Drug overdose deaths increased dramatically from 1980 to 2016, surpassing deaths from guns, HIV, and car crashes (1). At least half of the deaths involved a prescription opioid obtained primarily from a friend or relative (2). Furthermore, rates of opioid and drug misuse, including abuse and diversion, continue to rise (3).

Although opioid prescription rates have dropped in response to the opioid crisis, the average days of prescription supply have increased, and more than 40% of patients report that their pain is not treated adequately (4,5). As a result, clinicians face the challenge of providing necessary pain control for patients while maintaining a low risk for substance abuse.

Urine drug testing (UDT) is an effective tool in pain management to monitor compliance with prescribed medications (6). National guidelines recommend UDT not only to assess compliance but also to detect undisclosed substances and diversion (7-9). Consequently clinical laboratories must be equipped to offer an extensive UDT test menu that includes both commonly prescribed medications as well as commonly abused drugs.

According to an audience poll during a scientific session at the 70th AACC Annual Scientific Meeting in 2018, more than 50% of laboratories have adjusted their toxicology testing in response to the opioid crisis (10).

Due to its superior sensitivity and specificity, definitive testing—such as liquid chromatography-tandem mass spectrometry (LC-MS/MS)—is recommended by experts, including the American Society of Interventional Pain Physicians and AACC, over immunoassays for UDT for pain management monitoring (6,8,11). However, the audience poll at the AACC Annual Scientific Meeting revealed that 66% of laboratories continue to perform a combination of methodologies (e.g. immunoassay and mass spectrometry), with only 9% of laboratories using MS exclusively.

As laboratories adjust their testing methodologies to address clinical needs and improve patient management during the opioid crisis, defining more specific guidelines on the critical components of a definitive testing panel will be helpful. Should laboratories report quantitative and/or qualitative results? Should specimens be hydrolyzed prior to analysis? What cutoffs should be utilized?

In the absence of decisive guidelines to settle these questions, clinical laboratory professionals need to make the best decision possible in their individual institutions. In this article, we discuss the current evidence around these questions and how clinical laboratorians’ decisions on each affects how providers interpret test results.

Debate #1: Quantitative Versus Qualitative Results

Reasons for qualitative reporting

Reporting results quantitatively can mislead providers into utilizing numbers to assess compliance to a prescribed regimen. Many variables—including drug-drug interactions, genetic variation, pharmacokinetics, drug metabolism and clearance, and a patient’s clinical condition(s)—may affect drug and metabolite concentrations in urine (Figure 1) (9).

Notably, laboratory directors also face challenges in interpreting quantitative results given the lack of ­correlation studies between drug levels and drug dosage/timing. At the 70th AACC Annual Scientific Meeting scientific session, 24% of the audience responded erroneously that quantitative results for hydromorphone over a 3-month period could be utilized to determine whether a patient was taking medication appropriately.

In short, reporting a binary result (detected/not detected) often offers sufficient information to assess compliance. The technical aspect of reporting qualitative results is also favorable due to using less calibrator and quality control material.

Reasons for quantitative reporting

Quantitative results offer many advantages: Both providers and laboratories can detect simulated compliance (i.e. dropping a drug directly into the urine), normalize results to creatinine, distinguish between metabolism and drug impurities, and determine the parent drug that was ingested.

When attendees at the AACC scientific session saw qualitative results for methadone (detected) and 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) (detected) in a patient prescribed methadone, 90% responded to a poll indicating they believed that the patient was taking methadone as prescribed. However, when the results were updated to methadone (> assay range) and EDDP (5 ng/mL), only 4% of the audience agreed that the patient was compliant, suggesting attendees recognized simulated compliance when presented with the quantitative results.

Drug ratios may also be useful to assess compliance. For example, patients who are prescribed buprenorphine can be monitored for compliance by the metabolite (norbuprenorphine)-parent (buprenorphine) ratio. A ratio less than 0.02 is indicative of simulated compliance in which buprenorphine was spiked directly into the urine sample (12). In addition, the relative concentrations of morphine, hydromorphone, and codeine by LC-MS/MS in patients prescribed morphine help determine whether the prescribed medication and/or additional drugs were ingested.

In patients compliant with their morphine prescriptions, hydromorphone (a minor metabolite of morphine) concentrations are typically less than 5% of the total morphine concentration, and codeine (a potential contaminant in the morphine preparation) is typically less than 1% of the total morphine concentration.

Debate #2: Hydrolysis or No Hydrolysis

Reasons to hydrolyze samples before testing

Hydrolysis increases the sensitivity of an assay, as the total concentration of a drug is measured as opposed to the free and glucuronidated forms being measured separately. False negative results can be avoided with higher sensitivity. In addition, fewer standards and controls are required if drugs are hydrolyzed as fewer drugs, namely glucuronidated metabolites, are in a panel.

Finally, results should be less confusing for clinicians to interpret. For the opioids alone, at least six additional glucuronides would need to be evaluated if hydrolysis was not performed. If a laboratory designs a panel with appropriate drugs and metabolites such as oxycodone and the primary metabolite noroxycodone, including a hydrolysis step would not impact the ability to assess compliance (13).

Reasons not to hydrolyze before testing

Hydrolysis is time consuming and prolongs turnaround time; dilute-and-shoot allows for decreased sample preparation time. Chemical hydrolysis potentially degrades opioid and benzodiazepine drugs, while enzymatic hydrolysis may be incomplete and have variable efficiency (14).

Adding glucuronides might better assess compliance and drug taking patterns (13). For example, reporting morphine-6-glucuronide and morphine-3-glucuronide concentrations as opposed to only hydromorphone (a minor morphine metabolite not present in all patients) has allowed our laboratory to rule out simulated compliance (13). Lastly, laboratories can develop LC-MS/MS assays with sufficient analytical sensitivity to accurately detect parent compounds and glucuronides when measured separately.

Debate #3: How Low Should You Go?

Reasons to use standard cutoffs

Providers frequently ask questions such as Was the cocaine strongly or weakly positive? or The patient claims she took cocaine two weeks ago—is that consistent with the results? Using standard cutoffs will help deal with these questions. Results (i.e. detected or not detected) will also be more consistent across laboratories and less confusing for providers to interpret (15). Furthermore, scientific data exist defining drug detection windows using standard cutoffs (Table 1) (16).

Reasons not to use standard cutoffs

Defining the cutoff according to a method’s analytical sensitivity offers several advantages. An increase in positivity rate will be seen for many drugs and/or metabolites using the lower limit of quantitation (LLOQ) or lower limit of detection (LLOD), which is particularly helpful in detecting aberrant drug use. A recent study in our laboratory, where cutoffs are validated at the LLOQ or LLOD depending on the drug, demonstrated an increased rate of detection of all illicit drug combinations (13).

Furthermore, using the LLOQ or LLOD will reduce the number of false negative results associated with dilute urines or matrix effects. Pesce et al. reported an approach to define cutoffs and a target for the LLOQ in which they calculated the lower 2.5% of drug concentrations in patients positive for several medications, which may assist other laboratories switching to LC-MS/MS (17).

Result Interpretation

Misinterpreting UDT can have important negative consequences, and laboratory directors must partner with providers to avoid adverse outcomes. Patients may be falsely accused of aberrant behavior, potentially resulting in discontinuation of necessary medications. Moreover, illicit drugs, undisclosed prescription use, or simulated compliance—patients diluting their urine or dropping their medication directly into their urine—may go undetected if results are misinterpreted, perpetuating the opioid crisis.

The scientific literature suggests that both attending and resident physicians from a variety of specialties do not understand opioid metabolism or cross-reactivity of immunoassays and are therefore not proficient in interpreting UDT (18,19). As laboratories transition to definitive testing and possibly reporting both free and glucuronidated drugs, we postulate this knowledge gap will widen. Consequently, clinical laboratory professionals need to educate providers so that they interpret results correctly.

At a minimum, laboratories performing this testing should have a director with expertise to assist providers in interpreting results (9). Laboratories also might offer formal clinical pathology consultations for more complex cases in which medical records need to be reviewed.

In our opinion, laboratories should provide more systematic interpretations of results in conjunction with medications. This will ensure providers can effectively manage patients. Importantly, these interpretations must be documented in patients’ medical records.

Conclusions

Until we have definitive guidelines on how to approach whether quantitative or qualitative results should be reported, whether specimens should be hydrolyzed prior to analysis, and whether standard cutoffs should be utilized, clinical laboratories need to decide what is best for their pro­viders and patient population. In the end, it may be a compromise or require various combinations of results reporting.

In our laboratory, some drugs are reported quantitatively and ­others qualitatively, specimens are not hydrolyzed, and cutoffs are defined at the LLOQ or LLOD. Our laboratory also is in the process of developing a systematic approach to providing result interpretation as well as an assessment of how it impacts patient care.

Athena K. Petrides, PhD, is the medical director for pathology informatics and assistant medical director of clinical chemistry at Brigham and Women’s Hospital. She is also an assistant professor of pathology at Harvard Medical School in Boston, Massachusetts. Email: apetrides@bwh.harvard.edu

Stacy E.F. Melanson, MD, PhD, is the associate director of clinical laboratories, co-director of chemistry, medical director of phlebotomy, and associate director of residency training at Brigham and Women's Hospital. She is also an associate professor of pathology at Harvard Medical School in Boston Massachusetts. Email: semelanson@bwh.harvard.edu

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