Solving Clinical Toxicology Mysteries: Cocaine & Benzoylecgonine

Urinalysis is the main laboratory testing vehicle Addiction Professionals utilize to determine whether or not a patient is using drugs and/or alcohol. To the uninitiated, an Addiction Professional only looks at a toxicology result through a binary lens: negative, or positive. True clinicians know that toxicology is much more complex than that. This article is just one example. Let's dig in:

Let's suppose that a patient is suspected of having used cocaine recently because their urinalysis results showed positive for the substance. That's simple enough. However, their results also show them being positive for benzoylecgonine which is one of the 11 metabolites of cocaine.

But how can that be? How can the patient be positive for both cocaine and a metabolite of cocaine at the same time? You look at the patient's toxicology history and see that this never happened with this patient before. This has to be some kind of false positive, right? And, after all, the metabolite is only supposed to show up after cocaine has fully worked through a patient's system, right?

Not so.

Every situation is not the same

Before we solve the mystery, let's first discuss a few understandings that can be applied to the use of all substances:

- All substances don't metabolize in the body at exactly the same rate.

- All patients don't metabolize substances in the exact same timeframe and in perfect sequence. The term for these differences from the norm is known as pharmacogenetic variability. What this means is that a patient can have an abnormal, unexpected, or genetically determined reaction to a substance that differs from the reactions seen in the general population. This is based on the concept of enzyme variant profiles which we'll discuss shortly.

- Alcohol and most drugs metabolize through the liver. A patient's metabolization functions can be slowed by liver conditions.

- The kidneys filter the blood. While the liver breaks drugs and alcohol down, the kidneys filter and excrete the remaining waste. A patient with decreased kidney function will have these substances linger in their system longer—sometimes much longer—than normal.

- Even using the same drug, every metabolization period with the same patient will not be the same.

While the window of detection for specific substances is good to know, it's not as perfect and exact as many believe. The above examples are why.

Enzyme variant profiles... What???

The body uses various enzymes. Each person fits into a specific enzyme variant profile (formally known as patient metabolizer phenotypes). In the case of many substances like opioids and benzodiazepines, we look primarily to the CYP450 family of enzymes. 

~5% of cocaine is processed by the liver's CYP450 system (specifically the CYP3A4 enzyme). The remaining 95% of cocaine metabolization relies on spontaneous hydrolysis (~5%) and esterases (~90%). The esterases are carboxylesterases (~45%) and butyrylcholinesterase (~45%). No matter the enzyme, each person fits into a specific profile.

The profiles are as follows:

• Poor Metabolizers (PM) - Patients in this category have very low or missing enzyme activity in their body. As a result, substances build up in their system rapidly. This can lead to profound toxicity or overdose at normal doses at worst. At best, this can result in the body taking longer than normal to metabolize substances.

• Intermediate Metabolizers (IM) - Patients in this category have enzyme activity that is noticeably reduced. This causes them to process substances slower than the average person does. Patients of this profile can experience an elongated, intensified "high," making them prone to accidental cumulative overdoses if they continue to use before the previous amount of the substance has fully cleared their system.

• Normal / Extensive Metabolizers (NM or EM) - Patients in this category are considered to have a "normal" rate of metabolism, comparable to what is found in the majority of the population.

• Ultra-rapid Metabolizers (UM) - Patients in this category can have substantially elevated enzyme activity. This allows them to break down substances exceptionally fast. This rapid metabolization can blunt the psychoactive "high," pushing the patient to take dangerously large doses to feel any effect. Or, it can trigger a sudden, overwhelming rush of toxicity if the substance is a prodrug (such as the way codeine converts rapidly into morphine).

Important note: For cocaine, the above CYP phenotypes play an important but comparatively minor role because most metabolization occurs via esterases. Because of this, the PM/IM/NM/UM framework has a greater clinical focus for marijuana, opioids, antidepressants, antipsychotics, and benzodiazepines.

... But what does a positive for a substance and a positive for its metabolite mean?

Despite all of the science behind it, what it means is surprisingly quite simple. It means that some of the substance (in this case, cocaine) has not metabolized, and some of the substance has metabolized into its metabolite (in this case, benzoylecgonine). It's completely normal. 

Mystery solved.

But there is still another piece to this puzzle to consider regarding how the patient may be using a harmful substance. 

Timing.

Timing of use: "The fresh use window"

It's virtually impossible to look at a toxicology result and determine how much of a substance a patient has used, or exactly how long ago they've used it. Granted, windows of detection for specific drugs can give us an idea of how long ago a patient used a substance. But, it's not meant to be exact, it's meant to provide a range, hence the term "window."

Having said those things, in the case of cocaine, a result showing cocaine + benzoylecgonine indicates that the patient has likely—but not guaranteed to have—used somewhere in the neighborhood of 2-6 hours before providing the urine specimen. We'll refer to this as "The fresh use window." This window can stretch from 6 to 24 hours if a patient is a poor metabolizer.

Timing of use: "The scenario of overlapping doses"

Let's suppose the patient has been using cocaine repeatedly over the course of a weekend or over a period of several hours. The patient is continuously dumping fresh "parent" cocaine into their system. This happens while benzoylecgonine builds up steadily from earlier doses, and inevitably, this is detected in a toxicology screen. This is another explanation for why cocaine and benzoylecgonine can appear together on the same toxicology result. Let's call this "The scenario of overlapping doses."

To be sure, co‑presence can occur after a single use or after repeated use. Overlapping doses are just one common pattern, and an important one. This helps us better understand a common use habit that patients display.

When in doubt, consider your patient's unique profile

Remember that every patient isn't the same. Every patient doesn't use substances the same way or in the same amount, nor do they all metabolize substances in the same way or the same amount. Any time a patient's toxicology results seem mysterious, dig deeper. Investigate. Consider the profile concept discussed in this article. Consider any possible medical conditions. Utilize your state-given authority to examine consented medical records, and make contact with the patient's consented medical providers for more information if necessary. Confirm what the issue is, and move accordingly to help your patient.