Identifying Levorphanol Ingestion Using Urine Biomarkers in Health Care Patients.

Background: Levorphanol is a long-acting opioid analgesic that is an optical isomer of dextrorphan, a metabolite of the over-the-counter cough suppressant dextromethorphan. Providers prescribing levorphanol for pain management may need to assess compliance through urine drug testing, as this agent is subject to abuse. Therefore, it is important to differentiate between dextromethorphan and levorphanol ingestion.

Objectives: This article is the first to report urine concentrations of levorphanol/dextrorphan and 3-hydroxymorphinan in human urine and assesses the need for an enantiomeric analysis to distinguish between dextromethorphan and levorphanol ingestion.

Study Design: Retrospective data review.

Methods: Medication compliance test results were reviewed for 521 urine samples submitted to Aegis Sciences Corporation between July 2014 and July 2016. Samples were included in this analysis if dextromethorphan or levorphanol testing was requested by the ordering provider. Urine samples were hydrolyzed with beta-glucuronidase and analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). An enantiomeric analysis to distinguish levorphanol from dextrorphan and (-)-3-hydroxymorphinan (norlevorphanol) from (+)-3-hydroxymorphinan was not performed.

Results: Nineteen urine samples with levorphanol listed as prescribed had median levorphanol/dextrorphan and 3-hydroxymorphinan concentrations of 1,881 ng/mL and 141 ng/mL, respectively. One-quarter of the urine samples with dextromethorphan listed as prescribed did not have any detectable dextromethorphan or 3-methoxymorphinan.

Limitations: An enantiomeric analysis was not utilized with the LC-MS/MS testing method; therefore, levorphanol could not be differentiated from dextrorphan, and (-)-3-hydroxymorphinan could not be differentiated from (+)-3-hydroxymorphinan. The hepatic and renal function for these patients was unknown; however, both could impact the metabolism, distribution, and excretion of levorphanol biomarkers in urine. The dextromethorphan and/or levorphanol dose and timing of last ingestion was also not assessed.

Conclusions: It may be impossible to distinguish between levorphanol and dextromethorphan ingestion based on urine biomarkers, unless dextromethorphan or 3-methoxymorphinan is present or an enantiomeric analysis is performed. Therefore, the potential exists for patients prescribed levorphanol to ingest dextromethorphan and appear compliant with levorphanol therapy. This should prompt clinicians to consider the parameters of their laboratory's testing method when interpreting levorphanol drug test results.

Key Words: Levorphanol, dextrorphan, dextromethorphan, 3-hydroxymorphinan, urine testing, urine concentration, drug testing, medication compliance testing.