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Laboratory monitoring for patients on buprenorphine: 10 questions
The opioid use disorder (OUD) epidemic is a major public health crisis in the United States.1 Naltrexone, methadone, and buprenorphine are first-line therapies for OUD and have high success rates.2 While studies have shown that naltrexone is effective, patients must achieve opioid detoxification and maintain 7 to 10 days of total abstinence to avoid a precipitated opioid withdrawal before it can be prescribed.3 Methadone does not require detoxification or a period of complete abstinence, but must be prescribed in special clinics and requires daily observed dosing for the first 90 days,4 though these requirements have been relaxed during the COVID-19 pandemic. In contrast, buprenorphine (with or without naloxone) can be used in office-based settings, which significantly improves the accessibility and availability of treatment for patients with OUD. Clinician knowledge and comfort prescribing buprenorphine are limiting factors to treatment.5 Increasing the number of clinicians proficient with buprenorphine management can improve access to effective treatment and recovery services, which is critical for patients with OUD.
Multiple resources are available for clinicians to learn how to prescribe buprenorphine, but clear guidance on laboratory testing for patients receiving buprenorphine is limited. To safely and effectively prescribe buprenorphine, clinicians need to understand its pharmacology (Box 16-9) and how laboratory testing influences treatment. In an effort to increase clinician knowledge of and proficiency with buprenorphine, this article answers 10 common questions about laboratory monitoring of patients receiving this medication.
Box 1
For patients with opioid use disorder, buprenorphine is indicated for opioid detoxification and maintenance. Oral formulations of buprenorphine (including tablets and buccal films) have long durations of action, and when dosed daily can prevent opioid withdrawal for at least 48 hours.6 The recommended formulation is a combination of buprenorphine and naloxone, because this formulation is associated with a lower risk of misuse and diversion compared to formulations containing only buprenorphine.7 However, buprenorphine alone can be effective in patients who experience adverse effects from or are unable to tolerate the combination buprenorphine/naloxone formulation.7 Despite the addition of naloxone, buprenorphine prescriptions may still be misused and diverted, so close monitoring is necessary.
Buprenorphine is metabolized by the cytochrome P450 system (CYP) (primarily CYP3A4) to its active metabolite, norbuprenorphine, both of which are primarily excreted in feces.8 However, small quantities of buprenorphine and norbuprenorphine are excreted in the urine,9 which makes urine specimen the best choice to monitor buprenorphine use for therapeutic purposes.
1. Why is laboratory monitoring important?
Proper laboratory monitoring discourages illicit substance use, encourages medication adherence, and influences treatment modifications. Patient self-reporting on medication compliance may be inaccurate or unreliable.10 Patients who relapse or use other illicit substances may also be reluctant to disclose their substance use.11
On the other hand, laboratory tests are objective markers of treatment outcome and adherence, and can verify a patient’s self-report.12 When used appropriately, laboratory monitoring can be therapeutic. It holds patients accountable, especially when used in conjunction with contingency management or other behavioral therapies.13 Laboratory monitoring is the most reliable method of determining if patients are abstaining from opioids and other illicit substances, or if the treatment plan requires revision.
2. Which tests should I order?
When initiating or maintaining a patient on buprenorphine, order a general urine drug screen (UDS), urine opioid screen (availability varies by institution), urine creatinine levels, urine buprenorphine/norbuprenorphine/naloxone/creatinine levels, urine alcohol metabolite levels, and a urine general toxicology test. It is also recommended to obtain a comprehensive metabolic panel (CMP) before starting buprenorphine,14,15 and to monitor CMP values at least once annually following treatment. Patients with a history of IV drug use or other high-risk factors should also be screened for hepatitis B, hepatitis C, and HIV.14,15
A general UDS can determine if opiates, amphetamines, cocaine, marijuana, or other common illicit substances are present to identify additional substance use. The proficiency of a general UDS may vary depending on the panels used at the respective institution. Some clinics use point-of-care UDS as part of their clinical management; these tests are inexpensive and provide immediate results.16 A basic UDS typically does not detect synthetic opioids due to the specificity of conventional immunoassays. As a result, specific tests for opioids such as oxycodone, hydrocodone, hydromorphone, oxymorphone, fentanyl, and methadone should also be considered, depending on their availability. Though buprenorphine treatment may trigger a positive opiate or other opioid screen,17 buprenorphine adherence should be confirmed using several urine tests, including creatinine, buprenorphine, norbuprenorphine, and naloxone urine levels.
In addition to screening for illicit substances and buprenorphine adherence, it is important to also screen for alcohol. Alcohol use disorder (AUD) is highly comorbid with OUD,18 and is associated with worse OUD treatment outcomes.19 Alcohol use may also affect liver function necessary for buprenorphine metabolism,8 so urine alcohol metabolites such as ethyl glucuronide and ethyl sulfate, serum transaminases, and gamma-glutamyl transferase should also be obtained.
Continue to: How frequently should patients be tested?
3. How frequently should patients be tested?
As part of the initial assessment, it is recommended to order CMP, UDS, and urine general toxicology.14 If indicated, specific laboratory tests such as specific opioid and alcohol metabolites screens can be ordered. After starting buprenorphine, the frequency of monitoring urine laboratory tests—including UDS, general drug toxicology, buprenorphine/norbuprenorphine/naloxone/creatinine, and alcohol and its metabolites—depends on a variety of factors, including a patient’s treatment response and stability as well as availability and cost of the tests. Ultimately, the frequency of laboratory monitoring should be determined on a patient-by-patient basis and clinicians should use their judgment.
The American Society of Addiction Medicine suggests testing more frequently earlier in the course of treatment (eg, weekly or biweekly), then spacing it out over time (eg, monthly or quarterly) as the patient’s recovery progresses.14,15 To conserve resources and reduce spending, some clinicians and guidelines recommend random monitoring as opposed to monitoring at every follow-up visit (eg, once out of every 3 to 5 visits, on average), which allows for longer intervals between testing while ensuring consistency with medication and abstinence from illicit substances.15,16 We suggest screening every 2 weeks for the first month, then spacing out to monthly and quarterly as patients demonstrate stability, with random screening as indicated. Monitoring of liver function should be done at least once annually.
4. How should urine buprenorphine and other results be interpreted?
There are several issues to consider when interpreting laboratory results. The clinician needs to know what to expect in the sample, and what approximate levels should be detected. To check treatment adherence, laboratory data should include stable urine buprenorphine and norbuprenorphine levels and negative urine screening for other illicit substances.14,15 While urine buprenorphine and norbuprenorphine levels have great interindividual variability due to genetic differences in hepatic metabolism, unusually high levels of buprenorphine (≥700 ng/mL) without norbuprenorphine suggests “urine spiking,” where patients put buprenorphine directly into their urine sample.20,21 Abnormally low or undetectable levels raise concern for medication nonadherence or diversion.
Though urine buprenorphine levels do not reliably correlate with dose, because there is typically not much intraindividual variability, patients should have relatively stable levels on each screen once a maintenance dose has been established.22 Furthermore, the buprenorphine-to-norbuprenorphine ratio (ie, “the metabolic ratio”) typically ranges from 1:2 to 1:4 across all individuals,20,21,23 regardless of dose or metabolic rate. Urine naloxone levels, which typically are included in commercial urine buprenorphine laboratory panels, also may aid in identifying tampered urine specimens when buprenorphine-to-norbuprenorphine ratios are abnormal or inconsistent with an individual’s prior ratio. Naloxone is typically (but not always) poorly absorbed and minimally detected in urine specimens.20 A high level of naloxone coupled with unusually high buprenorphine levels, particularly in the absence of norbuprenorphine in the urine, may indicate urine spiking.20,21,23
Urine creatinine is used to establish the reliability of the specimen. When urine creatinine concentration is <20 mg/dL, the concentration of most substances typically falls to subthreshold levels of detection.24 If a UDS is negative and the urine has a creatinine concentration <20 mg/dL, the patient should provide a new sample, because the urine was likely too diluted to detect any substances.
Continue to: The presence of alcohol...
The presence of alcohol metabolites can alert the clinician to recent alcohol use and possible AUD, which should be assessed and treated if indicated.
Liver enzymes should be normal or unchanged with short- and long-term buprenorphine use when taken as prescribed.25,26 However, acute liver injury may occur if patients inject buprenorphine intravenously, especially in those with underlying hepatitis C.25
5. What can cause a false negative result on UDS?
Laboratory monitoring may occasionally yield false negative drug screens. For urine buprenorphine levels, false negatives may occur in patients who are “rapid metabolizers,” infrequent or as-needed usage of the medication, patient mix-up, or laboratory error.27 For other substances, a false negative result may occur if the patient used the substance(s) outside the window of detection. The most common causes of false negative results, however, are overly diluted urine samples (eg, due to rapid water ingestion), or the use of an inappropriate test to measure a specific opioid or substance.27
Many laboratories use conventional immunoassays with morphine antibodies that react with various opioid substrates to determine the presence of a specific opioid. Some opioids—particularly synthetics such as oxycodone, hydrocodone, hydromorphone, oxymorphone, fentanyl, buprenorphine, and methadone—have poor cross-reactivity with the morphine antibody due to their distinct chemical structures, so standard immunoassays used to detect opioids may result in a false negative result.28 In such situations, a discussion with a clinical pathologist familiar with the laboratory detection method can help ensure proper testing. Additional tests for specific opioids should be ordered to more specifically target substances prone to false negative results.27
6. What can cause a false positive result on UDS?
The cross-reactivity of the morphine substrate may also result in a false positive result.28 Other over-the-counter (OTC) or prescription medications that have cross-reactivity with the morphine antibody include dextromethorphan, verapamil, quinine, fluoroquinolones, and rifampin, which can normally be found in urine 2 to 3 days after consumption.17,27 Poppy seeds have long been known to result in positive opiate screens on urine testing, particularly when laboratories use lower cutoff values (eg, 300 ng/mL), so advise patients to avoid consuming poppy seeds.29
Continue to: For other drugs of abuse...
For other drugs of abuse, false positives are typically caused by cross-reactivity with other prescription or OTC medications. Numerous substances cross-react with amphetamines and produce false positive results on amphetamine immunoassays, including amantadine, bupropion, ephedrine, labetalol, phentermine, pseudoephedrine, ranitidine, selegiline, and trazodone.27 Sertraline and efavirenz are known to produce false positive results on benzodiazepine UDS, and ibuprofen, naproxen, and efavirenz can produce false positive results for cannabinoids.27
7. How do I communicate the results to patients?
Effectively communicating test results to patients is just as important as the results themselves. A trusting, therapeutic alliance between patient and clinician is highly predictive of successful treatment,30 and how the clinician communicates affects the strength of this collaboration. A principle of addiction treatment is the use of neutral language when discussing laboratory results.31,32 To avoid unintentional shaming or moral judgment, use words such as “positive” or “negative” rather than stigmatizing terms such as “clean” or “dirty.”33
Additionally, make it clear that laboratory findings are not used to punish patients, but rather to improve treatment.34 Reassuring the patient that a positive screen will not result in withdrawal of care encourages a working relationship.14 All patients who receive buprenorphine treatment should be informed that collecting a UDS is the standard of care used to monitor their progress. You might want to compare using UDS in patients with OUD to monitoring HbA1c levels in patients with diabetes as an example to demonstrate how laboratory values inform treatment.35,36
Before reporting the results, a helpful strategy to maintain the therapeutic alliance in the face of a positive UDS is to ask the patient what they expect their UDS to show. When the patient has been reassured that treatment will not be withdrawn due to a positive result, they may be more likely to fully disclose substance use. This allows them the opportunity to self-disclose rather than be “called out” by the clinician.35
8. What happens when a patient tests positive for drugs of abuse?
If a patient tests positive for opioids or other drugs of abuse, convey this information to them, ideally by asking them what they expect to see on laboratory findings. Patients may have “slip ups” or relapses, or use certain prescription medications for medical reasons with the intention of establishing abstinence. It is essential to convey laboratory findings in a nonjudgmental tone while maintaining a supportive stance with clear boundaries.
Continue to: Though addiction specialists...
Though addiction specialists often advise complete abstinence from all substances, including alcohol, cannabis, and tobacco, the harm-reduction model emphasizes “meeting patients where they are” in terms of continued substance use.37 If a patient can reduce their substance use or abstain from some substances while continuing others, these accomplishments should be acknowledged.
For patients who continue to test positive for illicit substances (>3 instances) without a clear explanation, schedule an appointment to re-educate them about buprenorphine treatment and reassess the patient’s treatment goals. Consider changing the current treatment plan, such as by having more frequent follow-ups, increasing the dose of the buprenorphine for patients whose cravings are not sufficiently suppressed, switching to another medication such as methadone or naltrexone, or referring the patient to a higher level of care, such as intensive outpatient or residential treatment.
9. What should I do if the results indicate abnormal levels of buprenorphine, norbuprenorphine, and naloxone?
When urine buprenorphine, norbuprenorphine, or naloxone levels appear low or the results indicate a likely “spiking,” clarify whether the sample tampering is due to poor adherence or diversion. Similar to dealing with a positive result for substances of abuse, ask the patient what they expect to find in their urine, and discuss the results in a nonjudgmental manner. Patients who admit to difficulty following their medication regimen may require additional psychoeducation and motivational interviewing to identify and address barriers. Strategies to improve adherence include setting an alarm, involving the family, using a pillbox, or simplifying the regimen.38 A long-acting injectable form of buprenorphine is also available.
If you suspect diversion, refer to your clinic’s policy and use other clinical management skills, such as increasing the frequency of visits, random pill counts, and supervised medication administration in the clinic.39 If diversion occurs repetitively and the patient is not appropriate for or benefiting from buprenorphine treatment, it may make sense to terminate treatment and consider other treatment options (such as methadone or residential treatment).39
10. What should I do if a patient disagrees with laboratory findings?
It is common for patients to disagree with laboratory results. Maintaining an attitude of neutrality and allowing the patient to speak and provide explanations is necessary to ensure they feel heard. Explanations patients frequently provide include passive exposure (“I was around someone who was using it”) or accidental ingestion, when a patient reports taking a medication they were not aware was a substance of concern. In a calm and nonjudgmental manner, provide education on what leads to a positive drug screen, including the possibility of false positive findings.
Continue to: Because a screening test...
Because a screening test has high sensitivity and low specificity, false positives may occur.17,27 Therefore, when a result is in dispute, the use of a high-specificity confirmatory test is often needed (many laboratories have reflex confirmatory testing). However, in the case of diluted urine (urine creatinine concentrations <20 mg/dL), patients should be told the findings are physiologically implausible, and a new urine sample should be obtained.24
Goals of laboratory monitoring
Laboratory monitoring, including UDS and urine buprenorphine levels, is a mainstay of treatment for patients with OUD. The increased use of telehealth has affected how laboratory testing is conducted (Box 240,41). The goal of laboratory testing is to influence treatment and improve patient outcomes. Clinical data such as clinician assessment, patient self-reporting, and collateral information provide essential details for patient management. However, laboratory monitoring is often the most reliable and objective source by which to influence treatment.
Box 2
While delivering therapy via telehealth has been shown to decrease the stigma that surrounds treatment, reduce no-show rates, increase retention in care, improve treatment access for patients who have difficulty commuting, and allow for continuity of outpatient treatment during the COVID-19 pandemic, there are also challenges.40,41 Inducing patients on buprenorphine via telehealth, as well as managing complex treatment cases or repeated failed urine drug screen tests, can be especially challenging. However, treatment standards should be followed as much as possible, and laboratory monitoring as clinically indicated should still be used to improve treatment outcomes.
If needed, patients may be directed to community labs for urine screening and should have results sent to their clinicians prior to the telehealth visit. Complex treatment cases (eg, repeat positive opioid screens, or negative urine buprenorphine screens with comorbid psychiatric conditions) should be handled on an individual basis and in-person appointments may be needed. Video assessment is always preferable to telephone. For patients who are unable to use video and have difficulty maintaining negative drug screens, an in-person visit should be requested.
An increased understanding of recommended laboratory monitoring practices may improve your comfort with OUD treatment and motivate more clinicians to offer buprenorphine, a life-saving and disease-modifying treatment for OUD. Doing so would increase access to OUD treatment for patients to reduce the individual and public health risks associated with untreated OUD.
Bottom Line
Laboratory monitoring, particularly urine drug screens and urine buprenorphine levels, is the most reliable source of information in the treatment of patients with opioid use disorder (OUD). An increased understanding of monitoring practices may improve a clinician’s willingness to offer buprenorphine as an option for therapy and their ability to properly treat patients with OUD.
Related Resources
- Li X, Moore S, Olson C. Urine drug tests: how to make the most of them. Current Psychiatry. 2019;18(8):10-18,20.
- Moreno JL, Johnson JL, Peckham AM. Sublingual buprenorphine plus buprenorphine XR for opioid use disorder. Current Psychiatry. 2022;21(6):39-42,49. doi:10.12788/cp.0244
Drug Brand Names
Amantadine • Gocovri
Buprenorphine • Subutex, Sublocade
Bupropion • Wellbutrin, Zyban
Efavirenz • Sustiva
Fentanyl • Actiq
Hydrocodone • Hysingla
Hydromorphone • Dilaudid
Methadone • Methadose
Naloxone • Evzio
Naltrexone • Vivitrol
Oxycodone • Oxycontin
Oxymorphone • Opana
Phentermine • Ionamin
Quinine • Qualaquin
Ranitidine • Zantac
Rifampin • Rifadin
Selegiline • Eldepryl
Sertraline • Zoloft
Trazodone • Oleptro
Verapamil • Verelan
1. Substance Abuse and Mental Health Services Administration. Key substance use and mental health indicators in the United States: results from the 2018 National Survey on Drug Use and Health. HHS Publication PEP19-5068, NSDUH Series H-54. May 2019. https://www.samhsa.gov/data/
2. Volkow ND, Frieden TR, Hyde PS, et al. Medication-assisted therapies—tackling the opioid-overdose epidemic. N Engl J Med. 2014;370(22):2063-2066. doi:10.1056/NEJMp1402780
3. Lee JD, Nunes EV Jr, Novo P, et al. Comparative effectiveness of extended-release naltrexone versus buprenorphine-naloxone for opioid relapse prevention (X:BOT): a multicentre, open-label, randomised controlled trial. Lancet. 2018;391(10118):309-318. doi:10.1016/S0140-6736(17)32812-X
4. Sharma A, Kelly SM, Mitchell SG, et al. Update on barriers to pharmacotherapy for opioid use disorders. Curr Psychiatry Rep. 2017;19(6):35. doi:10.1007/s11920-017-0783-9
5. DeFlavio JR, Rolin SA, Nordstrom BR, et al. Analysis of barriers to adoption of buprenorphine maintenance therapy by family physicians. Rural Remote Health. 2015;15:3019. doi:10.22605/rrh3019
6. Kuhlman JJ Jr, Lalani S, Magluiolo J Jr, et al. Human pharmacokinetics of intravenous, sublingual, and buccal buprenorphine. J Anal Toxicol. 1996;20(6):369-378.
7. Fudala PJ, Bridge TP, Herbert S, et al. Office-based treatment of opiate addiction with a sublingual-tablet formulation of buprenorphine and naloxone. N Engl J Med. 2003;349(10):949-958. doi:10.1056/NEJMoa022164
8. Brown SM, Holtzman M, Kim T, et al. Buprenorphine metabolites, buprenorphine-3-glucuronide and norbuprenorphine-3-glucuronide, are biologically active. Anesthesiology. 2011;115(6):1251-1260. doi:10.1097/ALN.0b013e318238fea0
9. Cone EJ, Gorodetzky CW, Yousefnejad D, et al. The metabolism and excretion of buprenorphine in humans. Drug Metab Dispos. 1984;12(5):577-581.
10. Stirratt MJ, Dunbar-Jacob J, Crane HM, et al. Self-report measures of medication adherence behavior: recommendations on optimal use. Transl Behav Med. 2015;5(4):470-482. doi:10.1007/s13142-015-0315-2
11. Del Boca FK, Noll JA. Truth or consequences: the validity of self-report data in health services research on addictions. Addiction. 2000;95 Suppl 3:S347-S360. doi:10.1080/09652140020004278
12. Preston KL, Silverman K, Schuster CR, et al. Comparison of self-reported drug use with quantitative and qualitative urinalysis for assessment of drug use in treatment studies. NIDA Res Monogr. 1997;167:130-145.
13. Knezevic NN, Khan OM, Beiranvand A, et al. Repeated quantitative urine toxicology analysis may improve chronic pain patient compliance with opioid therapy. Pain Physician. 2017;20(2S):S135-S145. doi:10.36076/ppj.2017.s145
14. Kampman K, Jarvis M. American Society of Addiction Medicine (ASAM) national practice guideline for the use of medications in the treatment of addiction involving opioid use. J Addict Med. 2015;9(5):358-367.
15. The ASAM national practice guideline for the treatment of opioid use disorder: 2020 focused update. J Addict Med. 2020;14(2S Suppl 1):1-91. doi:10.1097/ADM.0000000000000633
16. McDonell MG, Graves MC, West II, et al. Utility of point-of-care urine drug tests in the treatment of primary care patients with drug use disorders. J Addict Med. 2016;10(3):196-201. doi:10.1097/ADM.0000000000000220
17. Algren DA, Christian MR. Buyer beware: pitfalls in toxicology laboratory testing. Mo Med. 2015;112(3):206-210.
18. Hartzler B, Donovan DM, Huang Z. Comparison of opiate-primary treatment seekers with and without alcohol use disorder. J Subst Abuse Treat. 2010;39(2):114-123. doi:10.1016/j.jsat.2010.05.008
19. Stapleton RD, Comiskey CM. Alcohol usage and associated treatment outcomes for opiate users entering treatment in Ireland. Drug Alcohol Depend. 2010;107(1):56-61. doi:10.1016/j.drugalcdep.2009.09.007
20. Warrington JS, Warrington GS, Francis-Fath S, et al. Urinary buprenorphine, norbuprenorphine and naloxone concentrations and ratios: review and potential clinical implications. J Addict Med. 2020;14(6):e344-e349. doi:10.1097/ADM.0000000000000676
21. Donroe JH, Holt SR, O’Connor PG, et al. Interpreting quantitative urine buprenorphine and norbuprenorphine levels in office-based clinical practice. Drug Alcohol Depend. 2017;180:46-51. doi:10.1016/j.drugalcdep.2017.07.040
22. Bai SA, Xiang Q, Finn A. Evaluation of the pharmacokinetics of single- and multiple-dose buprenorphine buccal film in healthy volunteers. Clin Ther. 2016;38(2):358-369. doi:10.1016/j.clinthera.2015.12.016
23. Suzuki J, Zinser J, Issa M, et al. Quantitative testing of buprenorphine and norbuprenorphine to identify urine sample spiking during office-based opioid treatment. Subst Abus. 2017;38(4):504-507. doi:10.1080/08897077.2017.1356796
24. Gowans EM, Fraser CG. Biological variation of serum and urine creatinine and creatinine clearance: ramifications for interpretation of results and patient care. Ann Clin Biochem. 1988;25( Pt 3):259-263. doi:10.1177/000456328802500312
25. Saxon AJ, Ling W, Hillhouse M, et al. Buprenorphine/naloxone and methadone effects on laboratory indices of liver health: a randomized trial. Drug Alcohol Depend. 2013;128(1-2):71-76. doi:10.1016/j.drugalcdep.2012.08.002
26. Fareed A, Eilender P, Ketchen B, et al. Factors affecting noncompliance with buprenorphine maintenance treatment. J Addict Med. 2014;8(5):345-350. doi:10.1097/ADM.0000000000000057
27. Moeller KE, Lee KC, Kissack JC. Urine drug screening: practical guide for clinicians. Mayo Clin Proc. 2008;83(1):66-76. doi:10.4065/83.1.66
28. Keary CJ, Wang Y, Moran JR, et al. Toxicologic testing for opiates: understanding false-positive and false-negative test results. Prim Care Companion CNS Disord. 2012;14(4).PCC.12f01371 doi:10.4088/PCC.12f01371
29. Zebelman AM, Troyer BL, Randall GL, et al. Detection of morphine and codeine following consumption of poppy seeds. J Anal Toxicol. 1987;11(3):131-132. doi:10.1093/jat/11.3.131
30. Meier PS, Barrowclough C, Donmall MC. The role of the therapeutic alliance in the treatment of substance misuse: a critical review of the literature. Addiction. 2005;100(3):304-316. doi:10.1111/j.1360-0443.2004.00935.x
31. Kelly JF, Saitz R, Wakeman S. Language, substance use disorders, and policy: the need to reach consensus on an “addiction-ary.” Alcohol Treat Q. 2016;34(1):116-123. doi:10.1080/07347324.2016.1113103
32. Broyles LM, Binswanger IA, Jenkins JA, et al. Confronting inadvertent stigma and pejorative language in addiction scholarship: a recognition and response. Subst Abus. 2014;35(3):217-221. doi:10.1080/08897077.2014.930372
33. Kelly JF, Wakeman SE, Saitz R. Stop talking ‘dirty’: clinicians, language, and quality of care for the leading cause of preventable death in the United States. Am J Med. 2015;128(1):8-9. doi:10.1016/j.amjmed.2014.07.043
34. Jarvis M, Williams J, Hurford M, et al. Appropriate use of drug testing in clinical addiction medicine. J Addict Med. 2017;11(3):163-173. doi:10.1097/ADM.0000000000000323
35. Martin SA, Chiodo LM, Bosse JD, et al. The next stage of buprenorphine care for opioid use disorder. Ann Intern Med. 2018;169(9):628-635. doi:10.7326/M18-1652
36. Katz N, Fanciullo GJ. Role of urine toxicology testing in the management of chronic opioid therapy. Clin J Pain. 2002;18(4 Suppl):S76-S82.
37. Klein A. Harm reduction works: evidence and inclusion in drug policy and advocacy. Health Care Anal. 2020;28(4):404-414. doi:10.1007/s10728-020-00406-w
38. Patel MX, David AS. Medication adherence: predictive factors and enhancement strategies. Psychiatry. 2007;6(9):357-361. doi:10.1016/j.mppsy.2007.06.003
39. Lofwall MR, Walsh SL. A review of buprenorphine diversion and misuse: the current evidence base and experiences from around the world. J Addict Med. 2014;8(5):315-326. doi:10.1097/ADM.0000000000000045
40. Wang L, Weiss J, Ryan EB, et al. Telemedicine increases access to buprenorphine initiation during the COVID-19 pandemic. J Subst Abuse Treat. 2021;124:108272. doi:10.1016/ j.jsat.2020.108272
41. Harris MTH, Lambert AM, Maschke AD, et al. “No home to take methadone to”: experiences with addiction services during the COVID-19 pandemic among survivors of opioid overdose in Boston. J Subst Abuse Treat. 2022;135:108655. doi:10.1016/j.jsat.2021.108655
The opioid use disorder (OUD) epidemic is a major public health crisis in the United States.1 Naltrexone, methadone, and buprenorphine are first-line therapies for OUD and have high success rates.2 While studies have shown that naltrexone is effective, patients must achieve opioid detoxification and maintain 7 to 10 days of total abstinence to avoid a precipitated opioid withdrawal before it can be prescribed.3 Methadone does not require detoxification or a period of complete abstinence, but must be prescribed in special clinics and requires daily observed dosing for the first 90 days,4 though these requirements have been relaxed during the COVID-19 pandemic. In contrast, buprenorphine (with or without naloxone) can be used in office-based settings, which significantly improves the accessibility and availability of treatment for patients with OUD. Clinician knowledge and comfort prescribing buprenorphine are limiting factors to treatment.5 Increasing the number of clinicians proficient with buprenorphine management can improve access to effective treatment and recovery services, which is critical for patients with OUD.
Multiple resources are available for clinicians to learn how to prescribe buprenorphine, but clear guidance on laboratory testing for patients receiving buprenorphine is limited. To safely and effectively prescribe buprenorphine, clinicians need to understand its pharmacology (Box 16-9) and how laboratory testing influences treatment. In an effort to increase clinician knowledge of and proficiency with buprenorphine, this article answers 10 common questions about laboratory monitoring of patients receiving this medication.
Box 1
For patients with opioid use disorder, buprenorphine is indicated for opioid detoxification and maintenance. Oral formulations of buprenorphine (including tablets and buccal films) have long durations of action, and when dosed daily can prevent opioid withdrawal for at least 48 hours.6 The recommended formulation is a combination of buprenorphine and naloxone, because this formulation is associated with a lower risk of misuse and diversion compared to formulations containing only buprenorphine.7 However, buprenorphine alone can be effective in patients who experience adverse effects from or are unable to tolerate the combination buprenorphine/naloxone formulation.7 Despite the addition of naloxone, buprenorphine prescriptions may still be misused and diverted, so close monitoring is necessary.
Buprenorphine is metabolized by the cytochrome P450 system (CYP) (primarily CYP3A4) to its active metabolite, norbuprenorphine, both of which are primarily excreted in feces.8 However, small quantities of buprenorphine and norbuprenorphine are excreted in the urine,9 which makes urine specimen the best choice to monitor buprenorphine use for therapeutic purposes.
1. Why is laboratory monitoring important?
Proper laboratory monitoring discourages illicit substance use, encourages medication adherence, and influences treatment modifications. Patient self-reporting on medication compliance may be inaccurate or unreliable.10 Patients who relapse or use other illicit substances may also be reluctant to disclose their substance use.11
On the other hand, laboratory tests are objective markers of treatment outcome and adherence, and can verify a patient’s self-report.12 When used appropriately, laboratory monitoring can be therapeutic. It holds patients accountable, especially when used in conjunction with contingency management or other behavioral therapies.13 Laboratory monitoring is the most reliable method of determining if patients are abstaining from opioids and other illicit substances, or if the treatment plan requires revision.
2. Which tests should I order?
When initiating or maintaining a patient on buprenorphine, order a general urine drug screen (UDS), urine opioid screen (availability varies by institution), urine creatinine levels, urine buprenorphine/norbuprenorphine/naloxone/creatinine levels, urine alcohol metabolite levels, and a urine general toxicology test. It is also recommended to obtain a comprehensive metabolic panel (CMP) before starting buprenorphine,14,15 and to monitor CMP values at least once annually following treatment. Patients with a history of IV drug use or other high-risk factors should also be screened for hepatitis B, hepatitis C, and HIV.14,15
A general UDS can determine if opiates, amphetamines, cocaine, marijuana, or other common illicit substances are present to identify additional substance use. The proficiency of a general UDS may vary depending on the panels used at the respective institution. Some clinics use point-of-care UDS as part of their clinical management; these tests are inexpensive and provide immediate results.16 A basic UDS typically does not detect synthetic opioids due to the specificity of conventional immunoassays. As a result, specific tests for opioids such as oxycodone, hydrocodone, hydromorphone, oxymorphone, fentanyl, and methadone should also be considered, depending on their availability. Though buprenorphine treatment may trigger a positive opiate or other opioid screen,17 buprenorphine adherence should be confirmed using several urine tests, including creatinine, buprenorphine, norbuprenorphine, and naloxone urine levels.
In addition to screening for illicit substances and buprenorphine adherence, it is important to also screen for alcohol. Alcohol use disorder (AUD) is highly comorbid with OUD,18 and is associated with worse OUD treatment outcomes.19 Alcohol use may also affect liver function necessary for buprenorphine metabolism,8 so urine alcohol metabolites such as ethyl glucuronide and ethyl sulfate, serum transaminases, and gamma-glutamyl transferase should also be obtained.
Continue to: How frequently should patients be tested?
3. How frequently should patients be tested?
As part of the initial assessment, it is recommended to order CMP, UDS, and urine general toxicology.14 If indicated, specific laboratory tests such as specific opioid and alcohol metabolites screens can be ordered. After starting buprenorphine, the frequency of monitoring urine laboratory tests—including UDS, general drug toxicology, buprenorphine/norbuprenorphine/naloxone/creatinine, and alcohol and its metabolites—depends on a variety of factors, including a patient’s treatment response and stability as well as availability and cost of the tests. Ultimately, the frequency of laboratory monitoring should be determined on a patient-by-patient basis and clinicians should use their judgment.
The American Society of Addiction Medicine suggests testing more frequently earlier in the course of treatment (eg, weekly or biweekly), then spacing it out over time (eg, monthly or quarterly) as the patient’s recovery progresses.14,15 To conserve resources and reduce spending, some clinicians and guidelines recommend random monitoring as opposed to monitoring at every follow-up visit (eg, once out of every 3 to 5 visits, on average), which allows for longer intervals between testing while ensuring consistency with medication and abstinence from illicit substances.15,16 We suggest screening every 2 weeks for the first month, then spacing out to monthly and quarterly as patients demonstrate stability, with random screening as indicated. Monitoring of liver function should be done at least once annually.
4. How should urine buprenorphine and other results be interpreted?
There are several issues to consider when interpreting laboratory results. The clinician needs to know what to expect in the sample, and what approximate levels should be detected. To check treatment adherence, laboratory data should include stable urine buprenorphine and norbuprenorphine levels and negative urine screening for other illicit substances.14,15 While urine buprenorphine and norbuprenorphine levels have great interindividual variability due to genetic differences in hepatic metabolism, unusually high levels of buprenorphine (≥700 ng/mL) without norbuprenorphine suggests “urine spiking,” where patients put buprenorphine directly into their urine sample.20,21 Abnormally low or undetectable levels raise concern for medication nonadherence or diversion.
Though urine buprenorphine levels do not reliably correlate with dose, because there is typically not much intraindividual variability, patients should have relatively stable levels on each screen once a maintenance dose has been established.22 Furthermore, the buprenorphine-to-norbuprenorphine ratio (ie, “the metabolic ratio”) typically ranges from 1:2 to 1:4 across all individuals,20,21,23 regardless of dose or metabolic rate. Urine naloxone levels, which typically are included in commercial urine buprenorphine laboratory panels, also may aid in identifying tampered urine specimens when buprenorphine-to-norbuprenorphine ratios are abnormal or inconsistent with an individual’s prior ratio. Naloxone is typically (but not always) poorly absorbed and minimally detected in urine specimens.20 A high level of naloxone coupled with unusually high buprenorphine levels, particularly in the absence of norbuprenorphine in the urine, may indicate urine spiking.20,21,23
Urine creatinine is used to establish the reliability of the specimen. When urine creatinine concentration is <20 mg/dL, the concentration of most substances typically falls to subthreshold levels of detection.24 If a UDS is negative and the urine has a creatinine concentration <20 mg/dL, the patient should provide a new sample, because the urine was likely too diluted to detect any substances.
Continue to: The presence of alcohol...
The presence of alcohol metabolites can alert the clinician to recent alcohol use and possible AUD, which should be assessed and treated if indicated.
Liver enzymes should be normal or unchanged with short- and long-term buprenorphine use when taken as prescribed.25,26 However, acute liver injury may occur if patients inject buprenorphine intravenously, especially in those with underlying hepatitis C.25
5. What can cause a false negative result on UDS?
Laboratory monitoring may occasionally yield false negative drug screens. For urine buprenorphine levels, false negatives may occur in patients who are “rapid metabolizers,” infrequent or as-needed usage of the medication, patient mix-up, or laboratory error.27 For other substances, a false negative result may occur if the patient used the substance(s) outside the window of detection. The most common causes of false negative results, however, are overly diluted urine samples (eg, due to rapid water ingestion), or the use of an inappropriate test to measure a specific opioid or substance.27
Many laboratories use conventional immunoassays with morphine antibodies that react with various opioid substrates to determine the presence of a specific opioid. Some opioids—particularly synthetics such as oxycodone, hydrocodone, hydromorphone, oxymorphone, fentanyl, buprenorphine, and methadone—have poor cross-reactivity with the morphine antibody due to their distinct chemical structures, so standard immunoassays used to detect opioids may result in a false negative result.28 In such situations, a discussion with a clinical pathologist familiar with the laboratory detection method can help ensure proper testing. Additional tests for specific opioids should be ordered to more specifically target substances prone to false negative results.27
6. What can cause a false positive result on UDS?
The cross-reactivity of the morphine substrate may also result in a false positive result.28 Other over-the-counter (OTC) or prescription medications that have cross-reactivity with the morphine antibody include dextromethorphan, verapamil, quinine, fluoroquinolones, and rifampin, which can normally be found in urine 2 to 3 days after consumption.17,27 Poppy seeds have long been known to result in positive opiate screens on urine testing, particularly when laboratories use lower cutoff values (eg, 300 ng/mL), so advise patients to avoid consuming poppy seeds.29
Continue to: For other drugs of abuse...
For other drugs of abuse, false positives are typically caused by cross-reactivity with other prescription or OTC medications. Numerous substances cross-react with amphetamines and produce false positive results on amphetamine immunoassays, including amantadine, bupropion, ephedrine, labetalol, phentermine, pseudoephedrine, ranitidine, selegiline, and trazodone.27 Sertraline and efavirenz are known to produce false positive results on benzodiazepine UDS, and ibuprofen, naproxen, and efavirenz can produce false positive results for cannabinoids.27
7. How do I communicate the results to patients?
Effectively communicating test results to patients is just as important as the results themselves. A trusting, therapeutic alliance between patient and clinician is highly predictive of successful treatment,30 and how the clinician communicates affects the strength of this collaboration. A principle of addiction treatment is the use of neutral language when discussing laboratory results.31,32 To avoid unintentional shaming or moral judgment, use words such as “positive” or “negative” rather than stigmatizing terms such as “clean” or “dirty.”33
Additionally, make it clear that laboratory findings are not used to punish patients, but rather to improve treatment.34 Reassuring the patient that a positive screen will not result in withdrawal of care encourages a working relationship.14 All patients who receive buprenorphine treatment should be informed that collecting a UDS is the standard of care used to monitor their progress. You might want to compare using UDS in patients with OUD to monitoring HbA1c levels in patients with diabetes as an example to demonstrate how laboratory values inform treatment.35,36
Before reporting the results, a helpful strategy to maintain the therapeutic alliance in the face of a positive UDS is to ask the patient what they expect their UDS to show. When the patient has been reassured that treatment will not be withdrawn due to a positive result, they may be more likely to fully disclose substance use. This allows them the opportunity to self-disclose rather than be “called out” by the clinician.35
8. What happens when a patient tests positive for drugs of abuse?
If a patient tests positive for opioids or other drugs of abuse, convey this information to them, ideally by asking them what they expect to see on laboratory findings. Patients may have “slip ups” or relapses, or use certain prescription medications for medical reasons with the intention of establishing abstinence. It is essential to convey laboratory findings in a nonjudgmental tone while maintaining a supportive stance with clear boundaries.
Continue to: Though addiction specialists...
Though addiction specialists often advise complete abstinence from all substances, including alcohol, cannabis, and tobacco, the harm-reduction model emphasizes “meeting patients where they are” in terms of continued substance use.37 If a patient can reduce their substance use or abstain from some substances while continuing others, these accomplishments should be acknowledged.
For patients who continue to test positive for illicit substances (>3 instances) without a clear explanation, schedule an appointment to re-educate them about buprenorphine treatment and reassess the patient’s treatment goals. Consider changing the current treatment plan, such as by having more frequent follow-ups, increasing the dose of the buprenorphine for patients whose cravings are not sufficiently suppressed, switching to another medication such as methadone or naltrexone, or referring the patient to a higher level of care, such as intensive outpatient or residential treatment.
9. What should I do if the results indicate abnormal levels of buprenorphine, norbuprenorphine, and naloxone?
When urine buprenorphine, norbuprenorphine, or naloxone levels appear low or the results indicate a likely “spiking,” clarify whether the sample tampering is due to poor adherence or diversion. Similar to dealing with a positive result for substances of abuse, ask the patient what they expect to find in their urine, and discuss the results in a nonjudgmental manner. Patients who admit to difficulty following their medication regimen may require additional psychoeducation and motivational interviewing to identify and address barriers. Strategies to improve adherence include setting an alarm, involving the family, using a pillbox, or simplifying the regimen.38 A long-acting injectable form of buprenorphine is also available.
If you suspect diversion, refer to your clinic’s policy and use other clinical management skills, such as increasing the frequency of visits, random pill counts, and supervised medication administration in the clinic.39 If diversion occurs repetitively and the patient is not appropriate for or benefiting from buprenorphine treatment, it may make sense to terminate treatment and consider other treatment options (such as methadone or residential treatment).39
10. What should I do if a patient disagrees with laboratory findings?
It is common for patients to disagree with laboratory results. Maintaining an attitude of neutrality and allowing the patient to speak and provide explanations is necessary to ensure they feel heard. Explanations patients frequently provide include passive exposure (“I was around someone who was using it”) or accidental ingestion, when a patient reports taking a medication they were not aware was a substance of concern. In a calm and nonjudgmental manner, provide education on what leads to a positive drug screen, including the possibility of false positive findings.
Continue to: Because a screening test...
Because a screening test has high sensitivity and low specificity, false positives may occur.17,27 Therefore, when a result is in dispute, the use of a high-specificity confirmatory test is often needed (many laboratories have reflex confirmatory testing). However, in the case of diluted urine (urine creatinine concentrations <20 mg/dL), patients should be told the findings are physiologically implausible, and a new urine sample should be obtained.24
Goals of laboratory monitoring
Laboratory monitoring, including UDS and urine buprenorphine levels, is a mainstay of treatment for patients with OUD. The increased use of telehealth has affected how laboratory testing is conducted (Box 240,41). The goal of laboratory testing is to influence treatment and improve patient outcomes. Clinical data such as clinician assessment, patient self-reporting, and collateral information provide essential details for patient management. However, laboratory monitoring is often the most reliable and objective source by which to influence treatment.
Box 2
While delivering therapy via telehealth has been shown to decrease the stigma that surrounds treatment, reduce no-show rates, increase retention in care, improve treatment access for patients who have difficulty commuting, and allow for continuity of outpatient treatment during the COVID-19 pandemic, there are also challenges.40,41 Inducing patients on buprenorphine via telehealth, as well as managing complex treatment cases or repeated failed urine drug screen tests, can be especially challenging. However, treatment standards should be followed as much as possible, and laboratory monitoring as clinically indicated should still be used to improve treatment outcomes.
If needed, patients may be directed to community labs for urine screening and should have results sent to their clinicians prior to the telehealth visit. Complex treatment cases (eg, repeat positive opioid screens, or negative urine buprenorphine screens with comorbid psychiatric conditions) should be handled on an individual basis and in-person appointments may be needed. Video assessment is always preferable to telephone. For patients who are unable to use video and have difficulty maintaining negative drug screens, an in-person visit should be requested.
An increased understanding of recommended laboratory monitoring practices may improve your comfort with OUD treatment and motivate more clinicians to offer buprenorphine, a life-saving and disease-modifying treatment for OUD. Doing so would increase access to OUD treatment for patients to reduce the individual and public health risks associated with untreated OUD.
Bottom Line
Laboratory monitoring, particularly urine drug screens and urine buprenorphine levels, is the most reliable source of information in the treatment of patients with opioid use disorder (OUD). An increased understanding of monitoring practices may improve a clinician’s willingness to offer buprenorphine as an option for therapy and their ability to properly treat patients with OUD.
Related Resources
- Li X, Moore S, Olson C. Urine drug tests: how to make the most of them. Current Psychiatry. 2019;18(8):10-18,20.
- Moreno JL, Johnson JL, Peckham AM. Sublingual buprenorphine plus buprenorphine XR for opioid use disorder. Current Psychiatry. 2022;21(6):39-42,49. doi:10.12788/cp.0244
Drug Brand Names
Amantadine • Gocovri
Buprenorphine • Subutex, Sublocade
Bupropion • Wellbutrin, Zyban
Efavirenz • Sustiva
Fentanyl • Actiq
Hydrocodone • Hysingla
Hydromorphone • Dilaudid
Methadone • Methadose
Naloxone • Evzio
Naltrexone • Vivitrol
Oxycodone • Oxycontin
Oxymorphone • Opana
Phentermine • Ionamin
Quinine • Qualaquin
Ranitidine • Zantac
Rifampin • Rifadin
Selegiline • Eldepryl
Sertraline • Zoloft
Trazodone • Oleptro
Verapamil • Verelan
The opioid use disorder (OUD) epidemic is a major public health crisis in the United States.1 Naltrexone, methadone, and buprenorphine are first-line therapies for OUD and have high success rates.2 While studies have shown that naltrexone is effective, patients must achieve opioid detoxification and maintain 7 to 10 days of total abstinence to avoid a precipitated opioid withdrawal before it can be prescribed.3 Methadone does not require detoxification or a period of complete abstinence, but must be prescribed in special clinics and requires daily observed dosing for the first 90 days,4 though these requirements have been relaxed during the COVID-19 pandemic. In contrast, buprenorphine (with or without naloxone) can be used in office-based settings, which significantly improves the accessibility and availability of treatment for patients with OUD. Clinician knowledge and comfort prescribing buprenorphine are limiting factors to treatment.5 Increasing the number of clinicians proficient with buprenorphine management can improve access to effective treatment and recovery services, which is critical for patients with OUD.
Multiple resources are available for clinicians to learn how to prescribe buprenorphine, but clear guidance on laboratory testing for patients receiving buprenorphine is limited. To safely and effectively prescribe buprenorphine, clinicians need to understand its pharmacology (Box 16-9) and how laboratory testing influences treatment. In an effort to increase clinician knowledge of and proficiency with buprenorphine, this article answers 10 common questions about laboratory monitoring of patients receiving this medication.
Box 1
For patients with opioid use disorder, buprenorphine is indicated for opioid detoxification and maintenance. Oral formulations of buprenorphine (including tablets and buccal films) have long durations of action, and when dosed daily can prevent opioid withdrawal for at least 48 hours.6 The recommended formulation is a combination of buprenorphine and naloxone, because this formulation is associated with a lower risk of misuse and diversion compared to formulations containing only buprenorphine.7 However, buprenorphine alone can be effective in patients who experience adverse effects from or are unable to tolerate the combination buprenorphine/naloxone formulation.7 Despite the addition of naloxone, buprenorphine prescriptions may still be misused and diverted, so close monitoring is necessary.
Buprenorphine is metabolized by the cytochrome P450 system (CYP) (primarily CYP3A4) to its active metabolite, norbuprenorphine, both of which are primarily excreted in feces.8 However, small quantities of buprenorphine and norbuprenorphine are excreted in the urine,9 which makes urine specimen the best choice to monitor buprenorphine use for therapeutic purposes.
1. Why is laboratory monitoring important?
Proper laboratory monitoring discourages illicit substance use, encourages medication adherence, and influences treatment modifications. Patient self-reporting on medication compliance may be inaccurate or unreliable.10 Patients who relapse or use other illicit substances may also be reluctant to disclose their substance use.11
On the other hand, laboratory tests are objective markers of treatment outcome and adherence, and can verify a patient’s self-report.12 When used appropriately, laboratory monitoring can be therapeutic. It holds patients accountable, especially when used in conjunction with contingency management or other behavioral therapies.13 Laboratory monitoring is the most reliable method of determining if patients are abstaining from opioids and other illicit substances, or if the treatment plan requires revision.
2. Which tests should I order?
When initiating or maintaining a patient on buprenorphine, order a general urine drug screen (UDS), urine opioid screen (availability varies by institution), urine creatinine levels, urine buprenorphine/norbuprenorphine/naloxone/creatinine levels, urine alcohol metabolite levels, and a urine general toxicology test. It is also recommended to obtain a comprehensive metabolic panel (CMP) before starting buprenorphine,14,15 and to monitor CMP values at least once annually following treatment. Patients with a history of IV drug use or other high-risk factors should also be screened for hepatitis B, hepatitis C, and HIV.14,15
A general UDS can determine if opiates, amphetamines, cocaine, marijuana, or other common illicit substances are present to identify additional substance use. The proficiency of a general UDS may vary depending on the panels used at the respective institution. Some clinics use point-of-care UDS as part of their clinical management; these tests are inexpensive and provide immediate results.16 A basic UDS typically does not detect synthetic opioids due to the specificity of conventional immunoassays. As a result, specific tests for opioids such as oxycodone, hydrocodone, hydromorphone, oxymorphone, fentanyl, and methadone should also be considered, depending on their availability. Though buprenorphine treatment may trigger a positive opiate or other opioid screen,17 buprenorphine adherence should be confirmed using several urine tests, including creatinine, buprenorphine, norbuprenorphine, and naloxone urine levels.
In addition to screening for illicit substances and buprenorphine adherence, it is important to also screen for alcohol. Alcohol use disorder (AUD) is highly comorbid with OUD,18 and is associated with worse OUD treatment outcomes.19 Alcohol use may also affect liver function necessary for buprenorphine metabolism,8 so urine alcohol metabolites such as ethyl glucuronide and ethyl sulfate, serum transaminases, and gamma-glutamyl transferase should also be obtained.
Continue to: How frequently should patients be tested?
3. How frequently should patients be tested?
As part of the initial assessment, it is recommended to order CMP, UDS, and urine general toxicology.14 If indicated, specific laboratory tests such as specific opioid and alcohol metabolites screens can be ordered. After starting buprenorphine, the frequency of monitoring urine laboratory tests—including UDS, general drug toxicology, buprenorphine/norbuprenorphine/naloxone/creatinine, and alcohol and its metabolites—depends on a variety of factors, including a patient’s treatment response and stability as well as availability and cost of the tests. Ultimately, the frequency of laboratory monitoring should be determined on a patient-by-patient basis and clinicians should use their judgment.
The American Society of Addiction Medicine suggests testing more frequently earlier in the course of treatment (eg, weekly or biweekly), then spacing it out over time (eg, monthly or quarterly) as the patient’s recovery progresses.14,15 To conserve resources and reduce spending, some clinicians and guidelines recommend random monitoring as opposed to monitoring at every follow-up visit (eg, once out of every 3 to 5 visits, on average), which allows for longer intervals between testing while ensuring consistency with medication and abstinence from illicit substances.15,16 We suggest screening every 2 weeks for the first month, then spacing out to monthly and quarterly as patients demonstrate stability, with random screening as indicated. Monitoring of liver function should be done at least once annually.
4. How should urine buprenorphine and other results be interpreted?
There are several issues to consider when interpreting laboratory results. The clinician needs to know what to expect in the sample, and what approximate levels should be detected. To check treatment adherence, laboratory data should include stable urine buprenorphine and norbuprenorphine levels and negative urine screening for other illicit substances.14,15 While urine buprenorphine and norbuprenorphine levels have great interindividual variability due to genetic differences in hepatic metabolism, unusually high levels of buprenorphine (≥700 ng/mL) without norbuprenorphine suggests “urine spiking,” where patients put buprenorphine directly into their urine sample.20,21 Abnormally low or undetectable levels raise concern for medication nonadherence or diversion.
Though urine buprenorphine levels do not reliably correlate with dose, because there is typically not much intraindividual variability, patients should have relatively stable levels on each screen once a maintenance dose has been established.22 Furthermore, the buprenorphine-to-norbuprenorphine ratio (ie, “the metabolic ratio”) typically ranges from 1:2 to 1:4 across all individuals,20,21,23 regardless of dose or metabolic rate. Urine naloxone levels, which typically are included in commercial urine buprenorphine laboratory panels, also may aid in identifying tampered urine specimens when buprenorphine-to-norbuprenorphine ratios are abnormal or inconsistent with an individual’s prior ratio. Naloxone is typically (but not always) poorly absorbed and minimally detected in urine specimens.20 A high level of naloxone coupled with unusually high buprenorphine levels, particularly in the absence of norbuprenorphine in the urine, may indicate urine spiking.20,21,23
Urine creatinine is used to establish the reliability of the specimen. When urine creatinine concentration is <20 mg/dL, the concentration of most substances typically falls to subthreshold levels of detection.24 If a UDS is negative and the urine has a creatinine concentration <20 mg/dL, the patient should provide a new sample, because the urine was likely too diluted to detect any substances.
Continue to: The presence of alcohol...
The presence of alcohol metabolites can alert the clinician to recent alcohol use and possible AUD, which should be assessed and treated if indicated.
Liver enzymes should be normal or unchanged with short- and long-term buprenorphine use when taken as prescribed.25,26 However, acute liver injury may occur if patients inject buprenorphine intravenously, especially in those with underlying hepatitis C.25
5. What can cause a false negative result on UDS?
Laboratory monitoring may occasionally yield false negative drug screens. For urine buprenorphine levels, false negatives may occur in patients who are “rapid metabolizers,” infrequent or as-needed usage of the medication, patient mix-up, or laboratory error.27 For other substances, a false negative result may occur if the patient used the substance(s) outside the window of detection. The most common causes of false negative results, however, are overly diluted urine samples (eg, due to rapid water ingestion), or the use of an inappropriate test to measure a specific opioid or substance.27
Many laboratories use conventional immunoassays with morphine antibodies that react with various opioid substrates to determine the presence of a specific opioid. Some opioids—particularly synthetics such as oxycodone, hydrocodone, hydromorphone, oxymorphone, fentanyl, buprenorphine, and methadone—have poor cross-reactivity with the morphine antibody due to their distinct chemical structures, so standard immunoassays used to detect opioids may result in a false negative result.28 In such situations, a discussion with a clinical pathologist familiar with the laboratory detection method can help ensure proper testing. Additional tests for specific opioids should be ordered to more specifically target substances prone to false negative results.27
6. What can cause a false positive result on UDS?
The cross-reactivity of the morphine substrate may also result in a false positive result.28 Other over-the-counter (OTC) or prescription medications that have cross-reactivity with the morphine antibody include dextromethorphan, verapamil, quinine, fluoroquinolones, and rifampin, which can normally be found in urine 2 to 3 days after consumption.17,27 Poppy seeds have long been known to result in positive opiate screens on urine testing, particularly when laboratories use lower cutoff values (eg, 300 ng/mL), so advise patients to avoid consuming poppy seeds.29
Continue to: For other drugs of abuse...
For other drugs of abuse, false positives are typically caused by cross-reactivity with other prescription or OTC medications. Numerous substances cross-react with amphetamines and produce false positive results on amphetamine immunoassays, including amantadine, bupropion, ephedrine, labetalol, phentermine, pseudoephedrine, ranitidine, selegiline, and trazodone.27 Sertraline and efavirenz are known to produce false positive results on benzodiazepine UDS, and ibuprofen, naproxen, and efavirenz can produce false positive results for cannabinoids.27
7. How do I communicate the results to patients?
Effectively communicating test results to patients is just as important as the results themselves. A trusting, therapeutic alliance between patient and clinician is highly predictive of successful treatment,30 and how the clinician communicates affects the strength of this collaboration. A principle of addiction treatment is the use of neutral language when discussing laboratory results.31,32 To avoid unintentional shaming or moral judgment, use words such as “positive” or “negative” rather than stigmatizing terms such as “clean” or “dirty.”33
Additionally, make it clear that laboratory findings are not used to punish patients, but rather to improve treatment.34 Reassuring the patient that a positive screen will not result in withdrawal of care encourages a working relationship.14 All patients who receive buprenorphine treatment should be informed that collecting a UDS is the standard of care used to monitor their progress. You might want to compare using UDS in patients with OUD to monitoring HbA1c levels in patients with diabetes as an example to demonstrate how laboratory values inform treatment.35,36
Before reporting the results, a helpful strategy to maintain the therapeutic alliance in the face of a positive UDS is to ask the patient what they expect their UDS to show. When the patient has been reassured that treatment will not be withdrawn due to a positive result, they may be more likely to fully disclose substance use. This allows them the opportunity to self-disclose rather than be “called out” by the clinician.35
8. What happens when a patient tests positive for drugs of abuse?
If a patient tests positive for opioids or other drugs of abuse, convey this information to them, ideally by asking them what they expect to see on laboratory findings. Patients may have “slip ups” or relapses, or use certain prescription medications for medical reasons with the intention of establishing abstinence. It is essential to convey laboratory findings in a nonjudgmental tone while maintaining a supportive stance with clear boundaries.
Continue to: Though addiction specialists...
Though addiction specialists often advise complete abstinence from all substances, including alcohol, cannabis, and tobacco, the harm-reduction model emphasizes “meeting patients where they are” in terms of continued substance use.37 If a patient can reduce their substance use or abstain from some substances while continuing others, these accomplishments should be acknowledged.
For patients who continue to test positive for illicit substances (>3 instances) without a clear explanation, schedule an appointment to re-educate them about buprenorphine treatment and reassess the patient’s treatment goals. Consider changing the current treatment plan, such as by having more frequent follow-ups, increasing the dose of the buprenorphine for patients whose cravings are not sufficiently suppressed, switching to another medication such as methadone or naltrexone, or referring the patient to a higher level of care, such as intensive outpatient or residential treatment.
9. What should I do if the results indicate abnormal levels of buprenorphine, norbuprenorphine, and naloxone?
When urine buprenorphine, norbuprenorphine, or naloxone levels appear low or the results indicate a likely “spiking,” clarify whether the sample tampering is due to poor adherence or diversion. Similar to dealing with a positive result for substances of abuse, ask the patient what they expect to find in their urine, and discuss the results in a nonjudgmental manner. Patients who admit to difficulty following their medication regimen may require additional psychoeducation and motivational interviewing to identify and address barriers. Strategies to improve adherence include setting an alarm, involving the family, using a pillbox, or simplifying the regimen.38 A long-acting injectable form of buprenorphine is also available.
If you suspect diversion, refer to your clinic’s policy and use other clinical management skills, such as increasing the frequency of visits, random pill counts, and supervised medication administration in the clinic.39 If diversion occurs repetitively and the patient is not appropriate for or benefiting from buprenorphine treatment, it may make sense to terminate treatment and consider other treatment options (such as methadone or residential treatment).39
10. What should I do if a patient disagrees with laboratory findings?
It is common for patients to disagree with laboratory results. Maintaining an attitude of neutrality and allowing the patient to speak and provide explanations is necessary to ensure they feel heard. Explanations patients frequently provide include passive exposure (“I was around someone who was using it”) or accidental ingestion, when a patient reports taking a medication they were not aware was a substance of concern. In a calm and nonjudgmental manner, provide education on what leads to a positive drug screen, including the possibility of false positive findings.
Continue to: Because a screening test...
Because a screening test has high sensitivity and low specificity, false positives may occur.17,27 Therefore, when a result is in dispute, the use of a high-specificity confirmatory test is often needed (many laboratories have reflex confirmatory testing). However, in the case of diluted urine (urine creatinine concentrations <20 mg/dL), patients should be told the findings are physiologically implausible, and a new urine sample should be obtained.24
Goals of laboratory monitoring
Laboratory monitoring, including UDS and urine buprenorphine levels, is a mainstay of treatment for patients with OUD. The increased use of telehealth has affected how laboratory testing is conducted (Box 240,41). The goal of laboratory testing is to influence treatment and improve patient outcomes. Clinical data such as clinician assessment, patient self-reporting, and collateral information provide essential details for patient management. However, laboratory monitoring is often the most reliable and objective source by which to influence treatment.
Box 2
While delivering therapy via telehealth has been shown to decrease the stigma that surrounds treatment, reduce no-show rates, increase retention in care, improve treatment access for patients who have difficulty commuting, and allow for continuity of outpatient treatment during the COVID-19 pandemic, there are also challenges.40,41 Inducing patients on buprenorphine via telehealth, as well as managing complex treatment cases or repeated failed urine drug screen tests, can be especially challenging. However, treatment standards should be followed as much as possible, and laboratory monitoring as clinically indicated should still be used to improve treatment outcomes.
If needed, patients may be directed to community labs for urine screening and should have results sent to their clinicians prior to the telehealth visit. Complex treatment cases (eg, repeat positive opioid screens, or negative urine buprenorphine screens with comorbid psychiatric conditions) should be handled on an individual basis and in-person appointments may be needed. Video assessment is always preferable to telephone. For patients who are unable to use video and have difficulty maintaining negative drug screens, an in-person visit should be requested.
An increased understanding of recommended laboratory monitoring practices may improve your comfort with OUD treatment and motivate more clinicians to offer buprenorphine, a life-saving and disease-modifying treatment for OUD. Doing so would increase access to OUD treatment for patients to reduce the individual and public health risks associated with untreated OUD.
Bottom Line
Laboratory monitoring, particularly urine drug screens and urine buprenorphine levels, is the most reliable source of information in the treatment of patients with opioid use disorder (OUD). An increased understanding of monitoring practices may improve a clinician’s willingness to offer buprenorphine as an option for therapy and their ability to properly treat patients with OUD.
Related Resources
- Li X, Moore S, Olson C. Urine drug tests: how to make the most of them. Current Psychiatry. 2019;18(8):10-18,20.
- Moreno JL, Johnson JL, Peckham AM. Sublingual buprenorphine plus buprenorphine XR for opioid use disorder. Current Psychiatry. 2022;21(6):39-42,49. doi:10.12788/cp.0244
Drug Brand Names
Amantadine • Gocovri
Buprenorphine • Subutex, Sublocade
Bupropion • Wellbutrin, Zyban
Efavirenz • Sustiva
Fentanyl • Actiq
Hydrocodone • Hysingla
Hydromorphone • Dilaudid
Methadone • Methadose
Naloxone • Evzio
Naltrexone • Vivitrol
Oxycodone • Oxycontin
Oxymorphone • Opana
Phentermine • Ionamin
Quinine • Qualaquin
Ranitidine • Zantac
Rifampin • Rifadin
Selegiline • Eldepryl
Sertraline • Zoloft
Trazodone • Oleptro
Verapamil • Verelan
1. Substance Abuse and Mental Health Services Administration. Key substance use and mental health indicators in the United States: results from the 2018 National Survey on Drug Use and Health. HHS Publication PEP19-5068, NSDUH Series H-54. May 2019. https://www.samhsa.gov/data/
2. Volkow ND, Frieden TR, Hyde PS, et al. Medication-assisted therapies—tackling the opioid-overdose epidemic. N Engl J Med. 2014;370(22):2063-2066. doi:10.1056/NEJMp1402780
3. Lee JD, Nunes EV Jr, Novo P, et al. Comparative effectiveness of extended-release naltrexone versus buprenorphine-naloxone for opioid relapse prevention (X:BOT): a multicentre, open-label, randomised controlled trial. Lancet. 2018;391(10118):309-318. doi:10.1016/S0140-6736(17)32812-X
4. Sharma A, Kelly SM, Mitchell SG, et al. Update on barriers to pharmacotherapy for opioid use disorders. Curr Psychiatry Rep. 2017;19(6):35. doi:10.1007/s11920-017-0783-9
5. DeFlavio JR, Rolin SA, Nordstrom BR, et al. Analysis of barriers to adoption of buprenorphine maintenance therapy by family physicians. Rural Remote Health. 2015;15:3019. doi:10.22605/rrh3019
6. Kuhlman JJ Jr, Lalani S, Magluiolo J Jr, et al. Human pharmacokinetics of intravenous, sublingual, and buccal buprenorphine. J Anal Toxicol. 1996;20(6):369-378.
7. Fudala PJ, Bridge TP, Herbert S, et al. Office-based treatment of opiate addiction with a sublingual-tablet formulation of buprenorphine and naloxone. N Engl J Med. 2003;349(10):949-958. doi:10.1056/NEJMoa022164
8. Brown SM, Holtzman M, Kim T, et al. Buprenorphine metabolites, buprenorphine-3-glucuronide and norbuprenorphine-3-glucuronide, are biologically active. Anesthesiology. 2011;115(6):1251-1260. doi:10.1097/ALN.0b013e318238fea0
9. Cone EJ, Gorodetzky CW, Yousefnejad D, et al. The metabolism and excretion of buprenorphine in humans. Drug Metab Dispos. 1984;12(5):577-581.
10. Stirratt MJ, Dunbar-Jacob J, Crane HM, et al. Self-report measures of medication adherence behavior: recommendations on optimal use. Transl Behav Med. 2015;5(4):470-482. doi:10.1007/s13142-015-0315-2
11. Del Boca FK, Noll JA. Truth or consequences: the validity of self-report data in health services research on addictions. Addiction. 2000;95 Suppl 3:S347-S360. doi:10.1080/09652140020004278
12. Preston KL, Silverman K, Schuster CR, et al. Comparison of self-reported drug use with quantitative and qualitative urinalysis for assessment of drug use in treatment studies. NIDA Res Monogr. 1997;167:130-145.
13. Knezevic NN, Khan OM, Beiranvand A, et al. Repeated quantitative urine toxicology analysis may improve chronic pain patient compliance with opioid therapy. Pain Physician. 2017;20(2S):S135-S145. doi:10.36076/ppj.2017.s145
14. Kampman K, Jarvis M. American Society of Addiction Medicine (ASAM) national practice guideline for the use of medications in the treatment of addiction involving opioid use. J Addict Med. 2015;9(5):358-367.
15. The ASAM national practice guideline for the treatment of opioid use disorder: 2020 focused update. J Addict Med. 2020;14(2S Suppl 1):1-91. doi:10.1097/ADM.0000000000000633
16. McDonell MG, Graves MC, West II, et al. Utility of point-of-care urine drug tests in the treatment of primary care patients with drug use disorders. J Addict Med. 2016;10(3):196-201. doi:10.1097/ADM.0000000000000220
17. Algren DA, Christian MR. Buyer beware: pitfalls in toxicology laboratory testing. Mo Med. 2015;112(3):206-210.
18. Hartzler B, Donovan DM, Huang Z. Comparison of opiate-primary treatment seekers with and without alcohol use disorder. J Subst Abuse Treat. 2010;39(2):114-123. doi:10.1016/j.jsat.2010.05.008
19. Stapleton RD, Comiskey CM. Alcohol usage and associated treatment outcomes for opiate users entering treatment in Ireland. Drug Alcohol Depend. 2010;107(1):56-61. doi:10.1016/j.drugalcdep.2009.09.007
20. Warrington JS, Warrington GS, Francis-Fath S, et al. Urinary buprenorphine, norbuprenorphine and naloxone concentrations and ratios: review and potential clinical implications. J Addict Med. 2020;14(6):e344-e349. doi:10.1097/ADM.0000000000000676
21. Donroe JH, Holt SR, O’Connor PG, et al. Interpreting quantitative urine buprenorphine and norbuprenorphine levels in office-based clinical practice. Drug Alcohol Depend. 2017;180:46-51. doi:10.1016/j.drugalcdep.2017.07.040
22. Bai SA, Xiang Q, Finn A. Evaluation of the pharmacokinetics of single- and multiple-dose buprenorphine buccal film in healthy volunteers. Clin Ther. 2016;38(2):358-369. doi:10.1016/j.clinthera.2015.12.016
23. Suzuki J, Zinser J, Issa M, et al. Quantitative testing of buprenorphine and norbuprenorphine to identify urine sample spiking during office-based opioid treatment. Subst Abus. 2017;38(4):504-507. doi:10.1080/08897077.2017.1356796
24. Gowans EM, Fraser CG. Biological variation of serum and urine creatinine and creatinine clearance: ramifications for interpretation of results and patient care. Ann Clin Biochem. 1988;25( Pt 3):259-263. doi:10.1177/000456328802500312
25. Saxon AJ, Ling W, Hillhouse M, et al. Buprenorphine/naloxone and methadone effects on laboratory indices of liver health: a randomized trial. Drug Alcohol Depend. 2013;128(1-2):71-76. doi:10.1016/j.drugalcdep.2012.08.002
26. Fareed A, Eilender P, Ketchen B, et al. Factors affecting noncompliance with buprenorphine maintenance treatment. J Addict Med. 2014;8(5):345-350. doi:10.1097/ADM.0000000000000057
27. Moeller KE, Lee KC, Kissack JC. Urine drug screening: practical guide for clinicians. Mayo Clin Proc. 2008;83(1):66-76. doi:10.4065/83.1.66
28. Keary CJ, Wang Y, Moran JR, et al. Toxicologic testing for opiates: understanding false-positive and false-negative test results. Prim Care Companion CNS Disord. 2012;14(4).PCC.12f01371 doi:10.4088/PCC.12f01371
29. Zebelman AM, Troyer BL, Randall GL, et al. Detection of morphine and codeine following consumption of poppy seeds. J Anal Toxicol. 1987;11(3):131-132. doi:10.1093/jat/11.3.131
30. Meier PS, Barrowclough C, Donmall MC. The role of the therapeutic alliance in the treatment of substance misuse: a critical review of the literature. Addiction. 2005;100(3):304-316. doi:10.1111/j.1360-0443.2004.00935.x
31. Kelly JF, Saitz R, Wakeman S. Language, substance use disorders, and policy: the need to reach consensus on an “addiction-ary.” Alcohol Treat Q. 2016;34(1):116-123. doi:10.1080/07347324.2016.1113103
32. Broyles LM, Binswanger IA, Jenkins JA, et al. Confronting inadvertent stigma and pejorative language in addiction scholarship: a recognition and response. Subst Abus. 2014;35(3):217-221. doi:10.1080/08897077.2014.930372
33. Kelly JF, Wakeman SE, Saitz R. Stop talking ‘dirty’: clinicians, language, and quality of care for the leading cause of preventable death in the United States. Am J Med. 2015;128(1):8-9. doi:10.1016/j.amjmed.2014.07.043
34. Jarvis M, Williams J, Hurford M, et al. Appropriate use of drug testing in clinical addiction medicine. J Addict Med. 2017;11(3):163-173. doi:10.1097/ADM.0000000000000323
35. Martin SA, Chiodo LM, Bosse JD, et al. The next stage of buprenorphine care for opioid use disorder. Ann Intern Med. 2018;169(9):628-635. doi:10.7326/M18-1652
36. Katz N, Fanciullo GJ. Role of urine toxicology testing in the management of chronic opioid therapy. Clin J Pain. 2002;18(4 Suppl):S76-S82.
37. Klein A. Harm reduction works: evidence and inclusion in drug policy and advocacy. Health Care Anal. 2020;28(4):404-414. doi:10.1007/s10728-020-00406-w
38. Patel MX, David AS. Medication adherence: predictive factors and enhancement strategies. Psychiatry. 2007;6(9):357-361. doi:10.1016/j.mppsy.2007.06.003
39. Lofwall MR, Walsh SL. A review of buprenorphine diversion and misuse: the current evidence base and experiences from around the world. J Addict Med. 2014;8(5):315-326. doi:10.1097/ADM.0000000000000045
40. Wang L, Weiss J, Ryan EB, et al. Telemedicine increases access to buprenorphine initiation during the COVID-19 pandemic. J Subst Abuse Treat. 2021;124:108272. doi:10.1016/ j.jsat.2020.108272
41. Harris MTH, Lambert AM, Maschke AD, et al. “No home to take methadone to”: experiences with addiction services during the COVID-19 pandemic among survivors of opioid overdose in Boston. J Subst Abuse Treat. 2022;135:108655. doi:10.1016/j.jsat.2021.108655
1. Substance Abuse and Mental Health Services Administration. Key substance use and mental health indicators in the United States: results from the 2018 National Survey on Drug Use and Health. HHS Publication PEP19-5068, NSDUH Series H-54. May 2019. https://www.samhsa.gov/data/
2. Volkow ND, Frieden TR, Hyde PS, et al. Medication-assisted therapies—tackling the opioid-overdose epidemic. N Engl J Med. 2014;370(22):2063-2066. doi:10.1056/NEJMp1402780
3. Lee JD, Nunes EV Jr, Novo P, et al. Comparative effectiveness of extended-release naltrexone versus buprenorphine-naloxone for opioid relapse prevention (X:BOT): a multicentre, open-label, randomised controlled trial. Lancet. 2018;391(10118):309-318. doi:10.1016/S0140-6736(17)32812-X
4. Sharma A, Kelly SM, Mitchell SG, et al. Update on barriers to pharmacotherapy for opioid use disorders. Curr Psychiatry Rep. 2017;19(6):35. doi:10.1007/s11920-017-0783-9
5. DeFlavio JR, Rolin SA, Nordstrom BR, et al. Analysis of barriers to adoption of buprenorphine maintenance therapy by family physicians. Rural Remote Health. 2015;15:3019. doi:10.22605/rrh3019
6. Kuhlman JJ Jr, Lalani S, Magluiolo J Jr, et al. Human pharmacokinetics of intravenous, sublingual, and buccal buprenorphine. J Anal Toxicol. 1996;20(6):369-378.
7. Fudala PJ, Bridge TP, Herbert S, et al. Office-based treatment of opiate addiction with a sublingual-tablet formulation of buprenorphine and naloxone. N Engl J Med. 2003;349(10):949-958. doi:10.1056/NEJMoa022164
8. Brown SM, Holtzman M, Kim T, et al. Buprenorphine metabolites, buprenorphine-3-glucuronide and norbuprenorphine-3-glucuronide, are biologically active. Anesthesiology. 2011;115(6):1251-1260. doi:10.1097/ALN.0b013e318238fea0
9. Cone EJ, Gorodetzky CW, Yousefnejad D, et al. The metabolism and excretion of buprenorphine in humans. Drug Metab Dispos. 1984;12(5):577-581.
10. Stirratt MJ, Dunbar-Jacob J, Crane HM, et al. Self-report measures of medication adherence behavior: recommendations on optimal use. Transl Behav Med. 2015;5(4):470-482. doi:10.1007/s13142-015-0315-2
11. Del Boca FK, Noll JA. Truth or consequences: the validity of self-report data in health services research on addictions. Addiction. 2000;95 Suppl 3:S347-S360. doi:10.1080/09652140020004278
12. Preston KL, Silverman K, Schuster CR, et al. Comparison of self-reported drug use with quantitative and qualitative urinalysis for assessment of drug use in treatment studies. NIDA Res Monogr. 1997;167:130-145.
13. Knezevic NN, Khan OM, Beiranvand A, et al. Repeated quantitative urine toxicology analysis may improve chronic pain patient compliance with opioid therapy. Pain Physician. 2017;20(2S):S135-S145. doi:10.36076/ppj.2017.s145
14. Kampman K, Jarvis M. American Society of Addiction Medicine (ASAM) national practice guideline for the use of medications in the treatment of addiction involving opioid use. J Addict Med. 2015;9(5):358-367.
15. The ASAM national practice guideline for the treatment of opioid use disorder: 2020 focused update. J Addict Med. 2020;14(2S Suppl 1):1-91. doi:10.1097/ADM.0000000000000633
16. McDonell MG, Graves MC, West II, et al. Utility of point-of-care urine drug tests in the treatment of primary care patients with drug use disorders. J Addict Med. 2016;10(3):196-201. doi:10.1097/ADM.0000000000000220
17. Algren DA, Christian MR. Buyer beware: pitfalls in toxicology laboratory testing. Mo Med. 2015;112(3):206-210.
18. Hartzler B, Donovan DM, Huang Z. Comparison of opiate-primary treatment seekers with and without alcohol use disorder. J Subst Abuse Treat. 2010;39(2):114-123. doi:10.1016/j.jsat.2010.05.008
19. Stapleton RD, Comiskey CM. Alcohol usage and associated treatment outcomes for opiate users entering treatment in Ireland. Drug Alcohol Depend. 2010;107(1):56-61. doi:10.1016/j.drugalcdep.2009.09.007
20. Warrington JS, Warrington GS, Francis-Fath S, et al. Urinary buprenorphine, norbuprenorphine and naloxone concentrations and ratios: review and potential clinical implications. J Addict Med. 2020;14(6):e344-e349. doi:10.1097/ADM.0000000000000676
21. Donroe JH, Holt SR, O’Connor PG, et al. Interpreting quantitative urine buprenorphine and norbuprenorphine levels in office-based clinical practice. Drug Alcohol Depend. 2017;180:46-51. doi:10.1016/j.drugalcdep.2017.07.040
22. Bai SA, Xiang Q, Finn A. Evaluation of the pharmacokinetics of single- and multiple-dose buprenorphine buccal film in healthy volunteers. Clin Ther. 2016;38(2):358-369. doi:10.1016/j.clinthera.2015.12.016
23. Suzuki J, Zinser J, Issa M, et al. Quantitative testing of buprenorphine and norbuprenorphine to identify urine sample spiking during office-based opioid treatment. Subst Abus. 2017;38(4):504-507. doi:10.1080/08897077.2017.1356796
24. Gowans EM, Fraser CG. Biological variation of serum and urine creatinine and creatinine clearance: ramifications for interpretation of results and patient care. Ann Clin Biochem. 1988;25( Pt 3):259-263. doi:10.1177/000456328802500312
25. Saxon AJ, Ling W, Hillhouse M, et al. Buprenorphine/naloxone and methadone effects on laboratory indices of liver health: a randomized trial. Drug Alcohol Depend. 2013;128(1-2):71-76. doi:10.1016/j.drugalcdep.2012.08.002
26. Fareed A, Eilender P, Ketchen B, et al. Factors affecting noncompliance with buprenorphine maintenance treatment. J Addict Med. 2014;8(5):345-350. doi:10.1097/ADM.0000000000000057
27. Moeller KE, Lee KC, Kissack JC. Urine drug screening: practical guide for clinicians. Mayo Clin Proc. 2008;83(1):66-76. doi:10.4065/83.1.66
28. Keary CJ, Wang Y, Moran JR, et al. Toxicologic testing for opiates: understanding false-positive and false-negative test results. Prim Care Companion CNS Disord. 2012;14(4).PCC.12f01371 doi:10.4088/PCC.12f01371
29. Zebelman AM, Troyer BL, Randall GL, et al. Detection of morphine and codeine following consumption of poppy seeds. J Anal Toxicol. 1987;11(3):131-132. doi:10.1093/jat/11.3.131
30. Meier PS, Barrowclough C, Donmall MC. The role of the therapeutic alliance in the treatment of substance misuse: a critical review of the literature. Addiction. 2005;100(3):304-316. doi:10.1111/j.1360-0443.2004.00935.x
31. Kelly JF, Saitz R, Wakeman S. Language, substance use disorders, and policy: the need to reach consensus on an “addiction-ary.” Alcohol Treat Q. 2016;34(1):116-123. doi:10.1080/07347324.2016.1113103
32. Broyles LM, Binswanger IA, Jenkins JA, et al. Confronting inadvertent stigma and pejorative language in addiction scholarship: a recognition and response. Subst Abus. 2014;35(3):217-221. doi:10.1080/08897077.2014.930372
33. Kelly JF, Wakeman SE, Saitz R. Stop talking ‘dirty’: clinicians, language, and quality of care for the leading cause of preventable death in the United States. Am J Med. 2015;128(1):8-9. doi:10.1016/j.amjmed.2014.07.043
34. Jarvis M, Williams J, Hurford M, et al. Appropriate use of drug testing in clinical addiction medicine. J Addict Med. 2017;11(3):163-173. doi:10.1097/ADM.0000000000000323
35. Martin SA, Chiodo LM, Bosse JD, et al. The next stage of buprenorphine care for opioid use disorder. Ann Intern Med. 2018;169(9):628-635. doi:10.7326/M18-1652
36. Katz N, Fanciullo GJ. Role of urine toxicology testing in the management of chronic opioid therapy. Clin J Pain. 2002;18(4 Suppl):S76-S82.
37. Klein A. Harm reduction works: evidence and inclusion in drug policy and advocacy. Health Care Anal. 2020;28(4):404-414. doi:10.1007/s10728-020-00406-w
38. Patel MX, David AS. Medication adherence: predictive factors and enhancement strategies. Psychiatry. 2007;6(9):357-361. doi:10.1016/j.mppsy.2007.06.003
39. Lofwall MR, Walsh SL. A review of buprenorphine diversion and misuse: the current evidence base and experiences from around the world. J Addict Med. 2014;8(5):315-326. doi:10.1097/ADM.0000000000000045
40. Wang L, Weiss J, Ryan EB, et al. Telemedicine increases access to buprenorphine initiation during the COVID-19 pandemic. J Subst Abuse Treat. 2021;124:108272. doi:10.1016/ j.jsat.2020.108272
41. Harris MTH, Lambert AM, Maschke AD, et al. “No home to take methadone to”: experiences with addiction services during the COVID-19 pandemic among survivors of opioid overdose in Boston. J Subst Abuse Treat. 2022;135:108655. doi:10.1016/j.jsat.2021.108655
