Impact of genetic variation in CYP2C19, CYP2D6, and CYP3A4 on oxycodone and its metabolites in a large database of clinical urine drug tests.

Urine drug testing (UDT) is a tool for monitoring drug use, including oxycodone. While variation in cytochrome P450 (CYP) genes is known to alter oxycodone metabolism, its impact on UDT results of oxycodone and its metabolites has not been well-studied. Here, multivariate analysis was performed on retrospective UDT results of 90,379 specimens collected from 14,684 genotyped patients prescribed oxycodone. Genetic variation in CYP2D6 and CYP2C19 had a significant impact on oxymorphone/oxycodone ratios, with a 6.9-fold difference between CYP2D6 ultrarapid metabolizers (UMs) and poor metabolizers (PMs; p < 10-300) and a 1.6-fold difference between CYP2C19 UMs and PMs (p = 1.50 × 10-4). CYP2D6 variation also significantly impacted noroxycodone/oxycodone ratios (p = 6.95 × 10-38). Oxycodone-positive specimens from CYP2D6 PMs were ~5-fold more likely to be oxymorphone-negative compared to normal metabolizers. These findings indicate that multivariate analysis of UDT data may be used to reveal the real-world impact of genetic and non-genetic factors on drug metabolism.

Polysubstance Use Among Patients Treated With Buprenorphine From a National Urine Drug Test Database.

Importance: Polysubstance use is a concern for patients treated for opioid use disorder (OUD). While buprenorphine can curtail harmful opioid use, co-occurring use of nonprescribed substances, such as cocaine, methamphetamine, and other opioids, may negatively affect treatment outcomes. Objective: To characterize factors associated with urine drug positivity for nonprescribed substances among patients prescribed buprenorphine. Design, Setting, and Participants: This cross-sectional study included patients who had been prescribed buprenorphine and who provided urine specimens for urine drug testing (UDT), as ordered by clinicians in primary care or behavioral health or at substance use disorder treatment centers, from 2013 to 2019. Specimens were analyzed by liquid chromatography-tandem mass spectrometry to assess positivity for several commonly used substances. Exposures: Buprenorphine prescription. Main Outcomes and Measures: Positivity for buprenorphine and several nonprescribed substances. Unadjusted trends in positivity for each nonprescribed substance were compared between specimens that did and did not test positive for buprenorphine. Multivariable logistic regression was used to examine factors associated with positivity; factors included patient age, sex, setting of care, payer, collection year, and census division. Results: The study included first UDT specimens from 150 000 patients, of whom 82 107 (54.74%) were men and 77 300 (51.53%) were aged 18 to 34 years. Across all specimens, 128 240 (85.49%) were positive for buprenorphine, and 71 373 (47.58%) were positive for 1 or more nonprescribed substances. From 2013 to 2019, positivity rates increased for most substances (eg, fentanyl: from 131 of 21 412 [0.61%] to 1464 of 13 597 [10.77%]). Factors associated with positivity varied widely by substance; for example, fentanyl positivity was highest for men (OR, 1.13; 95% CI, 1.06-1.21), patients aged 18 to 24 years (OR for patients ≥55 years, 0.46; 95% CI, 0.39-0.54), patients living in New England (OR, 1.19; 95% CI, 1.07-1.33), and patients with Medicaid (OR, 1.20; 95% CI, 1.11-1.31), whereas oxycodone positivity was greatest for women (OR for men, 0.84; 95% CI, 0.79-0.89), patients older than 55 years (OR, 1.42; 95% CI, 1.22-1.64), patients living in the South Atlantic (OR, 1.45, 95% CI, 1.33-1.58), and patients with private insurance (OR for Medicaid, 0.78; 95% CI, 0.73-0.84). Patients whose specimens were positive for buprenorphine were significantly less likely to be positive for other opioids (eg, fentanyl: OR for buprenorphine-negative samples, 6.71; 95% CI, 6.29-7.16; heroin: OR for buprenorphine-negative samples, 9.93; 95% CI, 9.31-10.59). Conclusions and Relevance: In this cross-sectional study, patterns of nonprescribed substance positivity among patients prescribed buprenorphine varied widely. This study highlights the utility of UDT in public health surveillance efforts related to patients treated with buprenorphine for OUD.

Seasonal and Regional Influences on Alcohol Consumption: An Analysis of Near-Real-Time Urine Drug Test Results in Those Seeking Health Care.

AIMS: To examine the probability of detecting alcohol via urine drug testing (UDT) as influenced by age, gender, seasonality, geography, COVID-19, and time in those seeking health care. METHODS: A cross-sectional study of UDT results from January 1, 2013, to December 31, 2020, was conducted using adult patient specimens submitted for testing by health care professionals as part of routine care. The UDT analysis used LC-MS/MS to detect two alcohol metabolites, ethyl glucuronide and ethyl sulfate. Seasonal adjustment of positivity rates was accomplished using the STL method; trend analysis was performed on seasonally adjusted rates. Logistic regression was used to associate demographic features, and an interaction term for collection year and U.S. census division was included to help understand the changing nature of alcohol use over time and across divisions. RESULTS: Alcohol positivity rate shows strong seasonal changes with an oscillating profile that peaks in the summer and is at a low point in winter. The highest predicted positivity rate for alcohol was in male patients, 45-64 years of age, and from a primary care setting. Alcohol positivity peaked in 2016 and declined the following year. While remaining relatively steady since 2017, a small but significant increase was noted after the COVID-19 emergency declaration on March 13, 2020. The probability of being alcohol-positive varies significantly by geographic region, and not all regions are changing at the same rate. CONCLUSIONS: Alcohol positivity in UDT in patients seeking health care is influenced by multiple factors and has increased during the COVID-19 pandemic.

The Cyclical and Evolving Nature of Methamphetamine Use: An Evaluation of Near Real-time Urine Drug Test Results.

OBJECTIVE: To determine methamphetamine positivity and copositivity with other drugs in urine drug test (UDT) results geographically through time. METHODS: This cross-sectional study of UDT results from January 1, 2014, through December 31, 2019, included patient specimens submitted by health care professionals across the United States. The analysis used LC-MS/MS to detect cocaine, heroin, alcohol, marijuana and nonprescribed methamphetamine, fentanyl, methadone, buprenorphine, benzodiazepines, and other opioids. Logistic regression was used to evaluate association of demographic features and model yearly methamphetamine detection patterns across US census divisions. Odds ratios (OR) from logistic modeling were used to evaluate the impact of methamphetamine positivity on the spatio-temporal detection patterns of additional nonprescribed or illicit drugs. RESULTS: The probability of being positive for methamphetamine increased nationally from 0.010 [0.010-0.011] in 2014 to 0.044 [0.042-0.046] in 2019, a 340% increase after correction for demographic covariates. The highest predicted positivity rate was in male patients, 25- to 34-years-old, from the West North Central division and from substance use disorder treatment centers. Nationally, copositivity ORs for fentanyl, heroin, and other opioids with methamphetamine were highest in 2019. Increases in ORs from 2014 through 2019 were statistically significant for heroin (P = 0.024) and fentanyl (P = 0.0085). Copositivity ORs for methamphetamine and other substances varied by census division. CONCLUSIONS: The probability of being positive for methamphetamine in UDT increased nationwide between 2014 and 2019. Not all census divisions are increasing at the same rate. Copositivity with additional substances is increasing in some census divisions, which further increases the risk of overdose and poor treatment outcomes.

Genetic Testing for BCHE Variants Identifies Patients at Risk of Prolonged Neuromuscular Blockade in Response to Succinylcholine.

BACKGROUND: Genetic variants in the BCHE (butyrylcholinesterase) gene are associated with reduced BChE enzyme activity and prolonged post-succinylcholine neuromuscular blockade, which can lead to postanesthetic apnea and respiratory depression. Testing for BChE deficiency is usually performed by biochemical methods and is generally only offered to patients who have a personal or family history of prolonged post-succinylcholine neuromuscular blockade. PURPOSE: Using a clinical test, we investigated the frequencies of BCHE genotypes that are associated with increased risk for prolonged post-succinylcholine neuromuscular blockade. MATERIALS AND METHODS: Five BCHE variants, including the A (atypical, rs1799807), K (Kalow, rs1803274), F1 (fluoride-1, rs28933389), F2 (fluoride-2, rs28933390), and S1 (silent-1, rs398124632), were genotyped in a large (n = 13,301), multi-ethnic cohort in the United States. Subjects were recipients of pharmacogenetic testing ordered by their physicians as part of routine care. RESULTS: The minor allele frequencies of A, K, F1, F2, and S1 were 1.60%, 19.93%, 0.08%, 0.47%, and 0.04%, respectively, in this cohort. Based on a review of biochemical and clinical data of these variants, we grouped BCHE genotypes into four phenotypic categories to stratify the risk for prolonged post-succinylcholine neuromuscular blockade. Approximately 0.06% of patients were predicted to have severe BChE deficiency, 8% were predicted to have moderate BChE deficiency, and 29% were predicted to have mild BChE deficiency. Compared to other ethnic groups, Caucasians were predicted to have the highest frequency of BChE deficiency. CONCLUSION: While severe BChE deficiency is rare in the United States, approximately 8% of Americans are at moderate risk of prolonged post-succinylcholine neuromuscular blockade, suggesting that a sizable percentage of patients may benefit from preoperative genetic testing of BCHE.

Fentanyl analog positivity among near-real-time urine drug test results in patients seeking health care.

Overdose deaths involving synthetic opioids continue to climb. Fentanyl analogs have been identified as important contributors to these overdoses, but little is known about their prevalence in patients seeking health care. This cross-sectional study of urine drug test (UDT) results from July 15, 2019, through March 12, 2020, included patient specimens analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS), submitted by health care professionals as part of routine care to detect fentanyl and fentanyl analogs. A convenience sample approach was used to select patient specimens from diverse health care practices across all 50 states, then stratified by fentanyl prescription status. Positivity rates, geographic distribution, and co-occurrence were quantified. The total positivity rate for ten fentanyl analogs was 40.55% in the non-prescribed fentanyl-positive population. The most common fentanyl analogs in this population were 4-ANPP (4-anilino-N-phenethylpiperidine), 30.74%; acetyl fentanyl, 19.40%; and carfentanil, 3.13%. The total positivity rate for four fentanyl analogs was 8.93% in the prescribed fentanyl-positive population, including 4-ANPP, 8.85%; acetyl fentanyl, 0.19%; acryl fentanyl, 0.05%; and 4-FiBF, 0.03%. Counties in Ohio and Kentucky had the highest positivity rates. Acetyl fentanyl and 4-ANPP copositivity occurred in 11.36% of non-prescribed patient specimens. However, acetyl fentanyl and 4-ANPP positivity may not be consistent with fentanyl analog use since both are process impurities, and 4-ANPP is a metabolite of fentanyl. Near-real-time, definitive UDT results reveal fentanyl analogs in patients seeking health care, helping clinicians and public health officials better understand their contribution to overdoses and help mitigate the risks they pose.

Rate of Fentanyl Positivity Among Urine Drug Test Results Positive for Cocaine or Methamphetamine.

Importance: Drug overdose deaths continue to increase, despite the leveling off of prescription opioid use and policy changes limiting opioid prescribing. Illicit fentanyl is the leading cause of drug overdose death, and it is important to characterize the emerging combination of other illicit drugs with fentanyl, which increases the risk of overdose. Objective: To determine whether rates of the combination of nonprescribed fentanyl with cocaine or methamphetamine have changed in urine drug test (UDT) results through time. Design, Setting, and Participants: This cross-sectional study of UDT results from January 1, 2013, through September 30, 2018, included patient specimens submitted for UDTs by health care professionals as part of routine care. Patients were selected from health care practices across the United States, including substance use disorder treatment centers, pain management practices, primary care practices, behavioral health practices, obstetrics and gynecology practices, and multispecialty groups. The UDT analysis used liquid chromatography-tandem mass spectrometry to detect benzoylecgonine (cocaine metabolite), methamphetamine, fentanyl, and norfentanyl. Specimens from individuals reported to have been prescribed fentanyl were excluded. A convenience sample approach was used to randomly select 1 million unique patient UDT specimens from Millennium Health's UDT database for further analysis. Each specimen had associated cocaine, methamphetamine, and fentanyl UDT results. Exposures: Medically necessary UDT to detect benzoylecgonine (cocaine metabolite), methamphetamine, fentanyl, and norfentanyl, ordered by a health care professional as part of routine patient care. Main Outcomes and Measures: Rates of nonprescribed fentanyl positivity among cocaine- or methamphetamine-positive UDT results, quantified through time. Results: In a sampling of 1 million unique patients' UDT specimens analyzed for cocaine and fentanyl (median [interquartile range] age, 44 [19-69] years; 55.0% women), positivity rates for nonprescribed fentanyl among the cocaine-positive results increased significantly, from 0.9% (n = 84) (95% CI, 0.7%-1.1%) in 2013 to 17.6% (n = 427) (95% CI, 16.1%-19.1%) in 2018, a 1850% increase (τ = 0.78; z = 9.45; P < .001). In the same sampling of 1 million specimens, positivity rates for nonprescribed fentanyl among the methamphetamine-positive results also increased significantly, from 0.9% (n = 29) (95% CI, 0.6%-1.2%) in 2013 to 7.9% (n = 344) (95% CI, 7.1%-8.7%) in 2018, a 798% increase (τ = 0.72; z = 8.75; P < .001). Conclusions and Relevance: An increasing number of UDT results positive for cocaine or methamphetamine were also positive for nonprescribed fentanyl. This provides additional insight into recently reported increases in cocaine- and methamphetamine-related overdoses. Stimulant users who may be opioid naive are at a heightened risk of overdose when exposed to fentanyl. Clinicians need to be aware that patients presenting for treatment of suspected drug overdose or substance use disorder may have been exposed, knowingly or unknowingly, to multiple substances, including the combination of stimulants and opioids.

A primer on definitive gas and liquid chromatography drug testing: What clinicians need to know.

OBJECTIVE: To describe the differences between mass spectrometry technologies and compare and contrast them with immunoassay techniques of urine drug testing (UDT). Highlight the potential importance of the differences among these technologies for clinicians so as to allow them make decisions in their use in patient care. METHODS: Review of mass spectrometry techniques, including gas chromatography, liquid chromatography, and time-of-flight techniques. RESULTS: The potential clinical implications of these technologies stemming from their scope and accuracy are presented. SIGNIFICANCE: UDT is an important clinical tool, though there are differences in technology and testing processes with important implications for clinical decision making. It is crucial, therefore, that clinicians have an understanding of the technologies behind the tests they order, so that their interpretation and use of results are based on an understanding of the strengths and weaknesses of the technologies used.

Trends in drug use from urine drug testing of addiction treatment clients.

OBJECTIVE: Urine drug testing (UDT) can play an important role in the care of patients in recovery from addiction, and it has become necessary for providers and programs to utilize specific, accurate testing beyond what immunoassay (IA) provides. DESIGN: A database of addiction treatment and recovery programs was sampled to demonstrate national trends in drug abuse and to explore potential clinical implications of differing results due to the type of testing utilized. SETTING: Deidentified data was selected from a national laboratory testing company that had undergone liquid chromatography tandem mass spectrometry (LC-MS/MS). PATIENTS/PARTICIPANTS: A total of 4,299 samples were selected for study. INTERVENTIONS: Descriptive statistics of the trends are presented. RESULTS: In total, 48.5 percent (n = 2,082) of the samples were deemed in full agreement between the practice reports and the results of LC-MS/MS testing. The remaining 51.5 percent of samples fell into one of seven categories of unexpected results, with the most frequent being detection of an unreported prescription medication (n = 1,097). CONCLUSIONS: Results of UDT demonstrate that more than half of samples yield unexpected results from specimens collected in addiction treatment. When comparing results of IA and LC-MS/MS, it is important to consider the limits of IA in the detection of drug use by these patients.

Exploring rates of abnormal pharmacogenetic findings in a pain practice.

Pharmacogenetic testing (PGT) is part of increasing efforts to personalize medicine, hopefully leading to better medication selection with more effective, less toxic therapies. Pharmacogenetic testing has relevance for chronic pain treatment, given the frequent comorbidities and polypharmacy. This retrospective study explored the prevalence of polymorphisms in a specialty pain practice in Louisiana. Pharmacogenetic testing was conducted for the cytochrome P450 (CYP) enzymes CYP2B6, CYP2C19, and CYP2D6, or the uridine diphosphate-glucuronosyltransferase 2 family polypeptide B15 (UGT2B15) enzyme utilizing a noninvasive, saliva-based test based on clinical decision-making. The sample consisted of 61 men (58.7%) and 41 women (39.4%), with an average age of 46.7 years (range = 23-83, SD = 11.5 years). Across all tests, 164 (42.3%) were extensive, 99 (25.5%) were intermediate, 28 (7.2%) were ultrarapid, and 27 (7%) were poor metabolizers. Only three patients who had been tested were found to be extensive (normal) for all four genes. These data demonstrate that genetic polymorphisms were frequently encountered. Consideration should be given to obtaining PGT as an aspect of evaluation and treatment planning when working with patients in need of specialty pain consultation and care. Caution is needed, as this brief report encompasses results from a single pain practice in one geographic location with a potentially distinct prevalence of genetic polymorphisms. Further prospective study is needed.

Pharmacist-physician collaboration in pain management practice.

Pain is one of the most common reasons patients seek out healthcare and management typically requires complex medication regimens. Pharmacists have become increasingly more involved in pain management. Historically, pharmacists and physicians have often had adversarial relationships because of regulatory influence. However, as medication experts, pharmacists can play a key role in optimizing outcomes in the management of pain and can be critical to the success of the medication regimen. Numerous opportunities for collaboration exist for pharmacists and physicians in various settings. One example is the VIGIL process, an effective risk management strategy that requires collaboration between pharmacists and physicians. The success of pharmacist-physician collaboration will depend on numerous factors, including strong physician and administrative support. A clear strategy and stepwise approach to developing a pain management pharmacist-physician collaborative practice is the key to its success. Once the collaboration is formalized, a management strategy should also be defined and should include regular chart review and regular feedback from the physician. Through physician-pharmacist collaboration, pain management outcomes can be optimized and risk can be managed.

Cannabinoids in cancer pain management.

The clinical use of cannabinoids in cancer pain management is reviewed. The endocannabionoid system, cannabinoid receptors, evidence for analgesic effects, other uses in cancer and related issues are discussed.

Adjuvant analgesics in cancer pain management.

Adjuvant analgesics are defined as drugs with a primary indication other than pain that have analgesic properties in some painful conditions. The group includes numerous drugs in diverse classes. Although the widespread use of these drugs as first-line agents in chronic nonmalignant pain syndromes suggests that the term "adjuvant" is a misnomer, they usually are combined with a less-than-satisfactory opioid regimen when administered for cancer pain. Some adjuvant analgesics are useful in several painful conditions and are described as multipurpose adjuvant analgesics (antidepressants, corticosteroids, alpha(2)-adrenergic agonists, neuroleptics), whereas others are specific for neuropathic pain (anticonvulsants, local anesthetics, N-methyl-D-aspartate receptor antagonists), bone pain (calcitonin, bisphosphonates, radiopharmaceuticals), musculoskeletal pain (muscle relaxants), or pain from bowel obstruction (octreotide, anticholinergics). This article reviews the evidence supporting the use of each class of adjuvant analgesic for the treatment of pain in cancer patients and provides a comprehensive outline of dosing recommendations, side effects, and drug interactions.