Interpreting Negative Urine Drug Test Results
When a clinician orders urine drug testing for a patient prescribed chronic opioid therapy (COT), it is essential that the results are interpreted correctly because they often have significant clinical implications. A positive test result showing drugs and/or metabolites found in urine is easily understood. A negative result, while initially simple to understand, can be more complicated and requires the clinician to be aware of several factors that can cause the urine sample to test negative for a compound. For example, a positive drug test for oxymorphone, a metabolite of oxycodone, can be misinterpreted as possible misuse of a “nonprescribed” medication. On the other hand, negative urine drug test results are clinically meaningful, especially when the possibility exists that the patient may be misusing, abusing, or diverting their medications. For the purpose of this article, the authors will focus on the implications of negative test results.
The Centers for Disease Control and Prevention have declared prescription drug abuse to be an epidemic in the United States.1 Drug abuse permeates all sections of society: male and female, rich and poor, young and old. Clinicians who prescribe opioids must make every effort to ensure that the prescriptions given to a patient are used by that individual and not misused. Thus, when a clinician receives urine drug test results with a negative result, it is imperative that the potential reasons are clearly understood so that the appropriate clinical decision can be made.
Over the last few years, states have enacted mandates at the clinician level to prevent misuse, abuse, and diversion, including the adoption of prescription drug monitoring programs, controlled substance treatment agreements with patients, and urine drug testing. As a result, clinicians have needed to familiarize themselves with drug metabolism and excretion times in order to interpret test results more effectively. Some potential explanations for why a prescribed drug might not be detected in a patient’s urine sample include medication hoarding or diversion, time between last dose and sample collection, self-escalation or binge use, failure to take the medication or taking only as needed, rapid metabolism, drug-drug interaction, and potential lab error.2 Other factors for a negative result include the integrity of the specimen submitted, analytical testing factors within the laboratory including false negatives, and steps within sample processing. Given the consequences surrounding negative urine drug test results, it is important to fully identify all possible causes for a negative drug test result.
Specimen validity testing (SVT) is a laboratory means to assess whether the submitted urine sample is consistent with characteristics of human urine. Generally these tests involve the evaluation of the following parameters: pH (ie, the alkalinity or acidity of a sample), amount of creatinine excreted, determination of specific gravity, and a test for oxidants. A sample may fall under the following categories: normal, dilute, invalid, substituted, or adulterated. Ko et al summarized each of these scenarios in “Focus on Screens: Specimen Validity Testing,” published in Practical Pain Management in June 2013.3 An abnormality in SVT can account for a negative test result because the specimen may be very dilute or contain an additive that could have resulted in drug degradation below the level of detection.
Analytical Testing Factors
Evaluating the laboratory’s established cutoff level is a critical step when interpreting a negative urine drug result. Cutoffs are administrative values chosen by the laboratory and often are based on multiple factors, such as analysis type (screening test via an immunoassay technique versus confirmation test via a mass spectrometer), specimen type, purpose of the testing (workplace versus treatment of COT patients), and the instrument’s capabilities and limitations (confirmation with a mass spectrometer versus tandem mas spectrometry). In addition, Point of Care cups for rapid screening may produce negative results for a prescribed drug because the urine level of the parent drug or metabolite may be below the threshold or cutoff level.
Testing methods may be limited by the availability of compounds used as reference standards. Reference standards are known materials used by laboratories to compare patient samples, and often are accompanied by certificates detailing the prepared concentration and purity. These standards allow for monitoring the most reliable target compound for evaluating the presence or absence of drug. If the parent drug or best metabolite to monitor adherence is not used, a false negative result is possible. Recently, this occurrence was demonstrated when patients were tested for the antipsychotic medication aripiprazole (Abilify). In testing urine samples from patients clinically assessed as adherent, the parent compound ari-
piprazole was detected only 50% of the time and its metabolite dehydroaripiprazole only 8% of the time. OPC3373, a lesser known metabolite, was identified above the cutoff level in 93% of samples.4
Some immunoassay tests are subject to the “hook effect,” a phenomenon that can result in a false negative test result.5 Immunoassays are based on the binding of an antibody and antigen. When a drug is present in such high concentrations that there are no more binding sites left on the antibody, the sample may present with falsely low values. If the low value is below the test cutoff, the result will be negative. Although this is rare, it cannot be ruled out, nor can it be predicted. Fortunately, the manufacturers of immunoassay testing kits have made design improvements over the years and the incidence of such a phenomenon has been greatly reduced.
Another point to consider is the degree of cross-reactivity between the target compound and structurally related compounds. For example, Fileger et al demonstrated how a sample containing lorazepam or 7-aminoclonazepam (primary metabolite of clonazepam) may result in a false negative benzodiazepine test result, because these compounds are known to have a low cross-reactivity with many traditional benzodiazepine immunoassay kits.6 Therefore, when a patient is prescribed a drug for which an assay has limited cross-reactivity, it is important that the laboratory conduct further testing, as is accomplished with a mass spectrometer.