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Oral Fluid Testing for Codeine Improves Accuracy of Clinical Monitoring

February 14, 2017
Evaluating oral fluids rather than urine samples revealed that hydrocodone is an important metabolite of codeine, which may be useful in monitoring medication use by pain patients and for drug testing.

Interviews with Maria Guevara, PharmD, and
Michael Gabay, PharmD, JD

The presence of hydrocodone in oral fluids may be used to improve confirmation of the appropriate use of prescribed codeine from the presence of nonprescribed medications, according to new study findings.1 In oral fluid samples of patients who were prescribed codeine but not its metabolites, morphine or hydrocodone, the unexpected presence of hydrocodone was deemed to have important interpretive significance in the clinical setting.

“Understanding that hydrocodone and morphine may be found as metabolites for patients prescribed codeine helps improve interpretation of oral fluid testing that is used to monitor patients prescribed opioids,” Maria Guevara, PharmD, director of clinical affairs, education and training at Millennium Health told Practical Pain Management. “In a clinical context, it could mean that a clinician does not falsely accuse a patient of having taken a concomitant medication.”   

Michael Gabay, PharmD, JD, Director of the Drug Information Group at the University of Illinois at Chicago College of Pharmacy concurred with Dr. Guervara, speaking to Practical Pain Management that, “The findings from this oral fluid drug testing analysis provide clinicians another potential explanation for a positive hydrocodone test in their patients.”

Drug testing of oral fluids improves accuracy of codeine use.

Improved Process for Analyzing Oral Samples 

Researchers conducted a retrospective analysis of results from oral fluids that had been collected by health care providers, using a standardized collection device, and submitted to Millennium Health for routine drug testing. These patient samples were analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS).

By filtering the test results collected over an 18-month period, the database grew to a cohort of 868 oral fluid samples taken from patients who were prescribed codeine, but not morphine or hydrocodone. Of those, 380 (43.7%) samples were found to be positive for codeine, and 72 (8.2%) samples were negative for codeine and positive for one or more of its metabolites. The remaining 416 (47.9%) tested negative for codeine and its metabolites.

Among the positive codeine samples, 260 (68.4%) were also positive for hydrocodone. In contrast, only 61 (12.5%) of the 488 negative codeine samples contained hydrocodone. Moreover, in the codeine negative samples, the median concentration for hydrocodone positives was 3.3 times higher than that in the codeine positive samples.

The authors offered two possible explanations for the differences in these results: either the codeine negative/hydrocodone positive samples were taken from individuals who were ultra-rapid metabolizers of codeine, or the samples represented unreported hydrocodone use. Similar results were also found with morphine but of a lesser magnitude. Here, 70 (18.4%) of the 380 codeine-positive samples tested positive for morphine, and only 2.6% of the codeine-negative samples were positive for morphine.

The researchers also examined the number of positive samples at different cut-off levels. The strong correlation between hydrocodone positives and codeine positives was maintained even at the higher cutoff levels that are used in workplace testing.

Implications for Drug Testing

These findings may be useful in the monitoring of patients being treated for chronic pain conditions, as well as for workplace drug testing. Most testing is done on urine samples, but an oral fluid test appears to offer several advantages over urine testing. The collection of samples could be observed, thereby reducing the possibility of adulteration.

“We generally see a mix of both parent drug and metabolite in both urine and oral fluid samples, with a higher concentration of parent drug in oral fluid samples and a higher concentration of metabolites in urine samples,” said Dr. Guevara. In addition, unlike urine testing, there may be a close correspondence between the parent drug and its metabolites in the oral fluid. Because of drug metabolism, urine drug testing generally detects the metabolites of a drug and not the parent drug.

In this study, there was a strong correlation between codeine positives and hydrocodone positives, indicating a mix of parent drug and metabolite. For codeine-negative samples with hydrocodone metabolite, it is possible that ultra-metabolism (UM) at the CYP2D6 enzyme took place, said Dr. Guevara, “but this isn’t necessarily consistent with hydrocodone presence per se. It’s consistent with the negative finding of codeine. We can’t yet say for certain that UM was the mechanism for the presence of hydrocodone. The specific mechanism for conversion of codeine to hydrocodone is still unknown.” The presence of hydrocodone in samples testing negative for codeine would be consistent with the ultrarapid metabolism of codeine.

The study results indicate that hydrocodone is an important metabolite of codeine in oral fluids with interpretive significance.

Since numerous factors contribute to the findings of drug testing, test results should always be interpreted within the clinical context of the individual patient.2 In clinical practice, an unexpected test result may arise from factors other than unprescribed or illicit drug use and should first stimulate a conversation with the patient before any action is taken. 


Last updated on: February 16, 2017
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Educating Patients About Pain Medications

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