The American Journal on Addictions, 23: 318–319, 2014 Copyright © American Academy of Addiction Psychiatry ISSN: 1055-0496 print / 1521-0391 online DOI: 10.1111/j.1521-0391.2014.12087.x
Differential Diagnosis for a Stable Patient Maintained on Buprenorphine Who Gives a Urine Toxicology Screen Negative for Buprenorphine Roopa Sethi, MD,1,2 Ismene Petrakis, MD1,2 1 2
Department of Psychiatry, Yale School of Medicine, Department of Addiction Psychiatry, West Haven, Connecticut VA Connecticut Health Care System, West Haven, Connecticut
CASE REPORT We present the case of a 33‐year‐old male who is prescribed buprenorphine/naloxone 24/6 mg daily for 10 months. As part of his treatment plan, he has weekly urine drug screens, which have consistently been positive for buprenorphine using the urine screening test‐cloned enzyme donor immunoassay (CEDIA; positive cut‐off value is at or above 5 ng/ml) and negative on other illicit substances. The other substances tested included amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, methadone, opiates, and oxycodone, using the enzyme linked immunosorbent assay (ELISA). After 10 months of stable treatment, he presented to the appointment as usual, but his urine drug screen laboratory results were negative for buprenorphine, also negative for any other illicit substances. A confirmatory test using gas chromatography‐ mass spectrometry (GCMS) was sent out and the results of the test showed buprenorphine levels that were negative, and norbuprenorphine levels were 11 ng/ml. For this test, a positive cut off value of buprenorphine and norbuprenorphine is 5 ng/ ml. On follow up visit, in response to a query about these results, he reported taking his buprenorphine/naloxone as prescribed. The patient was also prescribed the following medications: trazodone 50 mg every night at bedtime, sennoides 8.6 mg two times a day as needed and mirtazapine 7.5 mg at bedtime for sleep, but there had been no change in these medications. After a thorough review of systems, the patient also reported having experienced a poison ivy reaction on his left arm a week before this appointment and was prescribed a 7‐day course of prednisone 40 mg daily. He took the prescription for 7 days and then discontinued it. He denied
Received April 15, 2013; accepted May 10, 2013. Address correspondence to Sethi, Addiction Psychiatry Fellow, Yale School of Medicine, VA Connecticut Health Care system, 950 Campbell Avenue, West Haven, CT 06516. E‐mail: [email protected]. 318
any over the counter medications. How do we approach this case?
DISCUSSION This case is important for psychiatrists and addiction psychiatrists for having knowledge about buprenorphine screening tests, buprenorphine confirmatory tests and its metabolite is important for proper clinical care. From a clinical point of view, a negative buprenorphine on screening tests, and negative buprenorphine on confirmatory tests could imply (1) missed doses of buprenorphine and possible diversion, (2) possibly intake of other medications that could interfere with the metabolism, and (3) an individual who is a fast metabolizer of buprenorphine. Buprenorphine is a semi‐synthetic opioid derived from the baine, a naturally occurring alkaloid of the opium poppy.1 The sublingual absorption of buprenorphine is rapid and the peak plasma concentration occurs 1 hour after dosing.2 Buprenorphine undergoes extensive first‐pass metabolism and therefore has very low oral bioavailability; however, its bioavailability sublingually is extensive enough to make this a feasible route of administration for the treatment of opioid dependence.1 It is extensively metabolized in the liver by N‐ dealkylation to norbuprenorphine primarily through cytochrome P450 (CYP) 3A4.1 Both buprenorphine and norbuprenorphine undergo glucuronidation by extensive phase II metabolism to form inactive buprenorphine and norbuprenorphine conjugates.3 The terminal elimination half‐life of buprenorphine is long and there is considerable variation in reported values (mean values ranging from 3 to 44 hours).1 Our patient had no buprenorphine in his screening test (CEDIA immunoassay, cut off values of 5 ng/ml) and confirmatory test (GC‐MS test, cut off values of 5 ng/ml). He had positive values of norbuprenorphine (11 ng/ml, GC‐ MS test, cut off values of 5 ng/ml). This could imply missed doses.
Although there is limited evidence in the literature to date, drugs that are known to inhibit or induce CYP3A4 have the potential to diminish or enhance buprenorphine N‐dealkylation.1 Our patient was placed on prednisone 40 mg/day and prednisone is an inducer of CYP3A4 pathway; this could lead to a positive norbuprenorphine and no buprenorphine in the urine. It has been recommended that all urine drug screens (immunoassays) with negative buprenorphine be subjected to confirmatory tests (GCMS).4 The significance of the norbuprenorphine–buprenorphine ratio of
Differential Diagnosis for a Stable Patient Maintained on Buprenorphine Who Gives a Urine Toxicology Screen Negative for Buprenorphine Roopa Sethi, MD,1,2 Ismene Petrakis, MD1,2 1 2
Department of Psychiatry, Yale School of Medicine, Department of Addiction Psychiatry, West Haven, Connecticut VA Connecticut Health Care System, West Haven, Connecticut
CASE REPORT We present the case of a 33‐year‐old male who is prescribed buprenorphine/naloxone 24/6 mg daily for 10 months. As part of his treatment plan, he has weekly urine drug screens, which have consistently been positive for buprenorphine using the urine screening test‐cloned enzyme donor immunoassay (CEDIA; positive cut‐off value is at or above 5 ng/ml) and negative on other illicit substances. The other substances tested included amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, methadone, opiates, and oxycodone, using the enzyme linked immunosorbent assay (ELISA). After 10 months of stable treatment, he presented to the appointment as usual, but his urine drug screen laboratory results were negative for buprenorphine, also negative for any other illicit substances. A confirmatory test using gas chromatography‐ mass spectrometry (GCMS) was sent out and the results of the test showed buprenorphine levels that were negative, and norbuprenorphine levels were 11 ng/ml. For this test, a positive cut off value of buprenorphine and norbuprenorphine is 5 ng/ ml. On follow up visit, in response to a query about these results, he reported taking his buprenorphine/naloxone as prescribed. The patient was also prescribed the following medications: trazodone 50 mg every night at bedtime, sennoides 8.6 mg two times a day as needed and mirtazapine 7.5 mg at bedtime for sleep, but there had been no change in these medications. After a thorough review of systems, the patient also reported having experienced a poison ivy reaction on his left arm a week before this appointment and was prescribed a 7‐day course of prednisone 40 mg daily. He took the prescription for 7 days and then discontinued it. He denied
Received April 15, 2013; accepted May 10, 2013. Address correspondence to Sethi, Addiction Psychiatry Fellow, Yale School of Medicine, VA Connecticut Health Care system, 950 Campbell Avenue, West Haven, CT 06516. E‐mail: [email protected]. 318
any over the counter medications. How do we approach this case?
DISCUSSION This case is important for psychiatrists and addiction psychiatrists for having knowledge about buprenorphine screening tests, buprenorphine confirmatory tests and its metabolite is important for proper clinical care. From a clinical point of view, a negative buprenorphine on screening tests, and negative buprenorphine on confirmatory tests could imply (1) missed doses of buprenorphine and possible diversion, (2) possibly intake of other medications that could interfere with the metabolism, and (3) an individual who is a fast metabolizer of buprenorphine. Buprenorphine is a semi‐synthetic opioid derived from the baine, a naturally occurring alkaloid of the opium poppy.1 The sublingual absorption of buprenorphine is rapid and the peak plasma concentration occurs 1 hour after dosing.2 Buprenorphine undergoes extensive first‐pass metabolism and therefore has very low oral bioavailability; however, its bioavailability sublingually is extensive enough to make this a feasible route of administration for the treatment of opioid dependence.1 It is extensively metabolized in the liver by N‐ dealkylation to norbuprenorphine primarily through cytochrome P450 (CYP) 3A4.1 Both buprenorphine and norbuprenorphine undergo glucuronidation by extensive phase II metabolism to form inactive buprenorphine and norbuprenorphine conjugates.3 The terminal elimination half‐life of buprenorphine is long and there is considerable variation in reported values (mean values ranging from 3 to 44 hours).1 Our patient had no buprenorphine in his screening test (CEDIA immunoassay, cut off values of 5 ng/ml) and confirmatory test (GC‐MS test, cut off values of 5 ng/ml). He had positive values of norbuprenorphine (11 ng/ml, GC‐ MS test, cut off values of 5 ng/ml). This could imply missed doses.
Although there is limited evidence in the literature to date, drugs that are known to inhibit or induce CYP3A4 have the potential to diminish or enhance buprenorphine N‐dealkylation.1 Our patient was placed on prednisone 40 mg/day and prednisone is an inducer of CYP3A4 pathway; this could lead to a positive norbuprenorphine and no buprenorphine in the urine. It has been recommended that all urine drug screens (immunoassays) with negative buprenorphine be subjected to confirmatory tests (GCMS).4 The significance of the norbuprenorphine–buprenorphine ratio of
