 8, 2023.
• American Society of Addiction Medicine. Clinical Guidelines for Drug Testing.
• Core IM Podcast. 5 Pearls on Stigma in Opioid Use Disorder. September 29, 2021.
• Suzuki J, Zinser J, Issa M, Rodriguez C. Quantitative testing of buprenorphine and norbuprenorphine to identify urine sample spiking during office-based opioid treatment. Subst Abus. 2017 Oct-Dec;38(4):504-507.

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