Joseph Rudolf (Presenter)
Massachusetts General Hospital
Bio: I am a first year fellow in clinical informatics in the department of pathology at the Massachusetts General Hospital in Boston MA. I am training to be a core laboratory director and informatician. My current work involves clinical decision support for our provider order entry system, laboratory test utilization review, and reflex algorithm development. I also participate in more traditional laboratory practices including method verification. I completed my medical degree at the University of Washington in Seattle WA in 2012 and finished my residency training in clinical pathology at the Massachusetts General Hospital in 2015.
Authorship: Joseph W. Rudolf, MD (1,2) James G. Flood, PhD (1,2)
(1) Massachusetts General Hospital (2) Harvard Medical School
Guidelines for workplace screening and confirmation of semi-synthetic opiates in oral fluid have been proposed by SAMHSA. We evaluate the proposed guidelines for oxycodone/oxymorphone and hydrocodone/hydromorphone using results from our institution’s toxicology service (5406 samples). The proposed confirmatory cutoff of 15 ng/ml identifies a majority of our positive cases for oxycodone and hydrocodone. Simulated immunoassay class cross-reactivity did not substantially increase the number of cases requiring confirmation (221 to 223 for oxycodone, 27 to 32 for hydrocodone). Lowering the confirmatory cutoff to 4 ng/ml does increase the number of positive cases (256 to 310 for oxycodone, 35 to 49 for hydrocodone).
Semi-synthetic opiate drug abuse continues to be a problem. Oral Fluid presents an improved sample matrix over urine as it is easy to collect and less prone to adulteration (1). The new SAMHSA guidelines propose specific cutoff levels for the screening and confirmation of semi-synthetic prescription opiates in oral fluid including oxycodone/oxymorphone and hydrocodone/hydromorphone, and specifies targets for parent drug/metabolite screening immunoassay cross-reactivity (2). Previous studies have shown that the parent/metabolite relationship is markedly different for opiates in oral fluid than urine – parent drug predominates in oral fluid while metabolites predominate in urine (1, 3-7). We evaluated the SAMHSA guidelines in relationship to our large clinical oral fluid data set.
The Massachusetts General Hospital toxicology service processes ~200 oral fluid specimens per month, predominantly for outpatient addiction medicine clinics. Oral fluid toxicology screening by LC-MS was introduced in March of 2013 due to concerns about sample adulteration and substitution in urine. Oral fluid is collected with the Orasure Intercept sample collection device (Orasure Technologies, Bethlehem, PA, USA) as recommended by the manufacturer with the addition of two 40 ml water rinses/ingestions ten minutes preceding sample collection. Samples are frozen at -20°C prior to analysis. Analytes are evaluated at a limit of detection (LOD) of 2.0 ng/ml using reversed-phase chromatography with tandem mass spectrometric detection, and reported in ng analyte per ml of neat oral fluid. Clinical results were extracted from the laboratory information system (Sunquest Information Systems, Tuscon, AZ, USA) and compared with the 2015 SAMHSA guidelines. This retrospective, observational analysis and data simulation was performed in Microsoft Access 2007 (Microsoft, Redmond, Washington, USA).
Our data set includes 5406 samples on 1156 unique patients (ages 14 - 82, median age 36, predominantly male 3352/5406) over a 29-month period following oral fluid LC-MS implementation at our institution. 346 samples exceeded the LOD for oxycodone (median 100.6 ng/ml) while 65 samples exceeded the LOD for hydrocodone (median 20.3 ng/ml). There were fewer samples containing oxymorphone (82) and hydromorphone (35), and these had lower median concentrations (3.7 ng/ml and 2.9 ng/ml, respectively). At the SAMHSA proposed confirmatory cutoff of 15 ng/ml, the following number of positive cases would be expected: oxycodone (256), oxymorphone (8), hydrocodone (35), hydromorphone (7). At a cutoff of 4 ng/ml, the following positive cases would be reported: oxycodone (310), oxymorphone (38), hydrocodone (49), hydromorphone (12). A simulation of 120% cross reactivity between parent/metabolite pairs (oxycodone-oxymorphone, hydrocodone-hydromorphone) for screening purposes, as recommended by the SAMSHA guidelines, yielded an additional 2 cases for oxycodone (223 vs 221) and an additional 5 cases for hydrocodone (32 vs 27) requiring confirmation at a combined cutoff of 30 ng/ml. In 6 of these 7 additional cases the screened metabolite (oxymorphone, hydromorphone) was found in higher concentration than the possible parent (oxycodone, hydrocodone).
The rates of semi-synthetic opiate abuse merit the inclusion these analytes in substance screening. The currently proposed SAMHSA confirmatory cutoff of 15 ng/ml identifies a majority of the positive cases at our institution. Evaluation of a simulated immunoassay antibody class cross-reactivity between parent and metabolite did not screen in substantially more cases. This is likely due to the very low concentration of metabolites found in oral fluid as compared with the parent drug, and confirms prior reports concerning the disposition of oxycodone and hydrocodone in oral fluid. Most of the additional cases that were screened in by our cross-reactivity simulation contained significant quantities of “metabolite”, suggesting the presumed metabolite may have instead been the primarily ingested substance (oxymorphone or hydromorphone). Given the lower rates of abuse of oxymorphone and hydromorphone in the addiction medicine setting, screening immunoassay crossreactivity is unlikely to identify significant numbers of additional cases in our setting for subsequent confirmatory testing. However, lowering the confirmatory assay cutoff does result in significant numbers of additional positive cases.
References & Acknowledgements:
1. Tuyay J, Coulter C, Rodrigues W, Moore C. Disposition of opioids in oral fluid: Importance of chromatography and mass spectral transitions in lc-ms/ms. Drug Testing and Analysis 2012;4:395-401.
2. Department of Health and Human Services. Mandatory guidelines for federal workplace drug testing programs; notice. Federal Register 2015;80;2854-28101.
3. Cone EJ, DePriest AZ, Heltsley R, Black DL, Mitchell JM, LoDico C, Flegel R. Prescription opioids. IV: Disposition of hydrocodone in oral fluid and blood following single-dose administration. Journal of Analytical Toxicology 2015;39:510-8.
4. Cone EJ, Heltsley R, Black DL, Mitchell JM, Lodico CP, Flegel RR. Prescription opioids. II. Metabolism and excretion patterns of hydrocodone in urine following controlled single-dose administration. Journal of Analytical Toxicology 2013;37:486-94.
5. Cone EJ, DePriest AZ, Heltsley R, Black DL, Mitchell JM, LoDico C, Flegel R. Prescription opioids. III. Disposition of oxycodone in oral fluid and blood following controlled single-dose administration. Journal of Analytical Toxicology 2015;39:192-202.
6. Cone EJ, Heltsley R, Black DL, Mitchell JM, Lodico CP, Flegel RR. Prescription opioids. I. Metabolism and excretion patterns of oxycodone in urine following controlled single dose administration. Journal of Analytical Toxicology 2013;37:255-64.
7. Cao JM, Ma JD, Morello CM, Atayee RS, Best BM. Observations on hydrocodone and its metabolites in oral fluid specimens of the pain population: Comparison with urine. Journal of Opioid Management 2014;10:177-86.
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