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Identification of levorphanol ingestion using urine markers in chronic pain patients

Identifying Levorphanol Ingestion using Urine Markers in Chronic Pain Patients

Amber R. Watson1,2, Ali Roberts1,2, Rebecca Heltsley1, Timothy Robert1, David L. Black1,3

1 Aegis Sciences Corporation, Nashville, Tennessee

2 Belmont University College of Pharmacy, Nashville, Tennessee

3 Vanderbilt University Department of Pathology, Immunology, and Microbiology, Nashville, Tennessee

Background / Purpose:

Levorphanol is a long-acting opioid analgesic that binds mu, delta, and kappa opioid receptors in the brain; additionally, it decreases activity at the N-methyl-D-aspartate (NMDA) receptor and blocks uptake of serotonin and norepinephrine.1 It is a chemical isomer of dextrorphan, which is a metabolite of dextromethorphan.2,3 However, while dextromethorphan metabolizes to dextrorphan,3-methoxymorphinan, and (+)-3-hydroxymorphinan, levorphanol only metabolizes to norlevorphanol, or (-)-3-hydroxymorphinan. This study investigates urinary concentrations of levorphanol/dextrorphan and 3-hydroxymorphinan in chronic pain patients, and characterizes cases of potential levorphanol ingestion based on detection of relevant urinary markers.

Methodology:

Urine drug test results from chronic pain patients submitted to Aegis® Sciences between July 2014 and July 2015 were evaluated for the presence of levorphanol/dextrorphan and 3-hydroxymorphinan by liquid chromatography / tandem mass spectrometry (LC-MS/MS) above the limit of quantitation (LOQ) of 10 ng/mL (N = 279). An isomeric analysis was not performed; therefore, dextrorphan and levorphanol could not be differentiated. Results for patients with detectable concentrations of dextromethorphan or 3-methoxymorphinan were eliminated, as these are specific to dextromethorphan ingestion (N = 211).

Results:

Prescription Information

(per laboratory requisition form)

N

Mean Urinary Concentrations (ng/mL)[SEM (range)]

Levorphanol/Dextrorphan

3-hydroxymorphinan

Dextromethorphan

16

430.27

[213.14 (14.54-2663.01)]

358.65

[178.5 (27.71-2702.96)]

Levorphanol

4

5032.84

[2360.16 (1997.43-12070.9)]

514.5

[244.79 (173.96-1241.18)]

No Prescription Indicated

48

525.02

[124.48 (18.99-4789.87)]

306.71

[96.84 (19.56-4298.53)]

Total

68

767.89

[204.28 (14.54-12070.9)]

331.16

[80.75 (19.56-4298.53)]

The average parent to metabolite ratio for levorphanol/dextrorphan to 3-hydroxymorphinan for all patients was 2.56.

Conclusions:

To our knowledge, this is the first report identifying urinary concentrations of levorphanol/dextrorphan and 3-hydroxymorphinan in chronic pain patients. Mean concentrations of levorphanol and 3-hydroxymorphinan were elevated in patients prescribed levorphanol in comparison with those prescribed dextromethorphan; however, many patients prescribed dextromethorphan did not have any detectable urinary concentrations of dextromethorphan or 3-methyoxymorphinan at the time of urine collection. Therefore, it may be impossible to distinguish between levorphanol or dextromethorphan ingestion unless dextromethorphan or 3-methoxymorphinan are present or an isomeric analysis is performed.

References:

  1. 1. Gudin J, Fudin J, Nalamachu S. Levorphanol use: past, present, and future. Postgrad Med. 2015;early online:1-8.
  2. 2. Baselt RC. Disposition of toxic drugs and chemicals in man. 9th ed. Chemical Toxicology Institute, Foster City, CA. 2011.
  3. 3. Kikura-Hanajiri R, Kawamura M, Miyajima A, et al. Chiral analysis of dextromethorphan/levomethorphan and their metabolites in rat and human samples using LC/MS/MS. Anal Bioanal Chem. 2011;400:165-174.

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