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14 Articles in Volume 19, Issue #5
Agonism and Antagonism of the Muscles of the Shoulder Joint: An SEMG Approach
Analgesics of the Future: The Potential of IV Formulations for Post-Op Treatment of Pain
Blood Biomarkers Show Promise for Precision Pain Management
Can I Call Myself a “Pain Specialist?”
Cases in Urine Drug Monitoring Interpretation: How to Stay in Control (Part 2)
Fear-Avoidance and Chronic Pain: Helping Patients Stuck in the Mouse Trap
How to Avoid Patient Alienation When Discussing Stress
Managing Phantom Limb Pain with Medication
Nerve Blocks Lead to Improved Quality of Life
Sacroiliac Joint Dysfunction: New Methods in Evaluation and Management
SCS Therapy in a Patient with Advanced Bilateral Kienbocks
Thoracic Epidural Abscess with Cord Compression Following a High-Frequency SCS Trial
What is the evidence to support clonidine as an adjuvant analgesic?
What’s In A Name? In This Case, That Which We Call Addiction Is Not Dependence

Cases in Urine Drug Monitoring Interpretation: How to Stay in Control (Part 2)

Basic principles in UDM are reviewed and applied to a patient testing positive for delta-9-tetrahydrocannabinol (THC) and opiates.
Pages 58-61

This is the second case in a series focusing on the differences between presumptive and definitive urine toxicology analysis, with a focus on the opiate and cannabinoid immunoassays.The first case1 reviewed basic principles of urine drug monitoring (UDM), including its role in pain management, testing types, sample validity, and cut-off concentrations.


A 61-year-old female with chronic shoulder arthritis and back pain related to spinal stenosis presents to her pain management physician’s office with concerns regarding a cannabidiol (CBD) oil product. The patient underwent a routine urine drug screen for her job and was fired due to a positive result for tetrahydrocannabinol (THC). The patient has been using CBD oil that she purchased online for the past 6 months to help with her pain. The patient does not use marijuana. Prescribed medications include pantoprazole for gastroesophageal reflux disease (GERD), lisinopril for hypertension, rosuvastatin for hyperlipidemia, and oxycodone/acetaminophen 5 mg/325 mg every 6 hours as needed for pain. These disease states are all controlled on her current regimen. The patient’s immunoassay results are shown below.

Window of Detection

As discussed in the first case in this series,1 several factors may determine the window of detection, including pharmacologic characteristics of the substances being analyzed as well as patient-related factors.2 The window of detection in urine for most opioids, regardless of duration of use, is between 1 to 3 days. Methadone, with a variable half-life of 15 to 60 hours and significantly elevated half-lives in generic outliers, may be detectable for up to 11 days.2,3 Detection of heroin is not generally made through a report of heroin in the urine because it is only present for up to 30 minutes after use.4 In individuals using heroin, it is common to see a positive result for opiates on the urine drug screen for morphine present after definitive testing. Heroin’s metabolite, 6-monoacetylmorphine (6-MAM), may be detected for approximately 8 hours,5 and is then metabolized into morphine which remains detectable for up to 3 days (see Table I). Detection of marijuana in the urine depends on the quality of the substance, frequency of use, duration of use, the individual’s fat content (since THC is stored in fatty tissue), and the hydration status of the individual being tested (see Table II).2

Cannabidiol forms several metabolites, including: 6-OH-CBD, 7-OH-CBD, and 7-COOH-CBD. It is metabolized primarily by CYP3A4 and CYP2C19 which places it at risk for drug interactions with inhibitors/inducers of these enzymes. Furthermore, CBD may inhibit CYP2C8, CYP2C9, CYP2C19, and CYP1A2, as well as induce CYP1A2.6-7 Although there are many different CBD products available, there are not many studies available regarding the window of detection for CBD and its metabolites.

There is limited information available on CBD pharmacokinetics, so let’s use pharmaceutical CBD (Epidiolex) as a starting point. Pharmaceutical cannabidiol has a half-life of 56 to 61 hours after seven days of twice-daily use, has very little renal excretion, and due to its long half-life, may be detectable in urine drug monitoring for approximately 12 days.7

This case explores differences between presumptive and definitive urine toxicology analysis, with a focus on the opiate and cannabinoid immunoassays. (Source: 123RF)

Opiate Immunoassay

Opiate assays are meant to detect natural opiates that are structurally related to morphine and morphine metabolites. These include heroin, morphine, and codeine. Semisynthetic opioids such as oxycodone, hydrocodone, hydromorphone, and oxymorphone may or may not appear in urine drug screens depending on dose and slight structural dissimilarity to morphine, due in part to a lack of a hydroxy group on the common phenanthrene nucleus.2

Oxycodone generally requires a specific assay for detection and commonly does not show up on a routine opiate immunoassay because it is derived from thebaine, not morphine.2 Oxycodone has reduced affinity to the antibodies used in most opiate assays. Therefore, in order to be detected on an opiate drug screen, oxycodone requires six times higher urine concentrations than morphine. Some opiate assays have similar rates of detection of morphine and hydrocodone, whereas others require two to three times higher hydrocodone concentrations in order to generate a positive result.8 The synthetic opioids methadone, fentanyl, tramadol, tapentadol, and buprenorphine have specific assay tests that must be conducted in order to detect the substance.

Related Metabolism

It is important to understand opioid metabolism in order to make informed decisions regarding interpretation of opioids that may be present in urine drug screens.9 The flowchart below (Figure 1) explains this process.

Figure 1. Opioid metabolic pathways. Modified from reference 10.

There are several substances that may cause opiate false positives (see Table III). Poppy seeds seldom produce positive results on opiate immunoassays, for instance, as they do not contain morphine in concentrations > 2,000 ng/mL as required for detection.8 However, 15 grams of poppy seeds in a muffin, 1 teaspoon of poppy seed filling in a cookie, poppy seed bagels, and rolls containing 2 grams of poppy seed have been found to produce detectable amounts of morphine and codeine by immunoassay; however the data remains clinically weak.5,12-14 One method that may help determine whether poppy seeds are a potential offender is to conduct quantitative testing to determine a morphine:codeine ratio. If the ratio is > 2:1 respectively, poppy seeds or heroin may be present.8

Tetrahydrocannabinol Immunoassay

The cannabinoid immunoassay primarily detects 11-nor-delta-9-tetrahydrocannabinol-9-carboxylic acid, but also other metabolites of tetrahydrocannabinol. Food products prepared with hemp seeds (eg, hemp flour, hemp-infused alcoholic beverages, hemp seed tea, hemp seed oil, etc.) may produce THC metabolites. However, in most instances, food products do not contain enough THC to produce a positive urine drug screen.2

One study evaluating hemp seed tea discovered that cannabinoids could be found in the urine after ingestion of 12 to 24 ounces. None of the urine samples met the positive cutoff concentrations for urine drug screens or gas chromatography–mass spectrometry (GC-MS) testing. Several case reports have demonstrated the presence of THC in the urine after hemp seed oil consumption.5

Pure CBD should not produce a positive result on a cannabinoid screening because it is not metabolized into THC. For instance, 10,000 ng/mL of cannabidiol produced a negative result via a commercial cannabinoid screening product.15 CBD products must have less than or equal to 0.3% THC by dry weight to be consumed legally, according to the Agriculture Improvement Act of 2018. However, because CBD oil production is not regulated, there may be THC in excess of 0.3% present.16

Another study analyzing 83 CBD oil products via liquid chromatography (LC) discovered that 21% contained THC. Tetrahydrocannabinol content ranged from 0 to 6.43 mg/mL.17 Therefore, some of these samples contained 0.64% THC, which is more than double the legal limit. It is at the clinician’s discretion as to what steps may be taken if THC is present in the urine of a patient who is a known user of CBD oil. Further testing of the urine sample and CBD product may be prudent.

NSAIDs may cause THC false positives on UDM.5 Some studies have suggested that the active metabolite of efavirenz, efavirenz-8-glucuronide, may interact with cannabinoid immunoassays to generate a positive result for THC.5,11 Proton pump inhibitors have also resulted in THC false positives on urine drug screens.5 Dronabinol (Marinol) is likely to produce positive results on THC immunoassays because this medication consists of synthetic delta-9-tetrahydrocannabinol (see Table IV).18

Passive Exposure to Marijuana

There has been much debate regarding whether or not passive exposure to marijuana may lead to a positive urine drug screen result; there is some potential for an individual to have detectable amounts of THC in their system after being exposed to marijuana smoke. However, in most cases, the amount of THC present has not been shown to surpass 50 ng/mL to trigger positive results on UDM.

Additionally, specific conditions must exist in order for this to occur. For example, riding in a vehicle with all of the windows up while other individuals are smoking marijuana. Passive exposure in a more open or ventilated environment is not likely to amount to detectable THC via immunoassay.2,5

Return to the Patient Case

The patient’s UDM was positive for opiates, oxycodone, and THC. The positive opiate and oxycodone results were expected because the patient takes prescribed oxycodone. Additionally, the patient had an unexpected positive result for THC. (Note that the patient is prescribed pantoprazole for GERD. Proton pump inhibitors may rarely produce false positive results for THC on urine drug screens.) Since a positive result for THC created occupational ramifications for this patient—specifically, losing her job—definitive testing was ordered via GC-MS.

Results of the GC-MS testing came back as follows: pantoprazole, oxymorphone, oxycodone, acetaminophen, and THC. Urine creatinine was 56 mg/dL. Results showed expected prescribed medications as well as their metabolites, and the urine sample was untampered. However, THC was still present. What might a clinician do in this situation?

Laying down ground rules regarding the utilization of non-prescribed and illegal substances during an initial patient encounter is important. Be sure to provide the patient with a written agreement outlining your expectations, UDM requirements, and potential consequences for aberrant behavior or abnormal urine drug screen results.

Use of THC may or may not be allowed in your practice. In examples similar to the presented case, clinicians may consider testing of the CBD oil product to determine whether there is indeed THC content. If THC is not permitted, the clinician may remind the patient that continued use of the substance containing THC could lead to discontinuation of pain medications and/or dismissal from the clinic. If future urine drug screens show positive results for THC, this could be considered a breach of the controlled substance agreement and opioids may be tapered off at that point.

Clinical judgments should always be made on a case-by-case basis. However, the utilization of pain agreements and early discussions with the patient about the clinic rules will help to establish transparency and provide clear directions for the patient to follow.


Care should be taken when interpreting tetrahydrocannabinol and opioid immunoassays as there may be various reasons for a positive or negative result. In relation to THC, CBD oil production and sale is not regulated. Therefore, CBD oil products may contain more than the legal amount of THC content. Finally, understanding opioid metabolism may help prescribing clinicians to properly interpret urine drug monitoring results and to recognize when further screening may be needed.

Last updated on: January 29, 2020
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Cases in Urine Drug Monitoring Interpretation: How to Stay in Control (Part 1)
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