hydrocodone and dihydrocodeine

The Substance Abuse and Mental Health Services Administration (SAMHSA) is currently evaluating hydrocodone (HC) for inclusion in the Mandatory Guidelines for Federal Workplace Drug Testing Programs. This study evaluated the time course of HC, norhydrocodone (NHC), dihydrocodeine (DHC) and hydromorphone (HM) in paired oral fluid and whole blood specimens by liquid chromatography-tandem mass spectrometry (limit of quantitation = 1 ng/mL of oral fluid, 5 ng/mL of blood) over a 52-h period. A single dose of HC bitartrate, 20 mg, was administered to 12 subjects. Analyte prevalence was as follows: oral fluid, HC > NHC > DHC; and blood, HC > NHC. HM was not detected in any specimen. HC was frequently detected within 15 min in oral fluid and 30 min in blood. Mean oral fluid to blood (OF : BL) ratios and correlations were 3.2 for HC (r = 0.73) and 0.7 for NHC (r = 0.42). The period of detection for oral fluid exceeded blood at all evaluated thresholds. At a 1-ng/mL threshold for oral fluid, mean detection time was 30 h for HC and 18 h for NHC and DHC. This description of HC and metabolite disposition in oral fluid following single-dose administration provides valuable interpretive guidance of HC test results.

Topics: Analgesics, Opioid; Biotransformation; Chromatography, Liquid; Codeine; Healthy Volunteers; Humans; Hydrocodone; Hydromorphone; Limit of Detection; Predictive Value of Tests; Prescription Drugs; Reproducibility of Results; Saliva; Tandem Mass Spectrometry; Tissue Distribution

Hydrocodone (HC) is a highly misused prescription drugs in the USA. Interpretation of urine tests for HC is complicated by its metabolism to two metabolites, hydromorphone (HM) and dihydrocodeine (DHC), which are also available commercially and are misused. Currently, there is interest in including HC and HM in the federal workplace drug-testing programs. This study characterized the disposition of HC in human urine. Twelve healthy, drug-free, adults were administered a single, oral 20 mg immediate-release dose of HC in a controlled clinical setting. Urine specimens were collected at timed intervals for up to 52 h and analyzed by LC-MS-MS (limit of quantitation = 50 ng/mL) with and without enzymatic hydrolysis. All specimens were also analyzed for creatinine and specific gravity (SG). HC and norhydrocodone (NHC) appeared within 2 h followed by HM and DHC. Peak concentrations of HC and metabolites occurred at 3-9 h. Peak hydrolyzed concentrations were in the order: NHC > HC > HM > DHC. Only HM was excreted extensively as a conjugated metabolite. At a cutoff concentration of 50 ng/mL, detection times were ∼28 h for HC, 40 h for NHC, 26 h for HM and 16 h for DHC. Some specimens did not contain HC, but most contained NHC, thereby facilitating interpretation that HC was the administered drug. Creatinine and SG measures were highly correlated. Creatinine corrections of HC urinary data had variable effects of lowering or raising concentrations. These data suggest that drug-testing requirements for HC should include a hydrolysis step and a test for HM.

Topics: Administration, Oral; Adult; Analgesics, Opioid; Chromatography, Liquid; Codeine; Creatinine; Female; Humans; Hydrocodone; Hydrolysis; Hydromorphone; Limit of Detection; Male; Metabolic Clearance Rate; Prescription Drug Misuse; Substance Abuse Detection; Tandem Mass Spectrometry; Tissue Distribution; Young Adult

Opioids, both as prescription drugs and abuse substances, have been a hot topic and a focus of discussion in the media for the last few years. Although the literature published shows the occurrence of opioids and some of their metabolites in the aquatic environment, there are scarce data in the application of high resolution mass spectrometry (HRMS) for the analysis of these compounds in the environment. The use of HRMS allows increasing the number of opioids that can be studied as well as the detection of unknown opioids, their metabolites and potential transformation products. In this work, a retrospective analysis for the identification of opioids and their metabolites using a curated database was applied to surface water and wastewater samples taken in the state of Minnesota (U.S.) in 2009, which were previously analyzed by liquid chromatography/time-of-flight mass spectrometry (LC/TOF-MS) for antidepressants. The database comprised >200 opioids including natural opiates (e.g. morphine and codeine), their semi-synthetic derivatives (e.g. heroin, hydromorphone, hydrocodone, oxycodone, oxymorphone, meperidine and buprenorphine), fully synthetic opioids (e.g. fentanyl, methadone, tramadol, dextromethorphan and propoxyphene), as well as some of their metabolites (e.g. 6-monoacetylcodeine, dextrorphan, EDDP, normorphine and O-desmethyltramadol). Moreover, additional MS-MS experiments were performed to confirm their identification, as well as to recognize fragmentation patterns and diagnostic ions for several opioids. These data provide a better understanding of the historical occurrence of opioids and their metabolites in surface waters impacted by wastewater sources. The concentrations of individual opioids in surface water and wastewater effluent varied from 8.8 (EDDP) to 1640 (tramadol) ngL

Topics: Analgesics, Opioid; Chromatography, Liquid; Codeine; Data Analysis; Environmental Monitoring; Fentanyl; Heroin; Hydrocodone; Hydromorphone; Minnesota; Morphine; Morphine Derivatives; Oxycodone; Retrospective Studies; Substance Abuse Detection; Tandem Mass Spectrometry; Tramadol; Wastewater; Water Pollutants, Chemical

Postmortem changes can alter the concentration of drugs in the vascular compartment as compared with concentrations originally present at the time of death. Numerous drugs have been reported to increase due to postmortem redistribution (PMR). The potential for PMR of hydrocodone, a therapeutic opioid analgesic used to manage pain, is of particular interest due to its wide use. Hydrocodone concentrations in 39 peripheral blood, central blood, and liver specimens were compared. Dihydrocodeine (DHC), a commonly encountered hydrocodone metabolite, was present in 61% of the cases with an average concentration that was 29% of the hydrocodone value. Central blood to peripheral blood hydrocodone ratios were well correlated (R(2)=0.965) with an average (±S.D.) of 1.3 (±0.35) and a median of 1.2. The liver to peripheral blood (L/P) hydrocodone ratio was also well correlated (R(2)=0.915) with an average (±S.D.) of 3.4 (±1.7) L/kg and a median of 3.0 L/kg. This low L/P ratio suggests that hydrocodone is unlikely to undergo substantial PMR changes.

Topics: Analgesics, Opioid; Chromatography, Gas; Codeine; Forensic Toxicology; Humans; Hydrocodone; Liver; Postmortem Changes; Solid Phase Extraction; Tissue Distribution

High-resolution mass spectrometry (HRMS) is being applied in postmortem drug screening as an alternative to nominal mass spectrometry, and additional evaluation in quantitative casework is needed. We report quantitative analysis of benzoylecgonine, citalopram, cocaethylene, cocaine, codeine, dextromethorphan, dihydrocodeine, diphenhydramine, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine, hydrocodone, hydromorphone, meperidine, methadone, morphine, oxycodone and oxymorphone in postmortem blood by ultra-performance liquid chromatography (UPLC)-MS(E)/time-of-flight (TOF). The method employs analyte-matched deuterated internal standardization and MS(E) acquisition of precursor and product ions at low (6 eV) and ramped (10-40 eV) collision energies, respectively. Quantification was performed using precursor ion data obtained with a mass extraction window of ± 5 ppm. Fragment and residual precursor ion acquisitions at ramped collision energies were evaluated as additional analyte identifiers. Extraction recovery of >60% and matrix effect of <20% were determined for all analytes and internal standards. Defined limits of detection (10 ng/mL) and quantification (25 ng/mL) were validated along with a linearity analytical range of 25-3,000 ng/mL (R(2) > 0.99) for all analytes. Parallel UPLC-MS(E)/TOF and UPLC-MS/MS analysis showed comparable precision and bias along with concordance of 253 positive (y = 1.002x + 1.523; R(2) = 0.993) and 2,269 negative analyte findings in 159 postmortem cases. Analytical performance and correlation studies demonstrate accurate quantification by UPLC-MS(E)/TOF and extended application of HRMS in postmortem casework.

Topics: Blood Chemical Analysis; Chromatography, High Pressure Liquid; Chromatography, Liquid; Citalopram; Cocaine; Codeine; Dextromethorphan; Diphenhydramine; Evaluation Studies as Topic; Forensic Pathology; Humans; Hydrocodone; Hydromorphone; Meperidine; Methadone; Morphine; Oxycodone; Oxymorphone; Pyrrolidines; Quality Control; Reproducibility of Results; Tandem Mass Spectrometry

Opioids are frequently encountered in Forensic Toxicology casework. A PubMed literature search was conducted to find a method using electron impact-gas chromatography-mass spectrometry to examine whole blood specimens. A previously published method was identified, and an updated version was provided by the State of North Carolina Office of the Chief Medical Examiner. This procedure was used as a starting point for development and validation of a refined procedure to be used in the Palm Beach County Sheriff's Office Forensic Toxicology laboratory for routine analysis of antemortem forensic toxicology case samples. Materials and instrumentation common to most forensic toxicology laboratories were utilized while obtaining detection limits from 1 to 10 ng/mL and quantitation limits of 2.5 to 10 ng/mL using 1 mL of whole blood. Target compounds were chosen based on applicability to the method as well as availability and common use in the United States and include dihydrocodeine, codeine, morphine, hydrocodone, 6-monoacetylmorphine, hydromorphone, oxycodone, and oxymorphone. Each analyte demonstrated two zero-order linear ranges (r(2) > 0.990) over the concentrations evaluated (from 2.5 to 500 ng/mL). The coefficient of variation of replicate analyses was less than 12%. Quantitative accuracy was within ± 27% at 2.5 ng/mL, ± 11% at 10 ng/mL, and ± 8% at 50 ng/mL. The validated method provides a more sensitive procedure for the quantitation of common opioids in blood using standard laboratory equipment and a small amount of sample.

Topics: Analgesics, Opioid; Codeine; Forensic Toxicology; Gas Chromatography-Mass Spectrometry; Humans; Hydrocodone; Hydromorphone; Morphine; Morphine Derivatives; Oxycodone; Oxymorphone; Substance Abuse Detection

Urine drug testing of pain patients provides objective information to health specialists regarding patient compliance, diversion, and concurrent illicit drug use. Interpretation of urine test results for semi-synthetic opiates can be difficult because of complex biotransformations of parent drug to metabolites that are also available commercially and may be abused. Normetabolites such as norcodeine, norhydrocodone and noroxycodone are unique metabolites that are not available commercially. Consequently, detection of normetabolite in specimens not containing parent drug, provides conclusive evidence that the parent drug was consumed. The goal of this study was to evaluate the prevalence and patterns of the three normetabolites, norcodeine, norhydrocodone and noroxycodone, in urine specimens of pain patients treated with opiates. Urine specimens were hydrolyzed with beta-glucuronidase and analyzed by a validated liquid chromatography tandem mass spectrometry (LC/MS/MS) assay for the presence of codeine, norcodeine, morphine, hydrocodone, norhydrocodone, hydromorphone, dihydrocodeine, oxycodone, noroxycodone, and oxymorphone. The limit of quantitation (LOQ) for these analytes was 50ng/mL. The study was approved by an Institutional Review Board. Of the total specimens (N=2654) tested, 71.4% (N=1895) were positive (>or=LOQ) for one or more of the analytes. The prevalence (%) of positive results for codeine, hydrocodone and oxycodone was 1.2%, 26.1%, and 36.2%, respectively, and the prevalence of norcodeine, norhydrocodone and noroxycodone was 0.5%, 22.1%, and 31.3%, respectively. For specimens containing normetabolite, the prevalence of norcodeine, norhydrocodone and noroxycodone in the absence of parent drug was 8.6%, 7.8% and 9.4%, respectively. From one-third to two-thirds of these specimens also did not contain other metabolites that could have originated from the parent drug. Consequently, the authors conclude that inclusion of norcodeine, norhydrocodone and noroxycodone is useful in interpretation of opiate drug source and reduces potential false negatives that would occur without tests for these unique metabolites.

Topics: Analgesics, Opioid; Chromatography, Liquid; Codeine; False Negative Reactions; Forensic Toxicology; Humans; Hydrocodone; Medication Adherence; Morphinans; Oxycodone; Oxymorphone; Pain; Tandem Mass Spectrometry

Hydrocodone (HC) has received renewed interest in the US due to reported increases in opiate related deaths involving psychotherapeutic drugs. The relative contribution of dihydrocodeine (DHC) in these deaths is unknown since little testing of this compound is performed. The objective of the study was to determine the prevalence of DHC in HC positive decedents and report the range of concentrations detected in these cases in order to evaluate the potential role of DHC in the deaths and determine the usefulness of including this analyte in opioid testing protocols. Specimens were assayed by liquid-liquid or solid phase extraction followed by gas chromatography/mass spectrometry operated in the selected ion monitoring mode. A multipoint calibration was utilized in the linear range 2-600ng/mL. Accuracy for HC, DHC and hydromorphone (HM) was 101-106% and between day precision at 160ng/mL between 7% and 11%. One hundred and thirty six cases were identified with the majority male (62%) and white (83%). A search of HC positive cases identified 64 with DHC (47%). The range of HC concentrations was 9-3039ng/mL heart blood (n=43) and 42-12353ng/mL urine (n=21). DHC concentrations in these cases ranged 3-243ng/mL in heart blood and 5-1842ng/mL in urine. DHC/HC ratios ranged 0.00(7)-2.90 in blood (n=43), and 0.01-5.04 in urine (n=21) with 16% and 24% of these cases with ratios >0.50, respectively. HM was detected in only 9 HC cases with the majority positive in urine.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Analgesics, Opioid; Codeine; Female; Forensic Toxicology; Gas Chromatography-Mass Spectrometry; Humans; Hydrocodone; Hydromorphone; Male; Middle Aged; Postmortem Changes; Prevalence; Substance Abuse Detection; Young Adult

Opiates are commonly abused substances, and forensic urine drug-testing for them requires gas chromatographic-mass spectrometric (GC-MS) confirmation. There are also medical reasons to test urine for opiates, and confirmation procedures other than GC-MS are often used for medical drug-testing. A thin-layer chromatographic (TLC) method distinguishes morphine, acetylmorphine, hydromorphone, oxymorphone, codeine, dihydrocodeine, hydrocodone, and oxycodone in clinical specimens. In certain clinical circumstances, GC-MS confirmation is requested for opiates identified by TLC, but, to our knowledge, no previous report examines all of the above opiates in a single GC-MS procedure. We find that they can be distinguished by GC-MS analyses of trimethylsilyl (TMS) ether derivatives, and identities of 6-keto opiates can be further confirmed by GC-MS analysis of methoxime (MO)-TMS derivatives. Inclusion of deuterium-labeled internal standards permits identification of the opiates in urine at concentrations below the TLC cutoff level of 600 ng/ml, and the GC-MS assay is linear over a concentration range that spans that level. This GC-MS procedure has proved useful as a third-stage identification step in a medical drug-testing sequence involving prior immunoassay and TLC.

Topics: Codeine; Gas Chromatography-Mass Spectrometry; Humans; Hydrocodone; Hydromorphone; Molecular Structure; Morphine; Morphine Derivatives; Narcotics; Oxycodone; Oxymorphone

A fatal opiates overdose, where ethylmorphine, hydrocodone, dihydrocodeine and codeine were consumed concomitantly, is reported. This case report may contribute to data on fatal blood concentrations of drugs with rare incidence. The relative retention times in capillary gas chromatography and full mass spectra of various opiates in their silylated forms, detected together in one sample, may serve as a helpful analytical reference for clinical and forensic toxicologists.

Topics: Adult; Codeine; Drug Overdose; Ethylmorphine; Fatal Outcome; Gas Chromatography-Mass Spectrometry; Humans; Hydrocodone; Male; Opioid-Related Disorders; Toxicology

The method for the analysis of hydrocodone and its metabolite in urine by GC/MSD is reported. The urine was hydrolysed with HCl and extracted with diethyl ether/isopropanol. The gas chromatography/mass spectrometric properties of trimethylsilyl ether of hydrocodone, first reacted with methoxyamine to protect the carbonyl group, were studied. This method is sensitive and rapid for the determination of hydrocodone, codeine and dihydrocodeine.

Topics: Analgesics, Opioid; Antitussive Agents; Codeine; Gas Chromatography-Mass Spectrometry; Humans; Hydrocodone

Topics: Alkaloids; Aluminum Oxide; Chromatography; Codeine; Hydrocodone; Hydromorphone