A Descriptive analysis of urine drug screen results in patients with opioid use disorder managed in a primary care setting.

BACKGROUND: Urine drug screening (UDS) is commonly used as part of treatment for opioid use disorder (OUD), including treatment with buprenorphine-naloxone for OUD in a primary care setting. Very little is known about the value of UDS, the optimum screening frequency in general, or its specific use for buprenorphine treatment in primary care. To address this question, we thought that in a stable population receiving buprenorphine-naloxone in the primary care setting it would be useful to know how often UDS yielded expected and unexpected results. METHODS: We present a descriptive analysis of UDS results in patients treated with buprenorphine-naloxone for OUD in a primary care setting over a two-year period. An unexpected test result is: 1. A negative test for buprenorphine and/or 2. A positive test for opioids, methadone, cocaine and/or heroin. RESULTS: A total of 161 patients received care during the study period and a total of 2588 test results were analyzed from this population. We found that 64.4% of the patient population (n = 104 patients) demonstrated both treatment adherence (as measured by buprenorphine positive test results) and no apparent unexpected test findings, as defined by negative tests for opioids, methadone, cocaine and heroin. Of the 161 patients, 20 results were positive for opioids, 5 for methadone, 39 for heroin and 2 for cocaine. Analysis at the UDS level demonstrated that, of the 2588 test results, 38 (1.5%) results did not have buprenorphine. Of the 2588, 28 (1.1%) test results were positive for opioids, 8 (0.3%) were positive for methadone, 39 (1.5%) for cocaine and 2 (0.1%) for heroin. CONCLUSION: Given that the majority of patients in our study had expected urine results, it may be reasonable for less frequent urine testing in certain patients.

Patient-Centered Telehealth Solution for Observed Urine Collections in Substance Use Disorder Care Delivery During COVID-19 and Beyond.

Patients with substance use disorder (SUD) rely upon urine drug testing to support treatment adherence and to mitigate relapse. Before the onset of coronavirus 2019 (COVID-19), the logistical challenges of randomized observed collections for urine drug testing for the patient were significant. During COVID-19, these barriers were often insurmountable. Since SUD patients represent a population at a higher risk for complications from COVID-19, an alternative strategy to support COVID-19 testing was urgently needed. We designed and deployed a telehealth-based solution in which patients could use mobile devices to connect with trained collection professionals to perform observed urine collections, often referred to a UA (urinalysis). The solution was designed with patient-centered best practices for telehealth, stigma prevention, trauma-informed, empathy and compassion, and to remove barriers to access to care. This approach demonstrated high patient satisfaction scores thereby proving that it is possible to provide urine collection services in the patient's home via a telehealth technology, while still upholding SUD testing integrity best practices. This study lays the path for a more patient-centered way to support this population.

All Hands-On Deck and All Decks on Hand: Surmounting Supply Chain Limitations During the COVID-19 Pandemic.

Testing during the COVID-19 pandemic has been crucial to public health surveillance and clinical care. Supply chain constraints-spanning limitations in testing kits, reagents, pipet tips, and swabs availability-have challenged the ability to scale COVID-19 testing. During the early months, sample collection kits shortages constrained planned testing expansions. In response, the University of Vermont Medical Center, University of Vermont College of Medicine, Vermont Department of Health Laboratory, Aspenti Health, and providers across Vermont including 16 area hospitals partnered to surmount these barriers. The primary objectives were to increase supply availability and manage utilization. Within the first month of Vermont's stay-at-home order, the University of Vermont Medical Center laboratory partnered with College of Medicine to create in-house collection kits, producing 5000 per week. University of Vermont Medical Center reassigned 4 phlebotomists, laboratory educators, and other laboratory staff, who had reduced workloads, to participate (requiring a total of 5.3-7.6 full-time equivalent (FTE) during the period of study). By August, automation at a local commercial laboratory produced 22,000 vials of media in one week (reducing the required personnel by 1.2 FTE). A multisite, cross-institutional approach was used to manage specimen collection kit utilization across Vermont. Hospital laboratory directors, managers, and providers agreed to order only as needed to avoid supply stockpiles and supported operational constraints through ongoing validations and kit assembly. Throughout this pandemic, Vermont has ranked highly in number of tests per million people, demonstrating the value of local collaboration to surmount obstacles during disease outbreaks and the importance of creative allocation of resources to address statewide needs.

Measuring What Matters: How the Laboratory Contributes Value in the Opioid Crisis.

With over 20 years of the opioid crisis, our collective response has evolved to address the ongoing needs related to the management of opioid use and opioid use disorder. There has been an increasing recognition of the need for standardized metrics to evaluate organizational management and stewardship. The clinical laboratory, with a wealth of objective and quantitative health information, is uniquely poised to support opioid stewardship and drive valuable metrics for opioid prescribing practices and opioid use disorder (OUD) management. To identify laboratory-related insights that support these patient populations, a collection of 5 independent institutions, under the umbrella of the Clinical Laboratory 2.0 movement, developed and prioritized metrics. Using a structured expert panel review, laboratory experts from 5 institutions assessed possible metrics as to their relative importance, usability, feasibility, and scientific acceptability based on the National Quality Forum criteria. A total of 37 metrics spanning the topics of pain and substance use disorder (SUD) management were developed with consideration of how laboratory insights can impact clinical care. Monitoring these metrics, in the form of summative reports, dashboards, or embedded in laboratory reports themselves may support the clinical care teams and health systems in addressing the opioid crisis. The clinical insights and standardized metrics derived from the clinical laboratory during the opioid crisis exemplifies the value proposition of clinical laboratories shifting into a more active role in the healthcare system. This increased participation by the clinical laboratories may improve patient safety and reduce healthcare costs related to OUD and pain management.

Driving Access to Care: Use of Mobile Units for Urine Specimen Collection During the Coronavirus Disease-19 (COVID-19) Pandemic.

Patients with substance use disorders (SUD) are at increased risk of both coronavirus disease-19 complications as well as exacerbations of their current conditions due to social distancing and isolation. Innovations that provide increased access to support substance use disorder patients may mitigate long-term sequelae associated with continued or renewed drug use. To improve patient access during the coronavirus disease-19 pandemic, we deployed a mobile unit to enable access to urine drug testing where needed for patients suffering from substance use disorder. Over a 3-week pilot program, 54 patients received urine drug testing across 5 providers and 8 zip codes. The mobile unit was cost-effective, demonstrating a volume-dependent 19% lower cost compared to pre-coronavirus disease-19 patient service centers in a similar geographic region. The mobile unit was well-received by patients and providers with an average of 9 out of 10 satisfaction scores and allowed for access to urine drug testing for 67% patients who would not have received testing during this time frame. No statistically significant differences were found in substance use positivity rates in comparison to pre-coronavirus disease findings; however, some shifts in use included higher rates of fentanyl and opioid positivity and reductions in tetrahydrocannabinol and cocaine use in the mobile collections setting. Deployment of mobile collection services during the coronavirus disease-19 pandemic has shown to be an effective mechanism for supporting patients suffering from substance use disorder, allowing for access to care of this often stigmatized, vulnerable population.

Urinary Buprenorphine, Norbuprenorphine and Naloxone Concentrations and Ratios: Review and Potential Clinical Implications.

OBJECTIVES: Treatment with medications for opioid use disorder such as buprenorphine improves patient morbidity and mortality as well as treatment adherence, an important component of patient care. Buprenorphine is combined with naloxone to reduce misuse; and, when taken sublingually, naloxone is poorly absorbed. Urine testing for buprenorphine is a common way to monitor adherence. Some patients who want to appear adherent may directly tamper with their urine by adding buprenorphine to their urine to allow for the detection without ingestion. Practitioners may rely upon the concentration of buprenorphine and the metabolite, norbuprenorphine, and utilize the ratio of metabolite to parent compound (norbuprenorphine:buprenorphine - N:B ratio) to discern possible evidence of tampering; however, there remains debate as to what specific ratio may signify this practice. Testing for naloxone may also help determine if urine tampering occurred as only low naloxone concentrations are found in the urine when taken by a sublingual route. METHODS: To determine a reliable N:B ratio that may be used to identify possible urine tampering by adding parent drug directly to urine, we examined 136,605 urine samples for quantitative concentrations of buprenorphine and norbuprenorphine by LC-MS/MS performed at a commercial laboratory. After identifying abnormal ratios (<0.02), we then compared them with naloxone concentrations and specimen validity testing, other markers that may coincide with specimen tampering of this type. RESULTS: Correlating urinary buprenorphine and norbuprenorphine concentrations, we found 2 distinct patient populations, which could be distinguished by N:B ratios ranging from 0.01 to 0.2. In addition, while the distribution of urine naloxone concentrations itself did not demonstrate distinct populations, naloxone was able to further flag potential tampered specimens when combined with N:B ratios. Abnormal specimen validity testing was additionally found more commonly in cases with N:B ratios <0.02. CONCLUSIONS: This comprehensive study compared N:B ratios with naloxone concentrations and specimen validity testing. This study suggests that a N:B ratio of <0.02 in concert with high naloxone concentrations (>1000 ng/ml) can help to identify potential cases of tampered urine samples.

Use of urinary naloxone levels in a single provider practice: a case study.

BACKGROUND: Urine drug monitoring for medications for opioid use disorder (MOUD) such as buprenorphine can help to support treatment adherence. The practice of introducing unconsumed medication directly into urine (known as "spiking" samples) has been increasingly recognized as a potential means to simulate treatment adherence. In the laboratory, examination of the ratios of buprenorphine and its metabolite, norbuprenorphine, has been identified as a mechanism to identify "spiked" samples. Urine levels of naloxone may also be a novel marker in cases where the combination buprenorphine-naloxone product has been administered. This case study, which encompasses one provider's practice spanning two sites, represents a preliminary report on the utility of using urinary naloxone as an indicator of "spiked" urine toxicology samples. Though only a case study, this represents the largest published evaluation of patients' naloxone levels to date. CASE PRESENTATION: Over a 3-month period across two practice sites, we identified 1,223 patient samples with recorded naloxone levels, spanning a range of 0 to 12,161 ng/ml. The average naloxone level was 633.65 ng/ml with the majority (54%) of samples < 300 ng/ml. 8.0% of samples demonstrated extreme values of naloxone (> 2000 ng/ml). One practice site, which had increased evidence of specimen tampering at collections, had a greater percent of extreme naloxone levels (>  2000 ng/ml) at 9.3% and higher average naloxone level (686.8 ng/ml), in contrast to a second site (570.9 ng/ml; 6.4% at > 2000 ng/ml) that did not have known reports of specimen tampering. CONCLUSIONS: We postulate that naloxone may serve as an additional flag to identify patient "spiking" of urine samples with use of the combination product of buprenorphine-naloxone.

Integrating Social Determinants of Health and Laboratory Data: A Pilot Study To Evaluate Co-Use of Opioids and Benzodiazepines.

As the opioid crisis continues to have devastating consequences for our communities, families, and patients, innovative approaches are necessary to augment clinical care and the management of patients with opioid use disorders. As stewards of health analytic data, laboratories are uniquely poised to approach the opioid crisis differently. With this pilot study, we aimed to bridge laboratory data with social determinants of health data, which are known to influence morbidity and mortality of patients with substance use disorders. For the purpose of this pilot study, we focused on the co-use of opioids and benzodiazepines, which can lead to an increased risk of fatal opioid-related overdoses and increased utilization of acute care. Using the laboratory finding of the copresence of benzodiazepines and opioids as the primary outcome measure, we examined social determinants of health attributes that predict co-use. We found that the provider practice that ordered the laboratory result is the primary predictor of co-use. Increasing age was also predictive of co-use. Further, co-use is highly prevalent in specific geographic areas or "hotspots." The prominent geographic distribution of co-use suggests that targeted educational initiatives may benefit the communities in which co-use is prevalent. This study exemplifies the Clinical Lab 2.0 approach by leveraging laboratory data to gain insights into the overall health of the patient.

Pharmacogenetic differences and drug-drug interactions in immunosuppressive therapy.

With the advent of new immunosuppressants and formulations, the elucidation of molecular targets and the evolution of therapeutic drug monitoring, the field of organ transplantation has witnessed significant reductions in acute rejection rates, prolonged graft survival and improved patient outcome. Nonetheless, challenges persist in the use of immunosuppressive medications. Marked interindividual variability remains in drug concentrations and drug response. As medications with narrow therapeutic indices, variations in immunosuppressant concentrations can result in acute toxicity or transplant rejection. Recent studies have begun to identify factors that contribute to this variability with the promise of tailoring immunosuppressive regimens to the individual patient. These advances have uncovered differences in genetic composition in drug-metabolising enzymes, drug transporters and drug targets. This review focuses on commonly used maintenance immunosuppressants (including cyclosporin, mycophenolate mofetil, tacrolimus, sirolimus, everolimus, azathioprine and corticosteroids), examines current studies on pharmacogenetic differences in drug-metabolising enzymes, drug transporters and drug targets and addresses common drug-drug interactions with immunosuppressant therapies. The potential role of drug-metabolising enzymes in contributing to these drug-drug interactions is briefly considered.

Phenacetin and chlorzoxazone biotransformation in aging male Fischer 344 rats.

We evaluated the role of specific isoforms in the biotransformation of phenacetin and chlorzoxazone and examined the effect of age on these reactions using liver microsomes from Fischer 344 rats between 3 and 26 months of age. Using rat cDNA-expressed cytochrome P450 (CYP) enzymes, we found that phenacetin biotransformation was primarily mediated by CYP2C6 and CYP1A isoforms, while chlorzoxazone biotransformation was largely mediated by CYP2E1 and CYP1A1. Incubations with liver microsomes prepared from rats of varying ages demonstrated that both phenacetin and chlorzoxazone biotransformation declined with age. Metabolite formation rates in the old rats (25-26 months) were reduced by approximately 60-70% for these reactions. This study suggests that the activity of CYP2E and CYP1A enzymes decline with age in the rat liver. Also, the relative specificity of the index substrates phenacetin (for CYP1A2) and chlorzoxazone (for CYP2E1) in man appears not to be applicable in rats.

The effect of age on P-glycoprotein expression and function in the Fischer-344 rat.

We investigated the effect of age on P-glycoprotein (P-gp) expression and function in rat liver, intestine, kidney, and endothelial cells of the blood-brain barrier (BBB) and lymphocytes. Flow cytometric analysis was used to examine P-gp expression in lymphocytes from male Fischer-344 rats from three age groups (young at 3-4 months, intermediate at 13-14 months, and old at 25-26 months). In addition, P-gp function in lymphocytes was assessed by measuring the ability of the P-gp inhibitor verapamil to limit the efflux of the fluorescent P-gp substrate rhodamine 123. P-gp expression was evaluated in the remaining four tissues by Western blot analysis. The effect of age on P-gp expression was tissue-specific. Although lymphocytic and hepatic P-gp expression increased with age, renal P-gp content was lower in the old kidneys. No statistical difference was observed in P-gp expression in intestinal microsomes or in BBB cell lysates among the three age groups. P-gp function was also increased by 6- to 8-fold in lymphocytes from the old rats. When P-gp expression was compared with CYP3A expression in these rats (reported elsewhere in this journal), we found that P-gp expression increased with age, whereas CYP3A expression and activity declined in the old livers. The converse pattern was observed in the kidney. Thus, age-related changes in P-gp expression and function are likely to be tissue-specific, and these changes may be inversely related to differences in CYP3A expression.

Age-related differences in CYP3A expression and activity in the rat liver, intestine, and kidney.

We evaluated the effect of age on CYP3A expression and function in the liver, intestine, and kidney from young (3-4 months), intermediate (13-14 months), and old (25-26 months) male Fischer-344 rats. The biotransformation of triazolam to its primary hydroxylated products, 4-OH-TRZ (triazolam) and alpha-OH-TRZ, was used as a marker of CYP3A activity in rat liver and intestine. Immunoactive CYP3A expression was evaluated by Western blot analysis in the rat intestine, liver, and kidney. Since testosterone and NADPH reductase levels may modulate CYP3A activity, we also examined free plasma testosterone concentrations and NADPH reductase expression in these rats. The effect of age on CYP3A expression was tissue-specific. Although both CYP3A activity and expression were reduced by approximately 50 to 70% in the old livers compared with the young animals, intestinal CYP3A activity and expression did not change significantly with age. The expression of one CYP3A isoform was increased by 1.5-fold in the old kidneys. NADPH reductase expression was reduced by 23 to 36% with age in all tissues; this reached statistical significance only in the liver. Plasma testosterone levels declined by 74% in the old animals. This study suggests that the effect of age on CYP3A expression and function is tissue-specific. In addition, changes in testosterone levels and NADPH reductase expression may contribute to age-related differences in hepatic CYP3A activity.

The effect of age on sildenafil biotransformation in rat and mouse liver microsomes.

Sildenafil [SIL (Viagra); Pfizer, New York, NY] is a widely prescribed agent for erectile dysfunction in men older than 65 years. The present study evaluated experimental models to assess age-dependent changes in SIL biotransformation using hepatic microsomes from male rats and mice ranging from 6 weeks to 26 months of age. The role of specific isoforms in the conversion of SIL to its primary circulating metabolite, UK-103,320 (piperazine N-desmethyl sildenafil) in the mouse was also investigated using immunoinhibitory antibodies. Although CYP2C11 largely mediated UK-103,320 formation in the rat, UK-103,320 formation was principally inhibited by a CYP3A antibody in the mouse. An age-related decrement in metabolite formation rate was observed for both species, although this effect was more pronounced in the old rats (reduced to 7% of young) than in the old mice (reduced to 51% of young). CYP2C expression was assessed by Western blot analysis in rat and mouse livers. Age-related differences in hepatic CYP3A expression in the mouse were also compared with metabolite formation rates in the mouse model. Decrements with age in CYP2C and -3A expression in the aging rodents paralleled the decrements in SIL biotransformation, suggesting that age-related differences in SIL metabolic rate may, in part, reflect differences in expression. Although the role of specific CYP enzymes and the clearance values for this reaction may differ among species, age-related changes in these rodent models are consistent with the reduced clearance of SIL observed in human studies.

In vitro, pharmacokinetic, and pharmacodynamic interactions of ketoconazole and midazolam in the rat.

Interactions of midazolam and ketoconazole were studied in vivo and in vitro in rats. Ketoconazole (total dose of 15 mg/kg intraperitoneally) reduced clearance of intravenous midazolam (5 mg/kg) from 79 to 55 ml/min/kg (p < 0.05) and clearance of intragastric midazolam (15 mg/kg) from 1051 to 237 ml/min/kg (p < 0.05), increasing absolute bioavailability from 0.11 to 0.36 (p < 0.05). Presystemic extraction occurred mainly across the liver as opposed to the gastrointestinal tract mucosa. Midazolam increased electroencephalographic (EEG) amplitude in the beta-frequency range. Ketoconazole shifted the concentration-EEG effect relationship rightward (increase in EC(50)), probably because ketoconazole is a neutral benzodiazepine receptor ligand. Ketoconazole competitively inhibited midazolam hydroxylation by rat liver and intestinal microsomes in vitro, with nanomolar K(i) values. At a total serum ketoconazole of 2 microg/ml (3.76 microM) in vivo, the predicted reduction in clearance of intragastric midazolam by ketoconazole (to 6% of control) was slightly greater than the observed reduction in vivo (to 15% of control). However, unbound serum ketoconazole greatly underpredicted the observed clearance reduction. Although the in vitro and in vivo characteristics of midazolam in rats incompletely parallel those in humans, the experimental model can be used to assess aspects of drug interactions having potential clinical importance.

In vitro biotransformation of sildenafil (Viagra) in the male rat: the role of CYP2C11.

To assess the suitability of the male rat model for human studies on sildenafil metabolism, we examined the biotransformation of sildenafil in male rat liver microsomes and identified the role of specific cytochrome P450s (P450) using inhibitory antibodies and cDNA-expressed P450s. Rates of formation of the major circulating metabolite of sildenafil, UK-103,320, were 11-fold greater in the male rat than in human liver microsomes at 36 microM sildenafil, whereas substrate concentration corresponding to 50% V(max) (K(m) values) were 2.9-fold lower in the male rat. Although sildenafil is largely metabolized by CYP3A isoforms in humans, coincubation of rat liver microsomes with immunoinhibitory antibodies (CYP1A1/2, 2B1/2, 2C11, 2E1, and 3A1/2) revealed that metabolite formation was inhibited only by an antirat CYP2C11 antibody. Incubation of sildenafil with a cDNA-expressed CYP2C11 produced 10-fold higher levels of UK-103,320 than other P450s (CYP1A1, 1A2, 2B1, 2C6, 2C12, 2C13, 2E1, 3A1, and 3A2). Thus CYP2C11 contributes in a major way to the metabolism of sildenafil in the male rat. P450 isoforms mediating sildenafil biotransformation differ substantially between humans and the male rat, thereby limiting the applicability of this species as a model for sildenafil metabolism and drug interactions in humans.