With Buprenorphine

Use and Interpretation of Buprenorphine Metabolite Profiles During Maintenance Treatment 4/8/2017 Disclosure Information

Timothy J. Wiegand, MD, FASAM Researched Abuse Diversion and Addiction Related Surveillance (RADARS)* – Consulting Fee, Research and Consultation RADARS is subsidized through pharmaceutical support Timothy J. Wiegand, MD, FACMT, FAACT, FASAM Director of Toxicology and Associate Clinical Professor at the University of Rochester Medical Center Medical Director of Huther Doyle Chemical Dependency Treatment Program Martin Siegrist, PA-C Associate Medical Director of Huther Doyle Chemical Dependency Treatment Program 1.) There is a lot of variability in confidence, skill, knowledge and practice related to drug testing 3.) In general, and across various medical specialties, there has been very little provider education and guidance related to drug testing* White paper Drug Testing Workgroup

1.) Describe the drug testing process for buprenorphine and metabolites 3.) Review and describe buprenorphine pharmacokinetics and the established literature related to interpretation of levels and buprenorphine monitoring during treatment (MAT). 4.) Discuss case examples related to buprenorphine and metabolite interpretation during MAT ! A.) Review patient’s health/addiction history*. " In some settings may start bup without a lot of info other than the patient is in w/d (e.g. ED). ! B.) Explain treatment process, induction process* and sign contract. ! C.) Discuss administration " “No eating, drinking or smoking…” ! D.) Discuss monitoring process " Frequency of visits " Drug testing (urine, oral, observed) ! A 21 year-old M with history of substance ! use disorder presents to the medication Drug testing why? management clinic in the outpatient CD " A.) initial to confirm report of use* program he’s attending per referral from his addiction counselor. He is interested in " B.) Subsequent to document buprenorphine maintenance. effectiveness/ineffectiveness of treatment (buprenorphine, ! He has been using marijuana and counseling, other) prescription opioids and was recently seen in an Emergency Department after " C.) Confirm compliance with seizures from excessive tramadol use. buprenorphine administration ! Has been using tramadol and fentanyl patches –he has h/o OD while chewing a " Appropriate administration patch 8 months prior. " Consistent administration ! Initial screen is preliminary ! Need confirmatory testing for confirmation of positives and also quantification. ! Specimen Validity Testing important ! Important to know what is included in your assay and what is not. ! Capability of sending for specific analytes? ! Gas chromatography or liquid chromatography and mass spectroscopy " Confirmatory screens " quantification ! THC level is confirmed and quantified –here is a graph of [THC] over time with several test results.

! Needed to control for varying degrees of dilution or concentration.

! Patient undergoes ! Drug testing to confirm buprenorphine induction and is buprenorphine use stabilized on 2/0.5 mg of ! Drug testing to detect other drug buprenorphine/naloxone SL BID. use (illicit/Rx’d opiates for He has good attendance and is example and THC) contributing to group. " Trend over time ! Drug testing, along with other ! He moves from phase 1 to phase clinical information, to 2 in his IOP. determine effectiveness of buprenorphine ! Patient is maintained on lower dose of buprenorphine with good response. ! [THC] drops off. ! Engaged in group/counseling ! Testing confirms he is taking buprenorphine regularly/reliably. ! Specific testing negative for tramadol/other drugs* ! 2008 paper ! Single dose of buprenorphine (SL) ! Followed metabolite levels over time ! 18 volunteers given 0.4 mg SL x 1. ! Metabolites measured in urine by LC-MS- MS ! 170 samples*

! Hydrolysis (glucuronidase) !

Bup + bup-gluc = Bup AND Norbup + norbup-gluc = norbup

Indicates low ratio early on then higher ratio as time progresses* This is single dose SL bup (NOT maintenance or other continued dosing) Some of the information applies Buprenorphine metabolized primarily by P4503A4 (some 2C8).

Norbup

Bup Norbup-gluc

Bup-gluc ! Buprenorphine is metabolized by ! The “conjugates” include: 3A4 (dealkylation) subsequently " Buprenorphine-glucuronide conjugated: " Norbuprenorphine-glucuronide " Norbuprenorphine ! The ‘free’ drug includes: " Buprenorphine-glucuronide " buprenorphine " Norbuprenorphine-glucuronide " Norbuprenorphine ! Total drug (Tbup and Tnorbup): " Buprenorphine + buprenorphine-gluc " Norbuprenorphine + norbup-gluc

! Using various inhibitors and inducers of 3A4 and 2C8 Moody, et al showed that metabolic profile changes. ! Antiretroviral agents used in this study. ! From this data we see profiles* ! Scatterplot of bup, norbup, bup- gluc and norbup-gluc [conc] in 24 hour urine ! 31 patients taking only buprenorphine or bup/naloxone for 2 weeks (at least) " 16/4 mg bup/naloxone (30) " one 20/5 mg bup/naloxone. ! McMillan et al demonstrated variation in metabolite profiles. ! 1946 (out of >2477 urines) positive for buprenorphine metabolites described. ! 49% positive for norbup, bup- gluc and norbup-gluc ! 42% pos for bup*, norbup, bup- gluc, norbup-gluc " Bup very low in majority " Bup very high in small amount of samples (e.g. > 1000 ng/mg Cr) ! Small amount of other ratios " Norbup-gluc alone in 1.2%

Metabolic ratio = norbup/buprenorphine (free) –should be high. and low ‘ratio’ norbuprenorphine/bup (metabolic ratio) Specimens containing more than 100 ng/mL free buprenorphine (expected to be much higher if total buprenorphine is measured) are suspected of adulteration. These amounted to 4% of the examined database. Adulteration of samples may occur from placement of medication directly into the sample. For subjects with access to buprenorphine/naloxone (dual product), possible adulteration could be detected by quantitative analysis of free buprenorphine and free naloxone concentrations in urine.

515 urine samples from 9 pregnant females (twice weekly) during pregnancy and post- partum Low levels of [bup] Range of levels of other metabolites*

Reflect the variation in administration and compliance* as well as other effects on PK (pregnancy, individual variation) *e.g. 6% only norbup-gluc An appropriate lab platform includes: More knowledge of patient’s progress/use

• Confirmation and quantification of • Trending total buprenorphine buprenorphine/metabolite levels! and metabolite/Cr ratios over provide insight into patient use (? time provides information Appropriate) about compliance • Adding the urine creatinine (Cr) allows for standardization of levels • Can detect adulteration despite fluctuations in urine concentration. Patient A --Buprenorphine induction ! increasing metabolites ! maint dose ‘Street’ use buprenorphine to induction

• 37 yo heroin dep M (“bundle/day intermittent bup from street”) ! bup/ naloxone 8/2 mg SL BID. • Initial urine shows 6MAM, morphine, bup (Tbup/Cr 18 ng/mg, Tnorbup/Cr 63 ng/mg). • After 8/2 mg induction (week 1) Tnorbup/ Cr levels 305 ng/mg; (10 days of 8/2 mg bup/naloxone) 895 ng/mg (week 2) 1009 ng/mg

Patient 2 abruptly stopped buprenorphine Total Norbup/Cr (ng/mg Cr over time

! Case of patient entering into treatment who had been on stable dose of buprenorphine but was not continued* ! Missed follow-up apt with X-waivered physician. ! Attempted to reschedule apt but then left treatment. Case two –adulterated/spiked urine Urine ‘spiked’ with buprenorphine

• 47 yo opioid-dependent M starts bup/ naloxone 8/2 mg outpatient. • Good attendance and is doing well. • Urine Tbup/Cr levels are 100-120 ng/mg; Tnorbup/Cr 300-400 ng/mg. • Starts to falter, absences, looks disheveled and his counselor flags urine: Tbup/Cr of >4000 ng/mg; Tnorbup/Cr levels negligible (25 ng/mg Cr). • Confirmation also detects 6MAM, morphine and naloxone.

Case three fluctuations in levels = changes in patient administration Fluctuation in metabolite levels • 26 yo F stable on 8/2 mg of bup/naloxone. Her Tnorbup/Cr levels range 400-800 ng/ mg first 3 months. • At a f/u visit Tnorbup/Cr = 40 ng/mg and she tells the MD she is “running out” at the end of the month because she was taking extra doses earlier to relieve anxiety and insomnia. • Counseled and monitored closer –levels improve • ? Use to guage need for higher dose (if taking appropriately for appropriate indication) Case 5 –stable dosing/compliant patient Stable doses/admin of buprenorphine

! Compliant patient on 4/1 mg SL BID. ! Excellent consistency ! Stable administration/stable dose Discussion Case 4 stable/compliant dosing

• Case 1 shows that dosing influences metabolite levels -> street use to stable dosing and can show compliance over time. • A compliant patient has low levels of bup and higher levels of the metabolites (Tnorbup/Cr). • Case 2 with intermittent buprenorphine use has lower metabolite levels than stable dosing. • Case 3 was spiking/adulterating bup/naloxone into urine ! high bup levels (Tbup/Cr >4000 ng/mg Cr), naloxone in urine; no metabolites • The medication didn’t go through the patient before getting into the urine.

Patient has street use of buprenorphine/naloxone product (“two a day”) and has induction with 8/2 mg strip and kept on 12/3 mg one/day (ease of dosing) with dramatic increase in levels of metabolite/Cr (Tnorbup/ Cr) –felt tired on higher dose of two 8/2 mg strips/day. ! On 4/19 level 260 ng/mg Cr (norbuprenorphine) no use x 1 week and on induction day 4/25/2016 he has norbup-cr levels 20 ng/mg Cr (and had used heroin the few days prior. Was having very low level intermittent use of buprenorphine from the street, “because its 15 dollars a dose.”

! After induction on 8/2 mg SL BID norbup-cr levels increased nicely to …

Titration of dose ! assess symptoms, use (labs and self- disclosure) other factors

Patient started on buprenorphine then ? Attempt to engage, higher level of care, observed doses, engage sig other (if they are interested) Transition to other treatment (methadone, naltrexone etc.) Try again if not effective right from the start

2 day protocol –comes in for obs doses two days in a row and sits for 30 minutes in front of provider. Levels checked in afternoon and next day. Doing well -compliant Buprenorphine > 1000 But… Total norbup-cr: 1020 ng/mL Note that [buprenorphine] is very low (< 5 ng/mL) regularly Transferred to program on bup missed apt and then needed re-induction. Restarted on bup (bup/ naloxone) and again off (off/ disappeared) and restarted again before seeing some stability May see some fluctuation in levels even in structured setting. Higher levels right after inpatient/supervised ‘detox’ facility (where MAT started) or in observed doses (e.g. OTP model or approximates OTP) or halfway house*

Urine testing and Specimen Validity Testing –Cr, SG, temperature. Also use oral screens (confirm appropriate sample)* This sample from patient positive cocaine (bup ok) given ultimatum on entry to halfway house with positive cocaine Other tests –EtG/EtS if indicted Oral swabs: Standard profile with Clonazepam added* Other analytes available SVT with oral is via IgG confirm

On 2/27 the formal start 8/2 mg SL BID

Bottom of the Y axis is not at 0 (starts Y of 300 ng/mL) • Appropriate testing can reinforce and confirm compliance, detect adulteration and help guide therapy. • Individual variation is important. • Education of patient is critical • Results guide discussion and monitoring (frequency, dose adjustments, other…) • Tool in treatment of patients with buprenorphine.