title: Determining zolpidem compliance: urinary metabolite detection and prevalence in chronic pain patients.
abstract: Zolpidem (Ambien(®)) is the most prescribed insomnia treatment in the USA; however, little is known about zolpidem metabolite excretion in chronic pain patients. As zolpidem is extensively metabolized in vivo to zolpidem 4-phenyl carboxylic acid (ZCA), metabolite detection may provide improved accuracy for compliance determinations, thereby improving clinical decisions. Zolpidem and ZCA were extracted from 1 mL human urine by mixed-mode solid-phase extraction. Samples were analyzed by LC-MS-MS using positive electrospray ionization with multiple reaction monitoring mode employed for detection and quantification. Gradient chromatographic separation was achieved with a reversed-phase column in a rapid 1.8 min analysis. The assay was linear from 4 to 1,000 µg/L for zolpidem and 4 to 10,000 µg/L for ZCA. Interday recovery (bias) and imprecision (n = 20) were 100-107% of target and 2.4-3.7% relative standard deviation, respectively. Extraction efficiencies were 78-90%. Pain compliance samples (n = 3,142) were de-identified and analyzed for zolpidem and ZCA. Zolpidem was detected greater than limit of quantification in 720 specimens (22.9%), while ZCA was detected in 1,579 specimens (50.3%). Only five specimens contained zolpidem alone. ZCA was observed without parent zolpidem in 864 specimens, thereby increasing population detection rates by 27.5%. Addition of a zolpidem metabolite to compliance determinations substantially improved detection for zolpidem intake and also should prove useful in clinical and forensic settings.
authors.affiliation: Aegis Sciences Corporation, 515 Great Circle Road, Nashville, TN 37228, USA david.schwope@aegislabs.com.
authors.forename: David M
authors.initials: DM
authors.lastname: Schwope
authors.affiliation: Aegis Sciences Corporation, 515 Great Circle Road, Nashville, TN 37228, USA.
authors.forename: Anne
authors.initials: A
authors.lastname: DePriest
authors.affiliation: Aegis Sciences Corporation, 515 Great Circle Road, Nashville, TN 37228, USA Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, TN, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Black
authors.affiliation: School of Pharmacy, University of Maryland, Baltimore, MD, USA.
authors.forename: Yale H
authors.initials: YH
authors.lastname: Caplan
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Cone
authors.affiliation: Aegis Sciences Corporation, 515 Great Circle Road, Nashville, TN 37228, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Heltsley
mesh_terms: D002853:Chromatography, Liquid / Q000379:methods; D059350:Chronic Pain / Q000188:drug therapy* / Q000652:urine; D006801:Humans; D006993:Hypnotics and Sedatives / Q000652:urine*; D057230:Limit of Detection; D011725:Pyridines / Q000652:urine*; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D052616:Solid Phase Extraction; D053719:Tandem Mass Spectrometry / Q000379:methods; D000077334:Zolpidem
chemical_list: D006993:Hypnotics and Sedatives; D011725:Pyridines; D000077334:Zolpidem; C521325:zolpidem carboxylic acid