Urinary Buprenorphine, Norbuprenorphine and Naloxone Concentrations and Ratios: Review and Potential Clinical Implications

Abstract

Objectives: Treatment with medications for opioid use disorder such as buprenorphine improves patient morbidity and mortality as well as treatment adherence, an important component of patient care. Buprenorphine is combined with naloxone to reduce misuse; and, when taken sublingually, naloxone is poorly absorbed. Urine testing for buprenorphine is a common way to monitor adherence. Some patients who want to appear adherent may directly tamper with their urine by adding buprenorphine to their urine to allow for the detection without ingestion. Practitioners may rely upon the concentration of buprenorphine and the metabolite, norbuprenorphine, and utilize the ratio of metabolite to parent compound (norbuprenorphine:buprenorphine – N:B ratio) to discern possible evidence of tampering; however, there remains debate as to what specific ratio may signify this practice. Testing for naloxone may also help determine if urine tampering occurred as only low naloxone concentrations are found in the urine when taken by a sublingual route. Methods: To determine a reliable N:B ratio that may be used to identify possible urine tampering by adding parent drug directly to urine, we examined 136,605 urine samples for quantitative concentrations of buprenorphine and norbuprenorphine by LC-MS/MS performed at a commercial laboratory. After identifying abnormal ratios (<0.02), we then compared them with naloxone concentrations and specimen validity testing, other markers that may coincide with specimen tampering of this type. Results: Correlating urinary buprenorphine and norbuprenorphine concentrations, we found 2 distinct patient populations, which could be distinguished by N:B ratios ranging from 0.01 to 0.2. In addition, while the distribution of urine naloxone concentrations itself did not demonstrate distinct populations, naloxone was able to further flag potential tampered specimens when combined with N:B ratios. Abnormal specimen validity testing was additionally found more commonly in cases with N:B ratios <0.02. Conclusions: This comprehensive study compared N:B ratios with naloxone concentrations and specimen validity testing. This study suggests that a N:B ratio of <0.02 in concert with high naloxone concentrations (>1000 ng/ml) can help to identify potential cases of tampered urine samples.

A Descriptive analysis of urine drug screen results in patients with opioid use disorder managed in a primary care setting

“…Patients who have had several expected UDS results, are on a stable dose of buprenorphine-naloxone and keep scheduled appointments and are otherwise doing well in their recovery may be candidates for less frequent UDS testing[ 1 ]. Less frequent testing for appropriate patients will help to reduce the cost of these tests to the patient as well as the healthcare system and can reduce time away from work in patients in recovery who are employed[ 18 ]. A comprehensive economic analysis is beyond the scope of this study but an important area for future study.…”

“…Its absence was considered unexpected. To account for the risk of specimen tampering by intentional contamination of urine with the original drug, buprenorphine confirmation testing that demonstrated only buprenorphine with no corresponding metabolite norbuprenorphine was defined as unexpected [ 18 ]. We designated 4 unexpected categories, detection of cocaine, heroin, methadone, and other opioids.…”

Do buprenorphine doses and ratios matter in medication assisted treatment adherence?

“… 15 Studies demonstrate that ratios <0.02 may indicate urine adulteration, a signal of nonadherence and potential substance diversion. 16 , 17 The clinical significance between BUP/NBP concentrations and their ratios for assessing adherence and substance use is not well-described.…”

Determination of buprenorphine, norbuprenorphine, naloxone, and their glucuronides in urine by liquid chromatography–tandem mass spectrometry

“…BUP metabolite and NAL analysis in urine, involving metabolite concentration ratios, has been applied to estimate the time of BUP intake, 31 differentiating between therapeutic and illicit use of BUP products 32 and identifying urine adulterated by submerging BUP medication. 33,34 Liquid chromatography-tandem mass spectrometry (LC-MS/MS)based methods, with or without hydrolysis of conjugates, are commonly used to analyse one or more of the analytes BUP, NBUP, NAL, BUP-G, NBUP-G, and NAL-G. However, to our knowledge, to date, there is no published LC-MS/MS method for the simultaneous quantification of all six analytes, including NAL-G, in human urine.…”

“…Urine analysis seems to offer a better means of clinical interpretation in various contexts of clinical and forensic toxicology and in monitoring compliance in OAT patients. BUP metabolite and NAL analysis in urine, involving metabolite concentration ratios, has been applied to estimate the time of BUP intake, 31 differentiating between therapeutic and illicit use of BUP products 32 and identifying urine adulterated by submerging BUP medication 33,34 …”