CAP TODAY Pathology/Laboratory Medicine/Laboratory Management
Zolpidem (Ambien) is not excreted in urine predominantly as zolpidem, he says. “It’s excreted as the metabolite. And many laboratories today, reference laboratories, toxicology laboratories, are measuring the parent drug zolpidem.”
“Basically, you have labs doing the wrong thing,” Dr. El-Khoury says. He advises checking with a reference laboratory that reports a negative result for zolpidem so as not to miss patients, “especially on low-dose Ambien.”
In their case report, Dr. El-Khoury and coauthors write, “Zolpidem phenyl-4-carboxylic acid, the major metabolite of zolpidem, can be detected at high levels in urine even 72 hours after ingestion of low doses of zolpidem (5–10 mg). Zolpidem 6-carboxylic acid can also be detected in the patient’s urine at 72 hours but at lower concentrations.”
Case No. 3 is that of a 28-year-old male with a history of opioid abuse who was prescribed Suboxone to manage the disorder and submitted a urine specimen for a drug screen to verify compliance with the prescribed drug and abstinence from illicit compounds (Gall B, et al. Clin Chem. 2019;65[10]:1332–1333).
With Suboxone, buprenorphine is expected in the immunoassay result, and in this case the sample tested positive for buprenorphine by cloned enzyme donor immunoassay. Surprisingly, Dr. El-Khoury said, the screen was positive for oxycodone by homogeneous enzyme immunoassay, which is not expected. “Oxycodone is not in Suboxone.”
The physician then ordered confirmation testing by mass spectrometry and requested help in interpreting the results.
The mass spectrometry results were positive for buprenorphine (>1000 ng/mL; cutoff, 2 ng/mL), norbuprenorphine (15 ng/mL; cutoff, 2 ng/mL), and naloxone (>1000 ng/mL; cutoff, 100 ng/mL).
“You have over 1,000 [ng/mL] buprenorphine, you have very little norbuprenorphine, which is a major metabolite of buprenorphine, and there’s a lot of naloxone,” Dr. El-Khoury said.
“Norbuprenorphine is almost always more than twofold buprenorphine. The fact that in this case we had way higher buprenorphine and barely any norbuprenorphine is indicative of the patient spiking the urine with the pill of Suboxone.” If they spike it, he said, “you get a very high buprenorphine and almost no norbuprenorphine because they didn’t metabolize it—it didn’t go through their system.”
Naloxone in this case is also indicative of adulteration because it is not supposed to be seen in urine at such high concentrations. In patients taking Suboxone orally, usually it’s less than 300 ng/mL, Dr. El-Khoury said, noting there are different mechanisms for Suboxone use. “In the common form, you don’t see it that high.” These results show “the sample had been adulterated.” And in this case, he said, this would have been missed if not for the cross-reactivity of the immunoassay with naloxone and the oxycodone result.
Dr. El-Khoury cites a study published late last year of simulated adherence in 3,950 long-term buprenorphine-naloxone treatment patients, in which the authors report “simulated adherence is a recurring phenomenon” even among long-term treatment seekers (Rahman N, et al. Subst Use Misuse. Published online Nov. 10, 2023. doi:10.1080/10826084.2023.2275559). This is the first longitudinal study to analyze patients’ simulated adherence practices over a period of 18 months, the authors write. They found half of the patients positive for simulated adherence had multiple occurrences.
They write: “Out of 3950 patients, 411 (10.4%) had a history of one or more simulated adherence. On average, patients with multiple simulated adherences had 48.1% of their tests simulated, while on the contrary, patients with a single occurrence of simulated adherence had 17.6% of their tests simulated.” A quantitative urine drug toxicology profile in frequent visits will help address this issue, they conclude.
Similarly, Dr. El-Khoury and his coauthor write in their patient’s case of adulterated urine: “[Q]uantitative definitive testing by mass spectrometry is essential in cases like this because the ratios of parents to metabolites can help distinguish compliance from adulteration.”
“Metabolite/parent ratios matter,” Dr. El-Khoury said. “It’s not just about seeing certain things or the compound. The concentrations matter, and you need to investigate those.”
For high-risk patients with a history of opioid use disorder and who have been prescribed buprenorphine or methadone, Dr. El-Khoury’s recommendation for those who can do it in-house: “Mass spec is preferred because you can miss sample spiking with immunoassays.”
Amy Carpenter is CAP TODAY senior editor.