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Clinical Drug Monitoring & Medication Adherence
Brought to you by Quest Diagnostics and Practical Pain Management

Scenario: Metabolite Missing on Screen for a Patient on Medication-Assisted Treatment; Possible Adulteration

Conditions addressed
chronic pain, opioid use disorder (OUD)/opioid addiction

Medications addressed
buprenorphine, clonazepam, lorazepam, methadone, naltrexone, norbuprenorphine, nordiazepam, oxazepam, oxymorphone

Image: iStock

Patient Case

A 34-year-old woman was successfully tapered off her regimen of oxymorphone ER/IR as part of a medication-assisted treatment (MAT) plan for opioid use disorder (OUD). She is maintained on buprenorphine (4 mg sublingual, 3 times a day). She has a history of chronic pain from multiple traumas, including a recent motor vehicle accident. She smokes 1.5 cigarettes per day and states that she does not drink alcohol.

As part of her MAT clinical drug monitoring regimen, she recently tested positive for buprenorphine and benzodiazepine. The presumptive urine screen was conducted in-office using a point-of-care cup. Query of the state’s prescription drug monitoring program (PDMP) revealed no other current controlled substance prescriptions.

Based on these preliminary qualitative results, the provider would like to determine what specific benzodiazepine the patient is consuming and confirm that the patient is in compliance with her buprenorphine dosage. The provider queried the patient about other drug and alcohol use, as well as “doctor shopping.” She denied illicit drug use, concomitant benzodiazepine, and other opioid use.

Background: Drug Monitoring as Part of Medication Assisted Treatment

Medication-assisted treatment (MAT) is the use of FDA-approved medications, in combination with counseling and behavioral therapies, to provide a "whole-patient" approach to the treatment of substance use disorders, including opioid use disorder (OUD).1 The most commonly administered medications for MAT include methadone, buprenorphine, and naltrexone. Beyond behavioral or addiction medicine specialists, it is important for both primary care and pain management clinicians to have at least a basic understanding of how and why these agents are utilized as well as which drug monitoring strategies are used for these treatments. 

Under the Narcotic Addiction Treatment Act  of 1974,2 practitioners who prescribe opiate drugs for the treatment of addiction must obtain a separate registration. Methadone, a Schedule II substance under the Controlled Substances Act, treatment must be performed in a highly structured clinic; however, buprenorphine, a Schedule III substance, is the first medication to treat opioid addiction, or OUD, that is permitted to be prescribed or dispensed in physician offices. More specifically, under the Drug Addiction Treatment Act of 2000 (DATA 2000), qualified US physicians and mid-level practitioners with a waiver (also known as an “X-license”) may prescribe buprenorphine for drug addiction treatment in various settings, including in an office (physicians only), community hospital, health department, or correctional facility (mid-level practitioners).3 No special license or waiver is required to prescribe naltrexone, an opioid antagonist.

MAT is primarily used for the treatment of addiction to illicit drugs such as heroin as well as to prescription opioid analgesics. Prescribed medications attempt to normalize brain chemistry, relieve physiological cravings, and normalize body functions without the negative effects of the abused drug. Each MAT option has its own advantages; it is beyond the scope of this paper to discuss the detailed pharmacology of each, but drug metabolism is further discussed in regard to drug monitoring below. 

Clinical drug monitoring (eg, urine, oral fluid, blood) is recommended for patients enrolled in MAT programs to aid in the detection of drug diversion, illicit use, and compliance with treatment. The interpretation of urine drug monitoring, the most common matrix used, can be complex; as a result, clinicians need a basic understanding of what is involved in this testing. Read more about presumptive and definitive testing types and what they provide.

A Closer Look at MAT Metabolism and Drug Monitoring Results


Buprenorphine’s pharmacological and safety profile makes it an attractive treatment for patients addicted to opioids.4 A partial agonist at the mu opioid receptor and an antagonist at the kappa receptor, buprenorphine has a very high affinity and a low intrinsic activity at the mu receptor and, therefore, can displace full agonists from the receptor. Its partial agonist effects imbue buprenorphine with several clinically desirable pharmacological properties, including lower abuse potential, lower level of physical dependence, a ceiling effect on CO2 accumulation at higher doses, and greater safety in overdose compared with opioid full agonists. (Read more about the buprenorphine profile).

Definitive (quantitative) drug monitoring is typically utilized to monitor patients receiving buprenorphine for OUD treatment.  Buprenorphine, with a half-life ranging from 24 to 42 hours, is metabolized to norbuprenorphine mostly by the hepatic cytochrome P450 3A4 enzyme system. In 1 study, buprenorphine concentrations averaged 164 ng/mL with a standard deviation of 198 ng/ml and ranges of <5 to >10,000.5 Many have recommended analyzing the patterns of urine norbuprenorphine to buprenorphine levels, which may offer useful information regarding those patients suspected of tampering with their urine sample (ie, adding or “spiking” buprenorphine) to produce a positive test and simulate adherence to therapy. When this occurs, there is little to no metabolite in the sample; hence, the norbuprenorphine:buprenorphine ratio provides insights into specimen validity.6 The absence of metabolite, or its presence in low relative concentrations, may prove to be a useful clinical indicator of specimen adulteration.


Methadone has a short analgesic half-life of 6 to 12 hours but has a variable elimination half-life of 12 to 150 hours due to its lipid solubility, redistribution into fat, and polymorphic variability by phenotype. The substance has proven a useful agent in the treatment of OUD and chronic pain. Methadone elimination occurs mainly through metabolism in the liver by CYP3A4, CYP2B6, and CY2C19 and, to a lesser extent, by CYP2D6 and in the intestine by CYP3A4. Methadone is metabolized in the body to a number of inactive metabolites, but primarily to 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP).

Additionally, the methadone S-enantiomer increases risk of QTc prolongation. Since metabolism to the inactive EDDP relies on CYP 2B6, those patients that are phenotypically poor expressors of CYP 2B6 could be at higher risk of a methadone-induced cardiac event. Various studies have concluded that the parent drug, methadone, may be difficult to detect with some drug testing techniques, and that testing instead for the metabolite EDDP offers a sensitive and reliable technique to determine the compliance of subjects prescribed methadone for pain, opiate detoxification, and maintenance. Concentrations of EDDP can be highly variable because methadone metabolism is subject to wide variations in inter- and intra-individual pharmacokinetics. EDDP levels have been reported in the range of <100 and greater than 30,000 ng/mL.7


Naltrexone is an opioid antagonist that blocks the effects of mu opioid agonists. It does not have addictive properties or produce physical dependence; tolerance does not develop with use. The substance has a long half‐life, with therapeutic effects lasting up to 3 days. Naltrexone also decreases the likelihood of alcohol relapse when used to treat alcohol dependence. Unfortunately, many patients with OUD may not be interested in taking naltrexone because, unlike methadone, it has no opioid agonist effects; patients continue to experience cravings and are thereby unmotivated to maintain adherence to the medication regimen.

Naltrexone is available in a once-monthly extended release (ER) formulation, as well as in oral tablets. When administered orally, naltrexone is rapidly metabolized in the liver to its primary metabolite, 6-beta-naltrexol. The mean elimination half-life (T-1/2) values for naltrexone and 6-ß-naltrexol are 4 hours and 13 hours, respectively, according to drug labeling.8

Of importance, while oral formulation naltrexone can be used in MAT, it should be considered only for those patients where adherence can be supervised and enforced. ER injectable naltrexone is more suitable and preferred for all patients, especially those who have issues with treatment adherence. Patients who discontinue or do not achieve desired therapeutic outcomes with naltrexone may switch to buprenorphine.

The provider should confirm that an adequate period of opioid abstinence has occurred prior to naltrexone administration. Although not always possible, an opioid-free interval of a minimum of 7 to 10 days is recommended for patients previously dependent on short acting opioids.8 Clinicians can assess patient self-report and negative urine drug test results as well as monitor for symptoms of opioid withdrawal. Similar to buprenorphine, definitive drug testing should be used to assess both the parent naltrexone and its 6-beta metabolite, to confirm patient compliance with the oral formulation.   

Return to Patient Case and Discussion

Returning to the presented patient case above, a provider is seeking information on patient compliance and possible adulteration of a urine drug monitoring point-of-care sample for an oxymorphone ER/IR tapered patient.

Presumptive screen results were positive for an unprescribed benzodiazepine; definitive testing revealed diazepam and its metabolites nordiazepam and oxazepam. Reports in the literature have documented drug mixing with combinations of benzodiazepines and opioids; surprisingly, 1 in 5 samples shown positive for either an opioid or benzodiazepine were positive for an unprescribed opioid or benzodiazepine as well.9

Typical detection windows for benzodiazepines in the urine are 2 to 7 days, depending on the individual benzodiazepine drug used and other factors, such as time of last dose, drug half-life, route of administration, and individual differences in pharmacokinetics. Common limitations exist for screening benzodiazepines when using traditional point-of-care immunoassay (IA) tests. For instance, IA testing for benzodiazepines often targets nordiazepam and oxazepam to measure whether an antibody-antigen response occurs, resulting in a positive or negative test result. Unfortunately, low cross-reactivity of other benzodiazepines such as clonazepam and lorazepam may result in false negatives on these screens. For this reason, definitive testing using gas or liquid chromatography/mass spectrometry (GC, LC/MS) may be more useful.10

In this case, while the buprenorphine result was positive on the point-of-care screen, after the sample was sent to the laboratory for a definitive screen, results were as follows (see Table I):






Why is the parent drug buprenorphine positive and the major metabolite (norbuprenorphine) negative in this case? Buprenorphine is extensively metabolized via N-dealkylation to norbuprenorphine, the predominant analyte in urine, chiefly by CYP3A4.

According to the literature, in-office adulteration is possible. As on example, Suzuki J, et al, noted: “Patients may spike urine samples with buprenorphine during office-based opioid treatment to simulate adherence to prescribed buprenorphine, potentially to conceal overuse or diversion of medications. However, routine immunoassay screens do not detect instances of spiking, as these would simply result in a positive result for the parent compound,” in this case, buprenorphine.11

It appears as if this patient may have cut up and added a small amount of buprenorphine to her urine sample to achieve a positive effect. If the provider had not ordered definitive confirmation of the sample, compliance may have been assumed. There are other, more rare examples of buprenorphine-only positive presumptive screen results occurring when the patient had just recently ingested a single dose. However, in the case presented, the patient would have been at steady state plasma levels from taking her medicine 3 times daily for a number of months.

In this case, the provider would need to address the results with the patient, including a review of the Patient Agreement, and, if not already part of the treatment plan, consider referral for psychological services to provide more biopsychosocial support for treating the patient’s ongoing substance use disorder. 

Key Takeaways

  • Medication-assisted treatment (MAT) is the use of FDA-approved medications such as buprenorphine, methadone, and naltrexone, in combination with counseling and behavioral therapies, to provide a whole-patient approach to the treatment of substance use disorders, including opioid use disorder (OUD).1
  • While presumptive monitoring may be most the common drug testing method of choice, it is important that providers employ definitive testing for those patients undergoing MAT.
  • Definitive testing can help to ensure the integrity of  clinical drug monitoring results by measuring pH, creatinine, and specific gravity as well as by testing for adulterants that may have been added to the specimen.


Written by Jeff Gudin, MD.
Disclosure: Dr. Gudin serves as a medical advisor to Quest Diagnostics.

Last updated on: May 5, 2020
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