Clinical Variation in the Treatment Practices for Medication Nonadherence, Drug-Drug Interactions, and Recognition of Disease Progression in Patients with Chronic Cardiometabolic Diseases: A Cross-Sectional Patient Simulation Study among Primary Care Physicians.

Background: Medication nonadherence in patients with chronic diseases is common, costly, and often underdiagnosed. In the United States, approximately 40-50% of patients with cardiometabolic conditions are not adherent to long-term medications. Drug-drug interactions (DDI) are also underrecognized and may lead to medication nonadherence in this patient population. Treatment complexity associated with cardiometabolic conditions contributes to increased risk for adverse drug events and DDIs. Methods: We recruited a nationally representative sample of 246 board-certified family and internal medicine physicians to evaluate how they assessed, identified, and treated medication nonadherence, DDIs, and worsening disease. Participating physicians were asked to care for three online simulated patients, each with at least one chronic cardiometabolic disease, including atrial fibrillation, heart failure, diabetes mellitus, or hypertension, and who were taking prescription medications for their disease. Physicians' scores were based on evidence-based care recommendation criteria, including overall care quality and treatment for medication nonadherence and DDIs. Results: Overall, quality-of-care scores across all cases ranged from 13% to 87% with an average of 50.8% ± 12.1%. The average overall diagnostic plus treatment score was 21.9% ± 13.6%. Participants identified nonadherence in just 3.6% of cases, DDIs in 8.9% of cases, and disease progression in 30.3% of cases. Conclusions: Based on these study results, primary care physicians were unable to adequately diagnose and treat patients with chronic cardiometabolic diseases who either suffered from medication nonadherence, DDIs, or progression of the disease. Improved standardization and technique in identifying these diagnoses is needed in primary care. Trial Registration. This trial is registered with clinicaltrials.gov, NCT05192590.

Population Pharmacokinetics of Fentanyl in the Critically Ill.

OBJECTIVE: To characterize fentanyl population pharmacokinetics in patients with critical illness and identify patient characteristics associated with altered fentanyl concentrations. DESIGN: Prospective cohort study. SETTING: Medical and surgical ICUs in a large tertiary care hospital in the United States. PATIENTS: Patients with acute respiratory failure and/or shock who received fentanyl during the first 5 days of their ICU stay. MEASUREMENTS AND MAIN RESULTS: We collected clinical and hourly drug administration data and measured fentanyl concentrations in plasma collected once daily for up to 5 days after enrollment. Among 337 patients, the mean duration of infusion was 58 hours at a median rate of 100 µg/hr. Using a nonlinear mixed-effects model implemented by NONMEM, we found that fentanyl pharmacokinetics were best described by a two-compartment model in which weight, severe liver disease, and congestive heart failure most affected fentanyl concentrations. For a patient population with a mean weight of 92 kg and no history of severe liver disease or congestive heart failure, the final model, which performed well in repeated 10-fold cross-validation, estimated total clearance, intercompartmental clearance (Q), and volumes of distribution for the central (V1) and peripheral compartments (V2) to be 35 L/hr (95% CI, 32-39 L/hr), 55 L/hr (95% CI, 42-68 L/hr), 203 L (95% CI, 140-266 L), and 523 L (95% CI, 428-618 L), respectively. Severity of illness was marginally associated with fentanyl pharmacokinetics but did not improve the model fit after liver and heart diseases were included. CONCLUSIONS: In this study, fentanyl pharmacokinetics during critical illness were strongly influenced by severe liver disease, congestive heart failure, and weight, factors that should be considered when dosing fentanyl in the ICU. Future studies are needed to determine if data-driven fentanyl dosing algorithms can improve outcomes for ICU patients.

Mechanism of error caused by isotope-labeled internal standard: accurate method for simultaneous measurement of vitamin D and pre-vitamin D by liquid chromatography/tandem mass spectrometry.

RATIONALE: Bias of up to 25% has been observed for vitamin D3 and D2 samples exposed to heating during sample preparation, even when isotope-labeled internal standards are used. The goals of this study were to identify the mechanism of the positive bias observed in measuring vitamin D3 and D2 by liquid chromatography/tandem mass spectrometry (LC/MS/MS) and determine a way to eliminate the error source. METHODS: Several internal standards with varying locations of labeling were used for comparison in this study. Additionally, different temperatures (25, 37, 55, and 75 °C) and different treatment times were investigated for sample preparation and a LC/MS/MS method capable of simultaneously measuring vitamin D and pre-vitamin D was developed. RESULTS: It was demonstrated that the different conversion behaviors of the analyte and the internal standard were the cause of the positive bias. This bias was eliminated when internal standards with labeling remote from the double-bond area of the molecules were used. Additionally, sample preparation was shortened from overnight saponification at room temperature to 0.5 h at 75 °C. CONCLUSIONS: The use of an internal standard with labeling remote from the conjugated area eliminated the error source and gave accurate correction at all of the temperatures investigated. Heating may be used for rapid sample preparation as an alternative to overnight saponification at room temperature. This work not only describes the mechanism of an inaccurate internal standard correction, but also establishes a rapid LC/MS/MS method for simultaneous measurement of vitamin D and pre-vitamin D.

Chronic methamphetamine exposure produces a delayed, long-lasting memory deficit.

Methamphetamine (METH) is a highly addictive and neurotoxic psychostimulant. Its use in humans is often associated with neurocognitive impairment. Whether this is due to long-term deficits in short-term memory and/or hippocampal plasticity remains unclear. Recently, we reported that METH increases baseline synaptic transmission and reduces LTP in an ex vivo preparation of the hippocampal CA1 region from young mice. In the current study, we tested the hypothesis that a repeated neurotoxic regimen of METH exposure in adolescent mice decreases hippocampal synaptic plasticity and produces a deficit in short-term memory. Contrary to our prediction, there was no change in the hippocampal plasticity or short-term memory when measured after 14 days of METH exposure. However, we found that at 7, 14, and 21 days of drug abstinence, METH-exposed mice exhibited a deficit in spatial memory, which was accompanied by a decrease in hippocampal plasticity. Our results support the interpretation that the deleterious cognitive consequences of neurotoxic levels of METH exposure may manifest and persist after drug abstinence. Therefore, therapeutic strategies should consider short-term as well as long-term consequences of methamphetamine exposure.

Milk and serum standard reference materials for monitoring organic contaminants in human samples.

Four new Standard Reference Materials (SRMs) have been developed to assist in the quality assurance of chemical contaminant measurements required for human biomonitoring studies, SRM 1953 Organic Contaminants in Non-Fortified Human Milk, SRM 1954 Organic Contaminants in Fortified Human Milk, SRM 1957 Organic Contaminants in Non-Fortified Human Serum, and SRM 1958 Organic Contaminants in Fortified Human Serum. These materials were developed as part of a collaboration between the National Institute of Standards and Technology (NIST) and the Centers for Disease Control and Prevention (CDC) with both agencies contributing data used in the certification of mass fraction values for a wide range of organic contaminants including polychlorinated biphenyl (PCB) congeners, chlorinated pesticides, polybrominated diphenyl ether (PBDE) congeners, and polychlorinated dibenzo-p-dioxin (PCDD) and dibenzofuran (PCDF) congeners. The certified mass fractions of the organic contaminants in unfortified samples, SRM 1953 and SRM 1957, ranged from 12 ng/kg to 2200 ng/kg with the exception of 4,4'-DDE in SRM 1953 at 7400 ng/kg with expanded uncertainties generally <14 %. This agreement suggests that there were no significant biases existing among the multiple methods used for analysis.

Widespread Distribution of Xylazine Detected Throughout the United States in Healthcare Patient Samples.

OBJECTIVES: Xylazine is a tranquilizer commonly added into the illicit drug supply and a likely contributor to overdoses because it does not respond to naloxone reversal. The objective of this study was to perform a retrospective data analysis on xylazine-positive samples collected from patients in various outpatient healthcare settings to illustrate geographic distribution and common copositive substances, which may also contribute to risk of adverse events. METHODS: Samples for which providers ordered testing for xylazine were subjected to enzymatic hydrolysis, extracted, and analyzed using liquid chromatography-tandem mass spectrometry. Retrospective analysis was performed on xylazine-positive samples collected from April 2021 to March 2022, to include geographic location and copositive substances. RESULTS: Xylazine was identified in 413 of 59,498 samples from adults aged 20-73 years and originated from 25 of the 39 states where xylazine testing was ordered. The most common routine substances detected with xylazine were fentanyl, buprenorphine, naloxone, cocaine, d -methamphetamine, and delta-9-tetrahydrocannabinol. The most common designer drugs detected included fentanyl analogs, isotonitazene, and designer benzodiazepines. CONCLUSIONS: Xylazine is geographically spread throughout the United States, indicative of a wide incorporation into the illicit drug supply. These findings differ from previous studies in that these samples originated from healthcare providers in routine care settings, where other reports typically involve overdose deaths. This analysis illustrates that routine testing for xylazine in outpatient settings can afford providers the opportunity to educate individuals and adjust harm reduction measures to potentially mitigate overdose risk.

Randomized prospective trial to detect and distinguish between medication nonadherence, drug-drug interactions, and disease progression in chronic cardiometabolic disease.

BACKGROUND: Disentangling nonadherence (NA), drug-drug interactions (DDIs), and disease progression from each other is an important clinical challenge for providers caring for patients with cardiometabolic diseases. NAs and DDIs are both ubiquitous and often overlooked. We studied a novel chronic disease management (CDM) test to detect medication adherence and the presence and severity of DDIs. MATERIALS AND METHODS: We conducted a prospective, randomized controlled trial of 236 primary care physicians using computer-based, simulated patients, measuring clinical care with and without access to the CDM test. The primary outcomes were whether use of the CDM test increased the accuracy of diagnoses and ordering better treatments and how effective the intervention materials were in getting participants to order the CDM test. RESULTS: Physicians given the CDM test results showed a + 13.2% improvement in their diagnosis and treatment quality-of-care scores (p < 0.001) in the NA patient cases and a + 13.6% improvement in the DDI cases (p < 0.001). The difference-in-difference calculations between the intervention and control groups were + 10.4% for NA and + 10.8% for DDI (p < 0.01 for both). After controlling for physician and practice co-factors, intervention, compared to control, was 50.4x more likely to recognize medication NA and 3.3x more likely to correctly treat it. Intervention was 26.9x more likely to identify the DDI and 15.7x more likely to stop/switch the interacting medication compared to control. We found no significant improvements for the disease progression patient cases. CONCLUSION: Distinguishing between nonadherence, drug-drug interactions, and disease progression is greatly improved using a reliable test, like the CDM test; improved diagnostic accuracy and treatment has the potential to improve patient quality of life, medication safety, clinical outcomes, and efficiency of health delivery. TRIAL REGISTRATION: clinicaltrials.gov (NCT05192590).

Analysis of fentanyl pharmacokinetics, and its sedative effects and tolerance in critically ill children.

INTRODUCTION: Fentanyl pharmacokinetic and pharmacodynamic data are limited in mechanically ventilated children. This study aimed to assess the fentanyl pharmacokinetics (PK), the sedation outcome, and the development of tolerance in children receiving fentanyl continuous infusion. METHODS: This study included children admitted to the pediatric or cardiovascular intensive care unit between January 1 and October 31, 2016, who were >30 days to <18 years of age, receiving ventilatory support via endotracheal tube or tracheostomy, and receiving a fentanyl infusion. Population PK analysis was performed using a nonlinear mixed-effects model. The relationship between initial sedation outcome using State Behavioral Scale (SBS) and fentanyl exposure was assessed, and the observations consistent with tolerance were described. RESULTS: Seventeen children, with a median age of 0.83 years (range: 0.1-12) and weight of 8.7 kg (range: 3.4-52), were included. The fentanyl PK was adequately described by a weight-based allometry model with the power of 0.75 for clearance (CL=89.8 L/hr/70 kg) and distributional CL, and 1 for volumes of distribution. In infants <6.6 months, age was an additional factor for CL (31.4 L/h/70 kg) to account for age-related maturation. Seven of twelve nonparalyzed patients achieved goal sedation, defined as >80% of SBS scores ≤0 per 24 h, on the first day of fentanyl infusion with a median plasma concentration of 1.29 ng/ml (interquartile range: 0.78-2.05). Eight of the nine tolerant patients developed tolerance within a day of reaching goal sedation. CONCLUSION: Different weight-based fentanyl dosing rates may be required for infants and children of different ages to achieve similar plasma concentrations. Using SBS scores may guide the dosing titration of fentanyl that resulted in plasma concentrations within the therapeutic range of 1-3 ng/ml. For those who developed tolerance to fentanyl and/or a sedative, it was noted one day after goal sedation was achieved.

Randomized Trial to Improve Primary Care Patient Management and Patient Outcomes Using a Drug-Drug Interaction Test: Confirmation of the DECART Simulated Patient Clinical Utility Trial Results.

Drug-drug interactions (DDIs) are a serious problem in the healthcare system, leading to excess healthcare utilization and costs. We conducted a second prospective randomized, controlled trial to further establish the real-world clinical utility of a novel assay that objectively identifies potentially serious DDIs in real-world patients. Re-recruiting primary care physicians (PCPs) from our first randomized, controlled, simulated-patients study on DDIs, we experimentally introduced a definitive, urine-based mass spectrometry test intervention that the physicians could use when caring for their eligible patients. Patients were eligible if taking four or more prescription medications or suspected of taking other non-prescribed substances with potential medication interactions. The primary outcome was whether DDI testing changed clinical care. We explored a secondary outcome to see if the change in practice improved symptoms in patients with potential DDIs. A total of 169 control and 162 intervention patients were enrolled in the study, and their medical records were abstracted. In real-world patients, intervention physicians identified and/or treated a DDI at 3.0x the rate in their patient population compared to controls (21.6% vs. 7.1%, p < 0.001). Intervention physicians were more likely to discontinue or adjust the interacting agent compared to controls (62.9% vs. 8.3%, p = 0.001), and patient-reported symptoms also significantly declined (29.6% vs. 20.1%, p = 0.045). These results were nearly identical to concurrent measurements that used simulated patients, wherein intervention was more likely to both make a DDI diagnosis (56.3% vs. 21.6%, p < 0.001) and stop the interacting medications (58.3% versus 26.6%, p < 0.001). Bringing a new diagnostic test to market, particularly for an under-recognized clinical problem, requires robust data on both clinical validity and clinical utility. The results of this follow-up study showed that the use of DDI testing in real-world patients significantly improved (1) primary care patient management of drug interactions and (2) patient outcomes.

Presence of Parent Cocaine in the Absence of Benzoylecgonine in Urine.

Cocaine (COC) is widely abused and associated with significant adverse effects. Forensic and clinical laboratories often test for COC intake through detection of the primary metabolite, benzoylecgonine (BZE) in urine. Testing for BZE alone may result in false-negative determinations in situations where COC is recently administered or metabolism is impaired. To our knowledge, no data have been provided demonstrating the utility of adding parent COC to urine confirmation testing in routine analyses. For this study, random urine specimens from patients undergoing treatment for pain management and/or addiction were collected over six months from 800 clinics across 39 states. A total of 7,587 urine specimens tested positive for a COC marker (COC and/or BZE). A positive result was determined using a liquid chromatography-tandem mass spectrometry (LC-MS-MS) method with a limit of quantitation of 50 ng/mL. Of the positive specimens, 26% and 97% were positive for COC and BZE, respectively. Positive BZE-only specimens represented 74% of total positive specimens. However, 231 of the 7,587 urine specimens (3% of positive specimens) were positive for COC in the absence of BZE. The 231 COC-only positive specimens were collected from 206 patients, and two of these patients provided four COC-only positive specimens. Of a select group of COC-only specimens tested by both LC-MS-MS and immunoassay (IA) (N = 32), 81% were negative by IA, demonstrating the limitation of screening with BZE-specific IAs. A false-negative COC result can have profound impacts such as a delay in patient referral to addiction treatment, unintentional prescribing of a controlled substance to a patient actively abusing an illicit substance, or undetected cocaine use in the workplace. This study highlights the importance of testing for COC in addition to BZE in forensic and healthcare settings.

Prescription Opioids. VI. Metabolism and Excretion of Hydromorphone in Urine Following Controlled Single-Dose Administration.

Hydromorphone (HM), a prescription opioid and metabolite of morphine and hydrocodone, has been included in proposed revisions to the Mandatory Guidelines for Federal Workplace Drug Testing Programs. This study characterized the time course of HM in hydrolyzed and non-hydrolyzed urine specimens. Twelve healthy subjects were administered a single 8 mg controlled-release HM dose, followed by periodic collection of pooled urine specimens for 54 h following administration. Analysis of total and free HM was conducted by liquid chromatography tandem mass spectrometry at a 50 ng/mL limit of quantitation. Detection periods were determined over a range of thresholds from 50 to 2,000 ng/mL. HM was detected in 85.3% and 47.6% of hydrolyzed and non-hydrolyzed post-dose specimens, respectively. Initial detection of total HM was frequently observed in the first 4-6 h following dosing. The period of detection at the 50 ng/mL threshold averaged 52.3 h for total HM and 38.0 h for free HM. These data support that HM detection is optimized by using low thresholds (50-100 ng/mL) and including conjugated HM in the analysis.

Prescription Opioids. V. Metabolism and Excretion of Oxymorphone in Urine Following Controlled Single Dose Administration.

Oxymorphone (OM), a prescription opioid and metabolite of oxycodone, was included in the recently published proposed revisions to the Mandatory Guidelines for Federal Workplace Drug Testing Programs. To facilitate toxicological interpretation, this study characterized the time course of OM and its metabolite, noroxymorphone (NOM), in hydrolyzed and non-hydrolyzed urine specimens. Twelve healthy subjects were administered a single 10 mg controlled-release OM dose, followed by a periodic collection of pooled urine specimens for 54 h following administration. Analysis for free and total OM and NOM was conducted by liquid chromatography tandem mass spectrometry (LC-MS-MS), at a 50 ng/mL limit of quantitation (LOQ). Following enzymatic hydrolysis, OM and NOM were detected in 89.9% and 13.5% specimens, respectively. Without hydrolysis, OM was detected in 8.1% specimens, and NOM was not detected. The mean ratio of hydrolyzed OM to NOM was 41.6. OM was frequently detected in the first pooled collection 0-2 h post-dose, appearing at a mean of 2.4 h. NOM appeared at a mean of 8.3 h. The period of detection at the 50 ng/mL threshold averaged 50.7 h for OM and 11.0 h for NOM. These data support that OM analysis conducted using a 50 ng/mL threshold should include hydrolysis or optimize sensitivity for conjugated OM.

Prescription opioids. III. Disposition of oxycodone in oral fluid and blood following controlled single-dose administration.

Oxycodone (OC) is recommended to be included as an analyte tested in the proposed Substance Abuse and Mental Health Services Administration (SAMHSA's) Mandatory Guidelines for Federal Workplace Drug Testing Programs using Oral Fluid (OF) Specimens. This study demonstrates the time course of OC and metabolites, noroxycodone (NOC), oxymorphone (OM) and noroxymorphone (NOM), in near-simultaneous paired OF and whole blood (BL) specimens by liquid chromatography-tandem mass spectrometry (LC-MS-MS) (limit of detection = 1 ng/mL OF, 5 ng/mL BL). A single dose of OC 20 mg controlled-release was administered to 12 healthy subjects followed by specimen collections for 52 h. Analyte prevalence was as follows: OF, OC > NOC > OM; and BL, OC > NOC > NOM. OC and NOC were frequently detected within 15-30 min in OF and 30 min to 2 h in BL. NOM and OM appeared between 1.5-5 h post-dose. The mean OF-to-BL (OF:BL) ratios and correlations were 5.4 for OC (r = 0.719) and 1.0 for NOC (r = 0.651). The period of detection for OF exceeded BL by ∼2-fold at similar cutoff concentrations. At a 1 ng/mL cutoff for OF, the mean detection time was 34 h for OC and NOC. These data provide new information that should facilitate interpretation of OC test results.

Prescription Opioids. IV: Disposition of Hydrocodone in Oral Fluid and Blood Following Single-Dose Administration.

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.

Determining zolpidem compliance: urinary metabolite detection and prevalence in chronic pain patients.

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.

Prevalence of heroin markers in urine for pain management patients.

Surveys of current trends indicate heroin abuse is associated with nonmedical use of pain relievers. Consequently, there is an interest in evaluating the presence of heroin-specific markers in chronic pain patients who are prescribed controlled substances. A total of 926,084 urine specimens from chronic pain patients were tested for heroin/diacetylmorphine (DAM), 6-acetylmorphine (6AM), 6-acetylcodeine (6AC), codeine (COD), and morphine (MOR). Heroin and markers were analyzed using liquid chromatography tandem mass spectrometry (LC-MS-MS). Opiates were analyzed following hydrolysis using LC-MS-MS. The prevalence of heroin use was 0.31%, as 2871 were positive for one or more heroin-specific markers including DAM, 6AM, or 6AC (a known contaminant of illicit heroin). Of these, 1884 were additionally tested for the following markers of illicit drug use: 3,4-methylenedioxymethamphetamine (MDMA), 3,4-methylenedioxyamphetamine (MDA), methamphetamine (MAMP), 11-nor-9-carboxy-Δ(9)-tetracannabinol (THCCOOH), and benzoylecgonine (BZE); 654 (34.7%) had positive findings for one or more of these analytes. The overall prevalence of heroin markers were as follows: DAM 1203 (41.9%), 6AM 2570 (89.5%), 6AC 1082 (37.7%). MOR was present in 2194 (76.4%) and absent (

Urine drug testing of chronic pain patients. V. Prevalence of propoxyphene following its withdrawal from the United States market.

Propoxyphene is an opioid analgesic that was surrounded by controversy concerning its safety and efficacy during its lifespan in the US market. Propoxyphene was withdrawn in November of 2010 from the US market and is still being detected one year post-withdrawal in urine specimens from the pain management population. In this study, the prevalence of propoxyphene was determined in a total of 417,914 urine specimens collected from 630 clinics involved in pain management located in 24 states during the period of January 1, 2010, through December 31, 2011. Propoxyphene and norpropoxyphene were measured in urine by a validated liquid chromatography-tandem mass spectrometry procedure with a lower limit of quantitation of 50 ng/mL. The positivity rate for propoxyphene prevalence declined sharply between November and December of 2010 and further declined at a gradual rate, ending in a prevalence of 0.27% (one out of every 370 specimens, n = 25,658) for the month of December 2011. The presented data provide evidence of the dramatic decline in the use of propoxyphene products since their removal from the medical market, and may be beneficial to US urine drug testing programs determining the need for continual monitoring of propoxyphene levels.

Prescription opioids. I. Metabolism and excretion patterns of oxycodone in urine following controlled single dose administration.

The ongoing epidemic of prescription opioid abuse in the United States has prompted interest in semi-synthetic opioids in the federal workplace drug testing program. This study characterized the metabolism and disposition of oxycodone (OC) in human urine. Twelve healthy adults were administered a single oral 20 mg dose of OC in a controlled clinical setting. Urine specimens were collected at timed intervals up to 52 h and analyzed by liquid chromatography-tandem mass spectrometry (limit of quantitation: 50 ng/mL) for OC, oxymorphone (OM), noroxycodone (NOC) and noroxymorphone (NOM) with and without enzymatic hydrolysis. OC and NOC appeared in urine within 2 h, followed by OM and NOM. Peak concentrations of OC and metabolites occurred between 3 and 19 h. Mean peak concentrations in hydrolyzed urine were in the following order: NOC > OC > OM > NOM. Only OM appeared to be excreted extensively as a conjugated metabolite. OC concentrations declined more quickly than NOC and OM. At a cutoff concentration of 50 ng/mL, detection times were approximately 30 h for OC and 40 h for NOC and OM. Some specimens did not contain OC, but most contained NOC, thereby facilitating interpretation that OC was the administered drug; however, five specimens contained only OM. These data provide information that should facilitate the selection of appropriate test parameters for OC in urine and assist in the interpretation of test results.

Prescription opioids. II. Metabolism and excretion patterns of hydrocodone in urine following controlled single-dose administration.

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.

Oral fluid drug testing of chronic pain patients. II. Comparison of paired oral fluid and urine specimens.

A clinical study was conducted to compare the use of oral fluid to urine for compliance monitoring of pain patients. Patients (n = 133) undergoing treatment for chronic pain at four clinics participated in the study and provided paired oral fluid and urine specimens. Oral fluid specimens were collected with Quantisal(TM) saliva collection devices immediately following urine collection. Oral fluid specimens were analyzed for 42 drugs and/or metabolites by validated liquid chromatography-tandem mass spectrometry procedures. Accompanying urine specimens were initially screened by immunoassay and non-negative results were confirmed. Of the 1544 paired tests, 329 (21.3%) drug analytes were positive, and 984 (63.7%) were negative for both specimens resulting in an overall agreement of 85%. There were 83 (5.4%) analyte results that were positive in oral fluid and negative in urine, and 148 (9.6%) were negative in oral fluid and positive in urine for an overall disagreement of 15%. Cohen's Kappa value was 0.64, indicating "substantial" agreement. The primary exceptions to agreement were the lower detection rates for hydromorphone, oxymorphone, and benzodiazepines in oral fluid compared to urine. The authors conclude that, overall, oral fluid tests produced comparable results to urine tests with some minor differences in detection rates for different drug classes.