Monitoring buprenorphine in patients on medication-assisted treatment.

BACKGROUND: Buprenorphine is used for medication-assisted treatment of opioid dependence. PURPOSE: Monitoring of medication adherence involves testing of urine or oral fluid for the drug or its metabolite. METHODS: Quantitative results using liquid chromatography tandem mass spectrometer testing defined the excretion pattern of the drug and its metabolites. RESULTS: Frequency distribution curves of buprenorphine and norbuprenorphine describe the expected drug concentrations of patients on this medication. CONCLUSION: Urine and oral fluid drug testing can be used to monitor adherence in this population.

Letter to Editor: Observations of Deception in Urine Drug Testing.

OBJECTIVE: Determining deception in urine drug testing. Some of the patients undergoing urine drug tests have not taken the prescribed drug and attempt to deceive the laboratory test by placing the parent drug in the collection cup. METHODS: One of the ways to determine if this is occurring is to monitor the major metabolite of the drug. By using the metabolite/parent drug ratio this attempt at deception can be uncovered. RESULTS: Of the five drugs we examined, oxycodone, hydrocodone, buprenorphine, methadone, and fentanyl, we found buprenorphine to be the most prevalent drug to this type of deception. CONCLUSION: Deception can be identified using the metabolite/parent drug ratio.

Estimates of Drug Metabolism Using Drug Excretion Concentrations.

We propose that quantitative urine drug concentrations from LC-MS/MS measurements can be used to estimate zero and first order pharmacokinetics of the drugs oxycodone, hydrocodone, buprenorphine, methadone, and fentanyl. We observed the ratio of metabolite to parent drug could be used for this estimate. As the amount of observed parent drug increased, the metabolic ratio decreased, indicating a shift from first order to zero order metabolism. After making assumptions of bioavailability, percent of drug excreted into urine, we developed estimates of the saturating dosages for these drugs.

Changing Landscape of Fentanyl/Heroin Use and Distribution.

OBJECTIVE: To understand the geopolitics of the supply of fentanyl and heroin. RESULTS: In our practice, the percent of fentanyl positive drug tests increased from years 2016 to 2022, but heroin positive drug tests decreased by 80% in the same period. CONCLUSION: Fentanyl has replaced heroin as a street drug for opioid dependent drug users.

Follow-Up: Effects of a Pandemic and Isolation on Alcohol and Psychoactive Medication Use in a Population of Rehabilitation and Pain Patients.

OBJECTIVE: The conjunction of the coronavirus disease lockdown and the use of illicit drugs suggests the potential increase in drug usage and opioid deaths. Because of other studies, we felt the need to examine if the lockdown has caused a change in the drug intake of our population of substance abuse and pain management patients. Our initial study indicated no increase in the use of illicit and antianxiety drugs. This study is a continuation of that work. MATERIALS: Urine drug testing is a strategy to reduce harm to patients in pain management and substance abuse treatment programs. We analyzed trends in the clinical drug testing patterns of urine specimens sent by substance abuse and pain clinics to monitor their patients. These specimens were tested by a national clinical laboratory using LC-MS/MS definitive methods. The time frame of these comparative observations was the past six years, including the two years of the pandemic. RESULTS: We observed a 30% reduction in test requests during the second quarter of 2020, the number of test requests and specimens submitted was similar during other times of the six-year period. The observed drug use pattern was similar to the earlier study. Among the patients tested, positivity decreased greatly for the illicit drugs heroin and cocaine but increased for methamphetamine and fentanyl. Use of the antidepressant and anxiolytic drugs remained consistent or declined for some drugs, relative to pre-pandemic patterns. The percent of patients prescribed the opiates morphine and oxycodone decreased, while the use of hydrocodone increased. Positivity for the drug gabapentin increased greatly. The use of alcohol did not increase significantly during the lockdown period. CONCLUSION: In summary, these findings demonstrate relatively consistent drug use, with decreased positivity for high-risk drugs and dangerous drug combinations. We speculate that monitoring of these patients mitigates the possibility of drug misuse and potential overdose and is in concordance with the goals of these monitoring programs.

Update: Correlation of Fentanyl Positive Drug Screens with other Medications in Patients from Pain, Rehabilitation and Behavioral Programs.

OBJECTIVE: To monitor fentanyl polydrug use over past six years. METHOD: Calculate percent of fentanyl and other drugs positive in urine drug tests. RESULTS: Percent of fentanyl positive drug tests remained unchanged, but increases in fentanyl/methamphetamine and fentanyl/marijuana were observed. CONCLUSIONS: Fentanyl laced illicit drugs remain a major substance abuse problem.

Effects of a Pandemic and Isolation on Alcohol and Psychoactive Medication Use in a Population of Rehabilitation and Pain Patients.

OBJECTIVE: The conjunction of the coronavirus disease lockdown and the use of illicit drugs suggests the potential increase in drug usage and opioid deaths. Because of other studies, we felt the need to examine if the lockdown has caused a change in the drug intake of our population of substance abuse and pain management patients. MATERIALS: Urine drug testing is a strategy to reduce harm to patients in pain management and substance abuse treatment programs. We analyzed trends in the clinical drug testing patterns of urine specimens sent by substance abuse and pain clinics to monitor their patients. These specimens were tested by a national clinical laboratory using LC-MS/MS definitive methods. The time frame of these comparative observations was the past five years, including the time of the pandemic. RESULTS: The only decrease was a 30% reduction in test requests during the second quarter of 2020. Among the patients tested, positivity decreased greatly for the illicit drugs heroin and cocaine but increased for methamphetamine and fentanyl. Use of the antidepressant and anxiolytic drugs remained consistent or declined for some drugs, relative to pre-pandemic patterns. The percent of patients prescribed the opiates morphine and oxycodone decreased, while the use of hydrocodone increased. Positivity for the drug gabapentin increased greatly. The use of alcohol did not increase significantly during the lockdown period. CONCLUSION: In summary, these findings demonstrate relatively consistent drug use, with decreased positivity for high-risk drugs and dangerous drug combinations. We speculate that monitoring of these patients mitigates the possibility of drug misuse and potential overdose and is in concordance with the goals of these monitoring programs.

Reduction of Drug-Drug Interaction Risk; CDC Guidelines Influence on Opiate Benzodiazepine Prescribing.

We examined the results of 1.3 million drug tests performed on patients being monitored for compliance with pain medications and substance abuse rehabilitation to determine if the 2016 CDC prescribing guidelines had any impact on opiate benzodiazepine use. We observed that the combination of the opiate drugs morphine, oxycodone, and hydrocodone with the benzodiazepine metabolites oxazepam, alphahydroxyalprazolam, and 7-aminoclonazepam showed many patients were on a combination of these drugs. This ranged from approximately 9 to 16%. There was considerable variability between opiate drug pairs, but there was a general trend to fewer patients on the combination of opiate-benzodiazepine over the 2016 to 2019 time frame.

Correlation of Fentanyl Positive Drug Screens with Other Medications in Patients from Pain, Rehabilitation and Behavioral Programs.

Fentanyl has been associated with many drug overdose deaths; its presence in many street drugs has been postulated to be increasing. We examined 1.3 million urine drug tests from April 2016 to April 2019 for fentanyl and other drugs. The highest relationship was observed with heroin. Approximately 30%-40% of the drug tests positive for the heroin metabolite 6-monacetylmorphine (6-MAM) were also positive for fentanyl. There was a large variance over time, but the percent positive in 2016 and 2019 were similar. In contrast, there was a definite increase in the presence of fentanyl with cocaine and methamphetamine. There was not a large increase over time associated with methadone, buprenorphine, and marijuana.

Interpretation of Pain Management Testing Results Using Case Examples.

BACKGROUND: Because of the increasing volume of opiate-related overdoses, clinical testing of urine for drugs and related compounds in pain management clinics has become increasingly important. Interpreting findings of drugs present in urine specimens requires knowledge of pharmacokinetics, metabolism, drug purity, and cutoff concentrations used to report a positive result. CONTENT: This case-based mini-review provides examples of how to interpret immunoassay and quantitative confirmatory urine drug-testing results. Particular emphasis is placed on interpretation of opiate and benzodiazepine results, as these drugs have complicated metabolic profiles. SUMMARY: Both determining patient medication compliance and identifying the presence of additional drugs provides important information to the treating physician involved in managing pain. Mass spectrometry-based methods are required to identify specific drugs present and can provide important quantitative data for interpreting opiate medication compliance.

Lower Cutoffs for LC-MS/MS Urine Drug Testing Indicates Better Patient Compliance.

BACKGROUND: Urine drug testing is used by health care providers to determine a patient's compliance to their prescribed regimen and to detect non-prescribed medications and illicit drugs. However, the cutoff levels used by clinical labs are often arbitrarily set and may not reflect the urine drug concentrations of compliant patients. OBJECTIVES: Our aim was to test the hypothesis that commonly used cutoffs for many prescribed and illicit drugs were set too high, and methods using these cutoffs may yield a considerable number of false-negative results. The goals of this study were to outline the way to analyze patient results and estimate a more appropriate cutoff, develop and validate a high sensitivity analytical method capable of quantitating drugs and metabolites at lower than the commonly used cutoffs, and determine the number of true positive results that would have been missed when using the common cutoffs. STUDY DESIGN: This was a retrospective study of urine specimens submitted for urine drug testing as part of the monitoring of prescription drug compliance described in chronic opioid therapy treatment guidelines. SETTING: The study was set in a clinical toxicology laboratory, using specimens submitted for routine analysis by health care providers in the normal course of business. METHODS: Lognormal distributions of test results were generated and fitted with a trendline to estimate the required cutoff level necessary to capture the normal distributions of each drug for the patient population study. A validated laboratory derived liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis capable of achieving the required cutoff levels was developed for each drug and/or metabolite. RESULTS: The study shows that a lognormal distribution of patient urine test results fitted with a trendline is appropriate for estimating the required cutoff levels needed to assess medication adherence. The study showed a wide variation in the false-negative rate, ranging from 1.5% to 94.3% across a range of prescribed and illicit drugs. LIMITATIONS: The patient specimens were largely sourced from patients in either a long-term pain management program or in treatment for substance use disorder in the US. These specimens may not be representative of patients in other types of treatment or in countries with different approaches to these issues. CONCLUSIONS: The high-sensitivity method reduces false-negative results which could negatively impact patient care. Clinicians using less sensitive methods for detecting and quantifying drugs and metabolites in urine should exercise caution in assessing patient adherence using and changing the treatment plan based on those results. KEY WORDS: Urine drug testing, patient adherence, clinical toxicology, immunoassay, LC-MS, definitive drug testing, REMS, negative test results, false negative.

A sensitive assay for urinary cocaine metabolite benzoylecgonine shows more positive results and longer half-lives than those using traditional cut-offs.

Cocaine is a common drug of abuse. To detect its use, a screening detection concentration for the cocaine metabolite benzoylecgonine is commonly set at 150 ng/mL and its confirmatory cut-off is set at 100 ng/mL. Studies have suggested that these cut-offs may be set too high, allowing some patients with this substance abuse problem to be missed or improperly monitored. With the advent of liquid chromatography-tandem mass spectrometry (LC-MS/MS) technology it is possible to reliably detect and quantify lower concentrations of its metabolite benzoylecgonine as part of a larger drug panel. One purpose of the study was to establish if there was a significant increase in detection of cocaine use with a ten-fold more sensitive cut-off. A very sensitive dilute and shoot assay for benzoylecgonine was developed with a lower limit of quantitation of 5 ng/mL. Validation of the 5 ng/mL cut-off was achieved by plotting all the positive cocaine observations as a frequency distribution on a logarithmic scale. The number of positive results with measurable concentrations below the typical industry 100 ng/mL cut-off level but above the high sensitivity 5 ng/mL cut-off level was observed to be 51.9% of the observed positives. The lower cut-off also allowed a re-evaluation of the window of detection after cessation of use. It was observed to be between 17 and 22 days. © 2016 Precision Diagnostics, LLC. Drug Testing and Analysis published by John Wiley & Sons, Ltd.

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.

Differentiating medicinal from illicit use in positive methamphetamine results in a pain population.

In addition to illicit methamphetamine, there are prescription and over-the-counter medications that, if ingested, may yield positive methamphetamine (MAMP) results on laboratory urine drug tests. The purpose of the study is to estimate the prevalence of medicinal and illicit MAMP in the pain population using chiral analysis to determine the relative amounts of the d and l-MAMP enantiomers. This retrospective analysis included the LC-MS/MS results and prescriber provided medication histories of 485,889 de-identified urine specimens from patients treated for pain. Two groups of 100 specimens each were subjected to chiral analysis. Group 1 contained specimens that were MAMP positive and amphetamine negative. Group 2 contained randomly selected MAMP positive specimens. The overall MAMP positivity rate of the 485,889 specimens tested was 1.6%. The prevalence of MAMP medications based on reported medications and detection of l-MAMP in Group 1 and Group 2 was 44% and 6%, respectively. These data indicate that the use of both illicit and medicinal MAMP is found in this patient population, and that medicinal use is underreported in clinical histories. Therefore, clinical laboratories should provide on request chiral analysis to aid in differentiating illicit and medicinal MAMP.

Stability of pain-related medications, metabolites, and illicit substances in urine.

BACKGROUND: Effective urine drug testing requires an understanding of the stability of medications, metabolites and other substances excreted in the urine matrix. When the testing results do not fit the clinical picture, physicians frequently request repeat testing of the original specimen in order to corroborate the results. We determined the stability in urine of various medications, metabolites, and illicit substances commonly requested for testing by physicians treating patients with pain and pain-related disorders. METHODS: Quantitative analyses of urine specimens were performed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Two replicates at a high and low concentration were analyzed at time 0, and after 2, 3 and 6 months following storage at +4 °C and -20 °C. At each time interval, the percent difference from time 0 for each analyte was calculated and averaged for each storage condition. RESULTS: For the majority of medications, the percent differences were within 20% of the original measurement for all 3 storage conditions. All were within 30% of the original measurement after 2, 3 and 6 months in all storage conditions, except for 7-amino-clonazepam, and carboxy-tetrahydrocannabinol. CONCLUSIONS: The findings from the current study confirm that the majority of medications, metabolites, and illicit substances commonly requested for testing by physicians treating patients with pain and pain-related disorders are stable within 20% of the original concentration when stored refrigerated or frozen for up to 6 months. Thus, delayed testing, repeat testing, and add-on testing of urine specimens can yield reliable results for up to 6 months following the urine collection date.

Illicit drug use correlates with negative urine drug test results for prescribed hydrocodone, oxycodone, and morphine.

BACKGROUND: A number of studies indicate that 10.8%-34% of patients with chronic pain use illicit drugs. One hypothesis for this occurrence is that some patients may be supplementing their prescription medications with illicit drugs. OBJECTIVE: The primary purpose of this retrospective data analysis was to test the hypothesis that people whose urine specimens are positive for the medications that have been listed as being prescribed to them are positive for fewer illicit substances than those whose specimens were negative for their prescribed medications. The secondary purpose of the study was to correlate the use of illicit drugs and the amount of prescribed medications excreted in urine. STUDY DESIGN: A retrospective study of the incidence of patients using illicit drugs versus their consistency with reported medications. METHODS: Using urine specimens from a cohort of nearly 400,000 patients whose identities had been redacted, and who were being treated for chronic pain with opioid therapy, this study was performed to correlate the patients' positivity with their prescribed medication to the prevalence of illicit substance use. A secondary study was conducted to correlate the amount of prescribed medication excreted in urine (measured in ng/mL) with the incidence of illicit drug use. The specific prescription medications analyzed were hydrocodone, morphine, and oxycodone. RESULTS: Specimens defined as negative for prescribed hydrocodone (27.3%), morphine (11.5%) or oxycodone (19%) were more likely to contain illicit drugs than those found to be positive for the prescribed medication. The illicit drug prevalence among the inconsistent specimens was 15.3% for hydrocodone, 23.8% for morphine, and 24.4% for oxycodone. The secondary study showed no statistically significant difference in the excretion level of prescribed medication between those patients using and not using illicit drugs. LIMITATIONS: The study is limited in that no data was obtained to determine the causal relationships of illicit drug use. CONCLUSIONS: This work supports the hypothesis that people who are positive for their prescribed medications use fewer illicit drugs than those who do not take their medications. It may be beneficial for physicians to test more thoroughly for illicit drugs when patients' drug tests are negative for their prescribed medications.