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13 Articles in Volume 18, Issue #6
Authorities’ Use of Big Data May Harm—or Help—Your Chances of Investigation
Gaps in the Pharmacist’s Pain Management Role
How can cyproheptadine manage complicated chronic pain cases?
Letters to the Editor: Trackable Pills; Buprenorphine; CRPS Diagnosis
Managing a New High-Dose Opioid Patient
Managing Opioid Use Disorder
Medication Selection for Comorbid Pain Management (Part 2)
Mobile Trackers and Digital Therapeutics
New Insights in Understanding Chronic, Central Pain
Nocebo Effects: How to Prevent them in Patients
Polarizing Topics in Chronic Pain
The Fight to End Peripheral Neuropathy
Urine Drug Monitoring

Urine Drug Monitoring

Strategies for ordering, understanding, and communicating opioid therapy screening results.

Although not a novel tool, urine drug monitoring is increasingly being utilized by pain practitioners and primary care physicians to help monitor patients on opioid therapy. Endorsed by a plethora of guideline and industry peers,1-5 this clinical tool not only helps to ensure patient compliance with a prescribed regimen, but may also mitigate the abuse, misuse, or diversion of substances. Some of these guidelines include those from the Centers for Disease Control and Prevention, Federation of State Medical Boards, American Society of Interventional Pain Physicians, and the Department of Veterans Affairs/Department of Defense.1

There are many nuances when it comes to using urine drug monitoring (UDM) to guide therapy and improve the quality of care. Having a complete understanding of these subtle distinctions, therefore, may reduce the risk of inappropriate interpretation that could adversely affect patient outcomes. The following recommendations are based on a previous oral presentation.6

Types of Urine Drug Monitoring

In general, there are two main types of UDM used in ambulatory care settings: presumptive testing by immunoassay and definitive testing by chromatography. In traditional clinics, UDM immunoassay, also known as urine drug screen, serves as the initial differential test while chromatography confirms the assessment. (More on testing in the PPM/Quest Clinical Drug Monitoring online resource guide.)


The immunoassay method utilizes antibodies binding with specific drugs and/or metabolites to detect their presence in urine to evaluate potential use, misuse, or abuse of both prescribed and unprescribed medications or illicit substances. As an initial screen, immunoassay is relatively quick, inexpensive, and sensitive. One major drawback of this test is that it lacks specificity, which means false-positive or false-negative results are possible. Another drawback is that immunoassay has a relatively high cutoff value for detection.

A false-positive result may occur when the panel yielding a positive screen for a substance (an opiate for example) without the patient taking that substance due to similarities in chemical structures. In this situation, the patient could be accused of taking a substance that he/she is not taking, when in fact, another prescribed medication is falsely causing the positive result. The second issue to consider is that, for the specific substance to be detected in the urine, it must be present in a high enough concentration. If the urine concentration of the substance is not above the cutoff value for detection, it will yield a negative result. This determination is also subject to falsehoods, as anything that decreases substance concentration in the urine, such as variability in drug metabolism (due to drug-drug interactions and/or pharmacogenomics), length of time between drug ingestion and specimen acquisition, and kidney function, may potentially induce a false-negative result.

In general, most immunoassay screens include the “Federal Five Panel,” which includes opiates, cannabinoids, amphetamine, cocaine, and phencyclidine.1,7 Notably, benzodiazepines are also commonly incorporated into immunoassay screens. Table I depicts the parent compounds of these substances, as well as their specific metabolites detected by immunoassay enzymes. It is important to recognize which compounds and metabolites from each class are detected as the immunoassay antibodies will only bind to compounds with the same chemical structure. Notably, certain benzodiazepines are expected to test negative; these include but are not limited to clonazepam, alprazolam, and lorazepam due to their metabolic pathways compared to, for example, diazepam, oxazepam, and temazepam.

The designated “opiate panel” may only detect opium alkaloids and/or their metabolites, including morphine and codeine.1 As both morphine and codeine are in the chemical class of phenanthrenes, other phenanthrenes that are semi-synthetic (eg, hydrocodone, oxycodone, buprenorphine, and hydromorphone) may or may not be detected as an “opiate” depending on the dose. Heroin, another semi-synthetic phenanthrene, should always be detected due to its chemical structure of diacetylmorphine. Conversely, opiates that are completely synthetic with non-phenanthrene chemical structures (eg, methadone, fentanyl, tapentadol, and tramadol) will not be detected on immunoassay. See Table II for further delineation. (Disclaimer: Urintel, a software app developed by co-author J Fudin, Remitigate, LLC, automates potential negative or positive screen results.)


Quantitative testing such as chromatography is mainly utilized to confirm or verify immunoassay results when those initial results are unexpected or abnormal.3 This type of testing uses either a gas or liquid carrier medium to separate out the urine sample’s compounds by their molecular interactions (polarities) with the carrier medium.3 During the separation process, the separated compounds are fed into a mass spectrometer that ionizes the compounds, detecting different fragments using their mass-to-charge ratio.3 The end result is a unique fingerprint for that specific compound that may be identified against a reference standard.

The three most commonly utilized types of chromatography include gas chromatography/mass spectrometry (GC/MS), liquid chromatography tandem mass spectrometry (LC/MS/MS), and high performance liquid chromatography.7 Although GC/MS has remained the standard confirmatory test, LC/MS/MS is gaining favorability due to advantages over GC/MS.1,3 For example, LC/MS/MS requires less urine volume to conduct an analysis and includes a second analytical separation step, which reduces the chance for sample rejection due to inadequate specimen quantity and lowers susceptibility to “false” results caused by concomitant use of other medications.8,9

Regardless of the testing medium used, the primary reason quantitative confirmation through chromatography is more advantageous than immunoassay is due to increased accuracy. Chromatography is able to identify smaller quantities of specific drugs and metabolites, lowering the specific cutoff threshold value for those drugs, and reducing the chance for “false” results.1,10 Pesce, et al, identified false-negative rates associated with immunoassay to be 22%, 50%, and 23.4% for benzodiazepines, cocaine, and propoxyphene, respectively, when compared to LC/MS/MS.10 Perhaps the biggest and only limitations to chromatography use are that it takes longer to obtain results and that it is more costly than immunoassay.

Clinical Interpretation of Chromatography

Although chromatography offers a variety of advantages over immunoassay, it too needs to be appropriately evaluated and interpreted to ensure an accurate reflection. Similar to immunoassay, having extensive knowledge of pharmacokinetic and pharmacogenomic variability is crucial in understanding confirmatory testing results.

Consider a patient on extended-release oxycodone 30 mg twice daily, for example. Oxycodone is metabolized via cytochrome (CYP) P450 enzyme 3A4 into noroxycodone and, to a much lesser extent, by CYP2D6 into oxymorphone. If tested in a patient without any pharmacokinetic interactions or pharmacogenomic variability, one might suspect the patient’s urine level of oxycodone to be higher than either metabolite and the urine level of noroxycodone to be higher than that of oxymorphone. If there are only concentrations of oxycodone without any metabolite concentrations, the possible explanations are: a) the patient dissolved oxycodone directly into the urine sample without ingestion (bypassing metabolism); b) the patient is using medications that inhibit CYP2D6 and CYP3A4; c) the patient could be a CYP2D6 and CYP3A4 poor metabolizer. The latter option could be confirmed through pharmacogenetic testing. Weighing each possible explanation and evaluating their validity may help reduce the risk of incorrectly accusing a patient of misuse and allows for enhanced patient care.

Communicating Test Results

Perhaps the most essential part of the urine drug monitoring process is communicating the results to the patient. It is crucial to remember that healthcare professionals are not detectives, legal authorities, or legal enforcers. Unexpected UDM results must lead to a provider-patient discussion aimed at education and providing safe and effective care. When identifying a substance use disorder, proper counseling and support should be offered so that the patient may obtain treatment that specifically addresses his or her condition. (see sample video dialogues between clinicans and patients in the PPM/Quest Clinical Drug Monitoring online resource guide.)


Urine drug screening represents a valuable practitioner’s tool for the safe prescribing and monitoring of opioids and its acceptance as a standard of care by several guidelines and growing peer support is likely to only increase use in today’s pain management landscape. Appropriate use, understanding of results—including potential false-positives or false-negatives, and upfront patient communication around UDM may help to justify opioid therapy as well as track risky behaviors. It is essential that providers are equipped with knowledge regarding the interpretation and pitfalls of each method promoting universal, unbiased care for all patients.

More on this topic in the PPM/Quest Clinical Drug Monitoring online resource guide.

Last updated on: January 3, 2019
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Expert Panel Report on Urine Drug Monitoring for At-Risk Chronic Pain Patients
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