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.

Cyclodextrin-mediated micellar electrokinetic chromatography and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry for the enantiomer separation of racemorphan in human urine.

Micellar electrokinetic chromatography (MEKC) was successfully and conveniently applied to the chiral separation with the addition of cyclodextrins (CDs) as chiral selector to the running buffer. Chiral separation depended on the type of CD; in particular, beta-CD was effective for the chiral separation of racemorphan. We investigated the optimal conditions of type and concentration of CD as chiral selector for the routine enantiomeric separation of racemorphan with good reproducibility. The effects of other parameters such as buffer pH and detection wavelength were also investigated to obtain the optimum conditions for the enantiomeric separation of racemorphan. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry was used for confirmation of racemorphan. The optimal conditions for enantiomeric separation of the racemorphan were as follows: 50 mM borate buffer at pH 9.4 with 50 mM SDS, 10 mM beta-CD and 20% 1-propanol, 57 cm x 50 microns fused-silica capillary column, and UV detection at 192 nm. Based on the developed method, racemorphan in human urine was also separated and determined using solid-phase extraction and MEKC.

Chiral differentiation of the optical isomers of racemethorphan and racemorphan in urine by capillary zone electrophoresis.

A novel capillary zone electrophoretic method based on the use of propanol-modified beta-cyclodextrin buffers has been developed; it unambiguously detects and quantitates the optical isomers of racemethorphan and racemorphan without prior derivatization. Detection limits in urine down to 20 ppb have been obtained. The method uses a solid-phase extraction recovery of analytes followed by ultraviolet detection. Separation conditions include the use of 60mM beta-cyclodextrin and 50mM sodium dodecyl sulfate in a buffer containing 20% 1-propanol.

[Analysis of dextromethorphan and its metabolites in human urine by using gas chromatography-mass spectrometry].

A GC-MS method for the analysis of dextromethorphan and its metabolites is described. The urine sample was hydrolyzed with HCl, extracted with diethyl ether and derivatized with MSTFA (N-methyl-N-trimethylsilyltrifluoroacetamide)-MBTFA (N-methyl-bistrifluoroacetamide). Dextromethorphan and its 3 metabolites were detected in urine samples within 2-60 h after administration of the drug. Their structures and the variation of their concentration in urine were determined. The detection limit of dextromethorphan is 10 ng.

[Studies on the analysis of anileridine, levorphanol, nalbuphine and ethamivan in urine].

The method for the analysis of anileridine, levorphanol, nalbuphine and ethamivan in urine by means of GC/NPD and GC/MSD is described. TFAA and MSTFA-MBTFA have been used in this procedure for TFA and TMS derivatization. The parent forms and the metabolites of the four drugs can be found by GC/NPD screening and GC/MSD confirmation. The method is reliable, fast and sensitive.