Catherine Hammett-Stabler, PhD, is a professor of pathology and laboratory medicine and the executive director of the core laboratory of McLendon Clinical Laboratories at the University of North Carolina at Chapel Hill.
Anthony Okorodudu, PhD, is a professor of pathology and director of the clinical chemistry division at the University of Texas Medical Branch (UTMB) in Galveston and director of UTMB–Texas Department of Criminal Justice Hospital laboratory services. He also provides consulting services for physicians’ office laboratories.
Marion Snyder, PhD, is president of technical services and scientific director at Labsource, LLC, in Greenville, South Carolina.
Frederick Strathmann, PhD, is an assistant professor of pathology at the University of Utah and medical director of toxicology and associate scientific director of mass spectrometry at ARUP Laboratories in Salt Lake City
For those who work with urine drug testing (UDT), high-profile deaths from opioid overdose have brought into the headlines obscure words from our world—fentanyl, hydrocodone, and buprenorphine. So it is no surprise that UDT done by liquid chromatography-mass spectrometry (LC-MS/MS) for monitoring compliance with chronic opioid therapy has grown rapidly in proportion to the opioid abuse epidemic in the United States. High complexity LC-MS/MS, once limited to specialized laboratories, has found a home in physicians’ office laboratories and at both large and small commercial laboratories specializing in UDT to support pain management and substance abuse treatment.
Reisfield et al. have commented on the conundrum of regulating LC-MS/MS use for pain management UDT, as it “straddles the divide between medical and legal requirements for the integrity of laboratory results, and appropriate specifications have not been established” (1). Further complicating the picture, revenues for some UDT laboratories soared in the last decade. This in part was due to a disconnect between the capability of modern LC-MS/MS technology to rapidly quantify multiple drugs and metabolites in a single test versus payers offering relatively high reimbursement for each drug or drug class reported.
This growth in spending caught the eyes of both regulators and the public. In 2014, The Wall Street Journal reported that Medicare’s spending on 22 “high-tech” tests for drugs of abuse hit $445 million in 2012, up 1,423% in 5 years (2). In October 2015, the U.S. Department of Justice announced that Millennium Health, one of the largest UDT laboratories in the country, agreed to pay $256 million to resolve alleged violations of the False Claims Act for medically unnecessary urine drug and genetic testing (3).
In response, the Centers for Medicare and Medicaid Services (CMS) in the last 2 years made big changes to drug testing codes that are expected to decrease reimbursement (4, 5). According to CMS, the agency does not recognize the 2015 American Medical Association current procedural terminology code changes for UDT because of “our concern about the potential for overpayment when billing for each individual drug test rather than a single code that pays the same amount regardless of the number of drugs that are being tested” (4). CMS has disallowed billing for multiple, individual, quantitative drug tests/sample using definitive methods (mass spectrometry) and substituted instead just four definitive method G codes based on the number of drug classes reported either qualitatively or quantitatively, including metabolites, as Charles Root, PhD, explained in the May 2016 issue of CLN.
In March of this year, the Centers for Disease Control and Prevention (CDC) also weighed in on UDT in its Guideline for Prescribing Opioids for Chronic Pain (6). CDC includes a recommendation for UDT but with an evidence grade 4, the lowest level. Furthermore, the CDC guideline notes that UDT “does not provide accurate information about how much or what dose of opioids or other drugs a patient took. The clinical evidence review did not find studies evaluating the effectiveness of urine drug screening for risk mitigation during opioid prescribing for pain.”
Although further clinical studies are needed to standardize best practice for UDT utilization, we know much more about opioid pharmacology and analysis now than we did 10 years ago because of the growth in pain management UDT. We have comprehensive information about opioid metabolism with high, chronic dosing; are better able to describe trace contaminants in opioid pharmaceuticals; and have greater sophistication about our opioid LC-MS/MS testing methods, as well as more knowledge about the methods’ limitations (7–11).
Missing from all this discovery is a consensus guideline on laboratory best practice for pain management UDT with LC-MS/MS. We also need certified reference materials (CRM) that reflect the complex mix of free and glucuronide compounds in pain management specimens. Pain management UDT would do well to take a page from the cardiovascular disease/cholesterol testing and androgen disorders/testosterone analyses playbooks, which revealed that robust evaluation of a test’s clinical utility depends first on having in place an accurate and uniform laboratory testing infrastructure.
Fortunately, consensus guidelines from the Clinical and Laboratory Standards Institute and from AACC are on the horizon (Clinical Laboratory News 2016;43(7):34–8). In the November 2016 issue of the CLN Focus on Mass Spectrometry, Paul Jannetto, PhD, of Mayo Medical Laboratories will discuss the AACC Laboratory Medicine Practice Guidelines specifically in the context of LC-MS/MS testing.
With all these developments—decreased reimbursement, progress toward analytical standardization and best practice, the potential for FDA to modify its enforcement discretion for laboratory developed tests, and rising interest in UDT cost-benefit considerations—pain management UDT laboratories need to remain nimble and stay informed.
To shine light on this LC-MS/MS specialty testing area, we asked experts from four laboratories to characterize their current operations and provide insight into the future of the field. They represent the range of settings where pain management UDT takes place: academic medical centers, physicians’ office laboratories, full service reference laboratories, and specialized pain management UDT laboratories. This article and supplementary online content reflect our panelists’ thoughtful responses. We appreciate their contributions.
In addition to expert opinion, we are eager to hear what CLN readers involved with UDT have to say in response to the same questions. Participate now in a brief survey.
Automation and Workload
We asked our panelists to characterize workload and degree of analytical automation for the different laboratory settings (Table 1). The number of samples per day, catchment areas, and automation profiles are not surprising, but the answers about the service mix (% of UDT that is for pain management) are of interest. The goal of pain management UDT is often narrowly characterized as detection of non-compliance. But chronic opioid prescribing appears to have a greater than anticipated risk for opioid dependence, overdose, and substance abuse (6). If the manner (test menu, cutoffs) in which UDT is performed is a factor in mitigating patient harm from these disorders, then recommendations for UDT best laboratory practice may of necessity draw components from testing for substance abuse treatment as well as pain management.
Choosing Analytes for Pain Management Panels
We expected diversity in the number of analytes included in the pain management panels offered by each laboratory and found that to be true. Responses included <10, 10-20, and >50. All panelists cited physician request as the top reason for including analytes, among a choice of physician requests, menu offered by competitors, literature and expert opinion, personnel, reimbursement, or technical limitations. Many factors play a role, such as patient population, noted Anthony Okorodudu, PhD of the University of Texas Medical Branch. Marion Snyder, PhD, of LabSource, LLC, and Frederick Strathmann, PhD, of ARUP Laboratories, noted that their reference laboratories also take into account trends in drug abuse, which vary widely over time and between regions in the U.S.
All of the laboratories use quantitative reporting; only the reference laboratories offer qualitative reporting, normalization to urine creatinine, and interpretations of compliance or non-compliance with listed medications. “Literature support, in-house expertise, test utilization initiatives, and laboratory complexity were driving forces behind our qualitative offerings,” noted Frederick Strathmann, PhD, of ARUP Laboratories. “Though reported qualitatively, our assays use single point calibration with a mixture of analog and isotopically labeled internal standards for normalization that provide acceptable quantitative data that are used internally to provide final interpretations.” For compliance reporting, ARUP Laboratories uses a combination of data sources, including manual curation of medication information, software for visualization, and a protocol in which a board-certified toxicologist reviews each result manually.
Marion Snyder, PhD, noted that LabSource uses quantitative reporting when providers want to closely monitor patient trends over time or assess patient concentrations compared to averages, such as opioids. Qualitative reporting is used for “drugs and metabolites for which providers want to know whether the drug is present or absent, but the relative concentration does not impact the clinical decision,” Snyder commented. “These tests are run in the same way as the quantitative tests but with fewer calibrators.” For compliance reporting, LabSource uses automated algorithms.
Similarly, Catherine Hammett-Stabler, PhD, of the University of North Carolina-Chapel Hill, responded that quantitative results are helpful in assessing some of the drugs during consultations, such as buprenorphine, morphine/hydromorphone, and others.
Selecting Cutoff Concentrations
Cutoffs for the same compound vary between laboratories, and as expected, cutoff values for compliance monitoring are lower than forensic cutoffs (Table 2). All panelists saw value in even lower cutoffs for most analytes if it were to become analytically feasible. However, they emphasized the importance of being more alert to carryover—that is the potential for a small percentage of a very high concentration sample to cross-contaminate a neighboring negative sample during the LC-MS/MS testing process, thus a true negative could become a false positive. The risk for such an error increases when cutoffs are at low and sub ng/mL concentrations.
Strathmann pointed out that low cutoff concentrations are “a double-edged sword. While important to ensure adequate sensitivity for the intended setting (e.g., abuse versus compliance testing), the wide range in results for UDT in particular can provide analytical challenges that far exceed clinical benefits.” His laboratory uses retrospective review of internal data to assess percent positivity and compare with literature reports in order to select cutoffs. The lab also incorporates clinician requests as well as literature for pharmacokinetic studies where available.
LabSource has lowered cutoffs across the board to increase sensitivity and frequency of detection, according to Snyder. “The majority of our providers want to know any and all illicit and controlled drugs to which the patient has been exposed,” she explained. “Drugs with shorter half-lives, administered at lower doses, or used more remotely can require very low cutoffs for detection.” In a review of most analyte concentrations over a 3–6 month period, Snyder defined the lower limit of detection to detect >95% of positives where instrument performance allowed. She kept the cutoffs for some compounds, such as morphine, ethyl glucuronide, and tetrahydrocannabinol (THC) higher because these can be seen with environmental exposure. Her aim was to minimize the chance that a low-level positive due to other sources would trigger inappropriate clinical decisions. “Labs should be careful to avoid false positives due to carryover/contamination from other samples when adopting low cutoffs,” Snyder added.
Validating Analytical Accuracy
All panelists reported using either comparison with peer laboratories and/or CRM as aids in validating accuracy. Asked which drugs, metabolites, or drug classes were the most difficult to validate, panelists pointed to oxycodone, barbiturates, THC and its metabolites, buprenorphine and its metabolites, opioids, and designer synthetics.
In addition, all panelists responded that they would use—if available—CRM and/or proficiency testing programs that included drug metabolites in their native forms (glucuronide and sulfate conjugates), as well as parent drugs.
See the supplement to read the panelists' discussion of the impact of new codes on reimbursement, the use of alternative matrices, and more.
Shannon Haymond, PhD, is the director of clinical chemistry and mass spectrometry at Ann & Robert H. Lurie Children’s Hospital of Chicago and assistant professor of pathology at Northwestern University Feinberg School of Medicine. Email: [email protected]
Judith Stone, PhD, is the senior clinical laboratory scientist specialist at the University of San Diego toxicology laboratory in the Center for Advanced Laboratory Medicine. Email: [email protected]
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2. Weaver C. Doctors cash in on drug tests for seniors, and Medicare pays the bill. The Wall Street Journal. http://www.wsj.com/articles/doctors-cash-in-on-drug-tests-for-seniors-and-medicare-pays-the-bill-1415676782 (Accessed June 2016).
3. Millennium Health agrees to pay $256 million to resolve allegations of unnecessary drug and genetic testing and illegal remuneration to physicians. U.S. Department of Justice, Office of Public Affairs, Justice News. https://www.justice.gov/opa/pr/millennium-health-agrees-pay-256-million-resolve-allegations-unnecessary-drug-and-genetic (Accessed June 2016).
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CLN's Focus on Mass Spectrometry is sponsored by Waters Corporation.