Interpreting abnormal urine drug screen results

Opioids, benzodiazepines, cocaine, cannabis - a urine drug test can detect if your patient recently consumed any of them. How are opiates and opioids different? Do both trigger a positive opioid screen? How can you estimate how long a drug is detectable in urine? Find out the answers by watching this video presented by Dr. Stephen Holt, Co-Director at Yale Addiction Recovery Clinic, USA.

Stephen R. Holt, MD
Stephen R. Holt, MD
23rd Feb 2022 • 6m read

Opioids, benzodiazepines, cocaine, cannabis - a urine drug test can detect if your patient recently consumed any of them. How are opiates and opioids different? Do both trigger a positive opioid screen? How can you estimate how long a drug is detectable in urine? Find out the answers by watching this video presented by Dr. Stephen Holt, Co-Director at Yale Addiction Recovery Clinic, USA.

Start the first chapter of our Essentials of Addiction Medicine course for free

The need for clinicians who understand substance use disorder is growing! By combining the behavioral and pharmacological interventions included in this course, you’ll be equipped to handle the full spectrum of substance use disorders, whether you’re in the hospital, the emergency department, or the outpatient setting.

Join our Essentials of Addiction Medicine Course now!

Addiction can be devastating. Confidently diagnose and treat the most prevalent substance use disorders with this course!

Start the first chapter of our Essentials of Addiction Medicine course for free

Video Transcript

Let's now talk about how to interpret the urine test you've ordered. We'll start with a discussion of how the different substances are metabolized, since this will impact what we find in the urine. In this Medmastery lesson, we will focus specifically on opioids, benzodiazepines, and cocaine in the urine. Let's begin with opioids.

Imagine a patient found unconscious at home with a needle in her arm, EMS arrives, and they successfully arouse her with naloxone. She's brought to the emergency room where she eventually provides a urine sample. But lo and behold, the urine opiate screen is negative. Well, we just used an opioid antagonist naloxone to successfully wake her up, so how is it possible that there aren't any opiates in the urine? This will require understanding the difference between opioids and opiates.

An opioid is defined as any substance that binds to an opioid receptor. There are three broad classes of opioids, naturally occurring opiates, semi synthetic opioids, and purely synthetic opioids. As their name suggests, naturally occurring opiates are opioids that are found in nature. You don't need to make them in a lab, they come from the poppy plant. If you take any of those naturally occurring opiates, and modify them in a lab to create a novel compound that also activates opioid receptors, you have created something that is opiate like, this is called a semi synthetic opioid. And if you make a completely novel substance that is in no way derived from the opiates, but nonetheless activates opioid receptors, well, you've got yourself a synthetic opioid.

It turns out that there are a variety of substances from the opioid family that will cause a positive urine opiate screen, and a variety that will not. If we compile a list of all the different opioids and their tendency to trigger the opiate screen, it can become somewhat of a word salad. So let's look at a simple strategy to break the different opioids down into their three groups.

The naturally occurring opiates are codeine, and morphine, which are both made directly from Poppy plants. It turns out that in mammals, codeine, also metabolizes to morphine. Codeine also can metabolize to hydrocodone and both hydrocodone and morphine can metabolize to hydromorphone, so all these naturally occurring metabolites are considered opiates. As one might imagine, all these substances are structurally very similar. Everything else is an opioid, behaving similarly to an opiate, binding the same receptors, but not in the opiate club.

The most well known examples of semi synthetic opioids are oxycodone, and buprenorphine, which are derived from codeine and morphine, respectively. A simple way to remember which opiate, a semi synthetic opioid is derived from, is a clue embedded within the drugs name, shown here in blue, and yellow, telling me that oxycodone is derived synthetically from codeine, and buprenorphine from morphine. These then metabolize to oxymorphone and norbuprenorphine.

Purely synthetic opioids have no structural relationship to the opiates at all. This category includes methadone, and fentanyl. Note the absence of any code or orf references in their names. So, when you order an opiate screen, you're only going to detect natural opiates. Rarely, if a patient is on a very high dose of a semi synthetic opioids like oxycodone, you may trigger the opiate screen, since these semi synthetic substances are at least structurally similar to opiates. The synthetic opioids, however, will never trigger an opiate screen.

If you want to detect them, you need to ensure your urine toxicology screen specifically looks for each of those substances. So where does heroin fit into these groups? Well, as we reviewed much earlier in this course, heroin is simply a morphine molecule with two acetyl groups. Those two acetyl groups act like lipophilic rockets that fly right through the blood brain barrier, while morphine has to slowly get transported across it.

Well, it turns out that in mammals, heroin is fairly rapidly metabolized, first to 6-monoacetylmorphine, and then to morphine. Essentially, heroin and 6-monoacetylmorphone are semi synthetic opioids with downstream opiate metabolites. As such, well heroin itself would not trigger an opiate screen, it's metabolites would. Thus, if you ever see 6-monoacetylmorphine on your confirmatory GCMs result, you know, without any doubt that this patient recently used heroin.

Since its half life is less than 12 hours, you will find it in the urine for two to three days at most. Reflecting on our earlier case example, with her opiate negative urine, we can conclude that she likely injected either a synthetic opioid such as fentanyl, or a semi synthetic opioid like crushed oxycodone. This would explain why she was readily reversed with Naloxone but had no opiates in her urine. We can rule out the other opioids because heroin's metabolites, and other opiates would have shown up on the opiate screen.

Buprenorphine alone would never cause an overdose, and methadone, which could cause an overdose is very, very rarely injected. Now, let's briefly review benzodiazepine metabolism. Similar to opioids. Your typical benzo screen only detects a subset of common orally ingested benzos, shown here. Depending upon your lab, other benzos, including Clonazepam, Alprazolam, and Lorazepam might not be detected on a benzo screen, except at very high doses, and may require you to order a benzo specific confirmatory test, which will provide detailed quantitative data on various benzos and their metabolites. This will be extremely useful when you are prescribing one benzo but you're concerned the patient may be taking additional illicit benzos. After opioids and benzos.

I want to briefly touch on one of the stimulants cocaine. Cocaine has a single metabolite and the only point to mention here is that a routine urine drug screen very, very rarely yields false positives for cocaine. This is one of the only screening results that genuinely reflects what is in the urine. That is, if it's positive, you can be quite confident that cocaine is in the urine. It typically is detected for up to four days since last use.

When interpreting urine toxicology screens, we must consider the elimination half life of the drug in question. And this brings us back to an earlier section on pharmacokinetics. Opioids and benzodiazepines for example, undergo metabolism in the liver and elimination via the kidney at the same time that they are being absorbed and distributed throughout the body. The rate at which these processes occur depends upon the individual patient's liver and kidney and of course, the drug itself. The elimination half life is the time it takes for the drug to fall from the peak blood concentration Cmax to half of that concentration C 1/2. Oral methadone has a half life of nearly 24 hours, while IV hydromorphone has a half life of only two to three hours. Thus, you could expect evidence of a dose of IV hydromorphone to disappear from the urine entirely within a day or so.

While oral methadone could linger in the urine for five days or more, particularly in patients with higher maintenance doses or those with liver or kidney disease. While this is only a very general rule, you can guesstimate how long a drug might be detectable in the urine by multiplying its half life by five. One final factor to discuss is lipophilicity.

We've spoken elsewhere about the lipophilicity of various drugs, and how that can predict whether a drug rapidly crosses the blood brain barrier. Well, lipophilicity also predicts how long a drug might be found in the urine. If a lipophilic substance reaches high blood concentration levels, some portion of that drug is sequestered within fat cells, where it can be stored for days or even weeks. Highly lipophilic opioids such as fentanyl may have very short elimination half lives, but a very long tail due to this property, such that fentanyl can be found in the urine for up to seven days after last use. Similarly, THC the primary active ingredient in cannabis is another highly lipophilic compound that can be found in the urine of heavy daily users several weeks after last use.