1

BUPRENORPHINE

GEORGE SINGLETARY MD MPH

ASSOCIATE PROGRAM DIRECTOR

ADDICTION MEDICINE FELLOWSHIP

TULANE UNIVERSITY

NOVEMBER 13, 2020

DISCLOSURE

• I do not have any financial or

commercial relationship to disclose

pertaining to this educational activity

• I may speak about off-label use of

prescription medication in this talk;

however, any off-label use of

medications should be a shared decision

between prescriber and patient.

• Tulane ECHO program

• Extension Community Healthcare Outcomes

• Weekly ZOOM with 15-20 minute didactic lecture on various topics, opportunity for

community partners to present challenging cases, engagement and discussion

• Part of LASOR grant

• Provide collaborative community encouraging primary care to provide

addiction tx

• Echo.Tulane.edu

• ALL are welcome

• Social workers, office staff, MD’s, peer support, etc

2

LEARNING OBJECTIVES

Review

Buprenorphine Pharmacology

Review

Buprenorphine literature

Understand

Buprenorphine safety

Review

Buprenorphine Pharmacology

WHO ARE WE TALKING ABOUT?

• Buprenorphine should not be the first effort at managing pain.

• Exhaust other options

• Non-opioid

• Adjuvant treatments

• r/o necessary surgical interventions

• Chronic opioid therapy for chronic non-cancer pain

• About 20% develop aberrant drug behavior (SALSITZ 2016)

• No definitive studies on percentages development of Opioid Use Disorder/Opioid

Dependence. Range from 0-50% depending on definitions. (SALSITZ 2016)

3

BUPRENORPHINE

• Mixed opioid agonist/antagonist

• Partial agonist at 𝜇 and 𝛿 receptors

• Antagonist at 𝜅 receptor

• Highly lipophilic

• Extensive first pass metabolism via CYP450 (3A4 and 2C8)

• IV, IM, sublingual, buccal, transdermal

𝜇 RECEPTORS

• Centrally

• Thalamus, cerebral cortex, visual cortex, basal ganglia

• Nucleus accumbens (reward pathway)

• Peripheral

• Urinary retention, constipation, nausea, biliary spasm, decreased secretions

• Endogenous mu agonists

• Enkephalins and 𝛽-endorphin

𝛿 OPIOID RECEPTORS

• Central and peripheral actions similar to 𝜇 receptors

• Additionally shown to mediate convulsions, inhibit dopaminergic effects and modulate 𝜇

receptor effects on the reward pathway

• Active area of research for anti-depressant and anxiolytic effects and possible

therapeutic target

4

𝜅 OPIOID RECEPTORS

• Decreased craving with antagonism

• Decreased hyperalgesia

• Decrease depression

PAIN FORMULATIONS

• Transdermal patch

• 5-20 mcg/hr

• Plasma levels 12-24 hours

• Titration period with patches applied for 3-7 days

• Bioavailability 46-65%

• Half-life 26 hours (after patch removal)

• European patches 35, 52.5, 70 mcg/hr

• Buccal films

• 75-900 mcg BID

• Bioavailability 15-28%

• Half-life 27.6 hours

ADDICTION FORMULATIONS

• Multiple brands

• Combination buprenorphine/naloxone

• Naloxone poorly absorbed via mucosa and GI tract

• Mainly to prevent IV use

• 2/1mg, 4/1mg, 8/2mg, 12/3mg, 16/4mg

• 0.7/0.18mg, 1.4/0.36mg, 2.9/0.71mg, 5.7/1.4mg, 8.6/2.1mg, 11.4/2.9mg

• 2.1/0.3mg, 4.2/0.7mg, 6.3/1mg

• 2/0.5mg, 8/2mg

5

ULTIMATELY…

DIFFERENT?

• Same drug, different package and dosage

• Tested and found to be efficacious for patients seeking treatment for opioid

use disorder as well as reducing opioid overdose even when taken illicitly or

intermittently

6

Review

Buprenorphine literature

• 1. Partial agonist at 𝜇-opioid receptor

• Higher binding affinity but lower intrinsic activity at mu-opioid receptor than full agonists

• However, activity at other 𝛿- and 𝜅- opioid receptors may also confer analgesic effects

• Consider less of the ‘bad’ and more of the ‘good’

• 2. Utility of buprenorphine BEFORE Schedule IV or II

• ‘on the basis of patient’s underlying conditions’

• Determine risk profile

• Co-occurring SUD

• Respiratory insufficiency

• polypharmacy

7

• 3. perioperative/trauma patient management

• Buccal and transdermal dosages can be continued

• Utilize full agonist as needed

• INDIVIDUALIZE

buprenorphine % 𝜇 opioid

receptor

availability

0 100%

2mg 59%

16mg 20%

32mg 16%

• 4. reasons to convert from full 𝜇-agonist to buprenorphine

• Tolerance or hyperalgesia

• Risk/benefit profile

• SUD

• GI motility issues limiting oral formulations

• Need for longer acting/schedule III

• Converting safely

• Prescribing inserts recommend ≤30 MME

• Significant amount of literature supporting safety and efficacy of higher MME prior to

conversion

• Individualize and discuss with patient risk of precipitated withdrawal

8

• Stop after nighttime dose

• Start PRN 𝛼2 agonist and/or short acting opioid

• ≤90 MME

• 10 mcg/h TD or 150 mcg Buccal BID

• >90 MME

• 20 mcg/hr TD or 300 mcg Buccal BID

• Sponsored by manufacturers

• Retrospective review 1/1/2016-6/30/2019

• 157 patients reviewed

• 87.9% successful conversion to buprenorphine buccal film

• 9-AE, 5-lack efficacy, 2-cost, 2-patient choice, 1-instructed by provider

• Statistically significant reductions mean pain scores (1-10) in <90 MME subgroup

• When stratified with 1-5 and 6-10; statistically significant decrease observed in mean scores

in <90 MME, 90-149 MME, and 150-199 MME for higher pre-conversion scores (6-10)

• <90 MME

• Average 400mcg

• 90-149 MME

• Average 500mcg

• 150-199 MME

• Average 650mcg

• >200 MME

• Average 600mcg

9

• 84 direct conversion from long acting

• 74 had been titrated to <150 MME before conversion attempted

• 27=morphine, 26=oxycodone, 17=fentanyl, 6=methadone, 5=tapentadol,

2=hydromorphone ER, 1=oxymorphone ER

• 75 successful conversions (89.3%)

• 31 (41.3%) remained on break through opioids for pain

• Patients with >=150 MME of long acting underwent dose reduction of 30-

50% prior to transition and provided clonidine PRN

KEEP COMMUNICATING WITH COLLEAGUES

• 66 year old woman

• Falls x 2 (10/2015,1/2016)=L2 compression fracture progressing to L2 vertebral collapse

with kyphosis and stenosis

• Gradual worsening of pain

• Standing tolerance of <1 hour

• Inability to ambulate w/o assistive device

• 1/2016-10/2018

• No opioid medications to oxycodone 30mg CR BID + 10mg IR PRN (105 MME)

• Constipation and concerns for development of hyperalgesia given increasing pain despite

dose escalations

• Other than tolerance, no OUD criteria

• 1 ppd smoker x 30 years

10

• 11-hour procedure with multilevel fusion

• Intra op

• General anesthesia sufentanil and dexmedetomidine infusions

• Total 250 mcg fentanyl, 4mg hydromorphone, 60mg ketamine, 50mg lidocaine

• Post op

• Hydromorphone infusion 0.6mg/h x 24h then 0.2mg/h x 5d

• Ketamine 10mg/h x 24h then 5mg/h x 24h then 2.5mg/h x 24h

• Oral oxycodone throughout periop period

• Still with severe pain post op despite escalating opioid doses

• Oxycodone up to 135-205mg daily (30mg ER TID + supplemental IR)

• 202.5-307.5 MED

• POD 9 – methadone 5mg TID

• Stopped scheduled ER

• POD 13 – methadone 8mg TID

• Still 60-80mg oxycodone daily in addition

• Consulted Complex Pain and Addiction Consult Service

• How many people have a service like this available?

• Decision to proceed with 3d rapid microdose to bup/nal

• Decreased methadone to 6mg TID in preparation

• UDS (results as expected, also tested for fentanyl)

• Bup/nal 0.25/0.0625 q3hr x 8 doses d1 (COWS 0-4)

• 0.5/0.125mg q3hr x 8 doses d2 (COWS 1-2)

• 1/0.25mg q3hr for 8 doses d3 (COWS 1-2)

• Continued methadone PLUS oxycodone 5-10mg q3hr prn (60-80mg daily)

• D4 12/3mg x 1 and discontinued methadone (COWS 1-5)

• D5 16/4mg x1 and discontinue oxycodone

• Performed on neuro-ortho spine inpatient unit

• No significant withdrawal symptoms

• Improved pain and function, ability to transfer and ambulate independently with walker

11

HAVE TO HELP WITH THE TRANSITION

• Used existing data set from randomized open-label study comparing

buprenorphine to methadone treatment in OUD

• Dichotomized pain from SF-36

• No,very mild,mild pain=0

• Moderate,severe,very severe pain=1

• Examined baseline pain, pain at 4 weeks, and retention at 24 weeks

• NO association between baseline pain and retention

• Methadone arm DID NOT produce lower levels of pain

• POSITIVE association between improvement in pain at 4 weeks and retention

• Significantly higher drop out in buprenorphine arm (46.6% retained)

• Those randomized to methadone 2.78 times more likely to be retained 74.1% retained)

• HALF of the individuals included in analysis continued to have moderate to severe pain

• median

• Buprenorphine=24mg

• Methadone=90mg

• At OTP clinic so both were dosed only once per day

• Need to do better job at treating pain if we are going to retain patients in treatment.

12

LESSONS LEARNED/BARRIERS

• Important to learn from mistakes

• More specialty communication and interventions

• May have advocated more for surgical team to treat with narcotics in

immediate post-op period

• Patient seemed to tolerate initial post-op period well

• Complicated with re-exploration and wound vac

• Rushed hospital discharge

• Well documented behavioral problems prior to this episode

• Past history of significant opioid/heroin use

Understand

Buprenorphine safety

• Considering buprenorphine as an emergency access medication

available ‘behind-the-counter’

• Emergency contraception, age limits, pseudoephedrine, limit quantities w/o

prescription

• Someone who has tapered off bup with eminent relapse-may prevent

• Concerns

• 1. health risk-combination of Tylenol and alcohol also toxic, behind-the-counter

• 2. ‘gateway drug’-reported ‘modest’ euphoria (compared to pseudoephedrine

or dextromethorphan); most with OUD

• 3. diversion-illicit market likely to dissipate if readily available

13

NCHS 2020

• A paragraph ‘To the editor’ published in NEJM 1980

titled ’Addiction Rare in Patients treated with Narcotics’

• A review of HOSPITALIZED patient records

• N=39,496

• n=11,882 prescribed opioids w/ 4 cases of ‘addiction’

• ‘To the Editor’ in NEJM 2017

• 1980-2018 that paragraph was cited 608 times with a

significant increase when oxycontin introduced in 1995

• 72.2% (439) citations listed it as evidence that ‘addiction

was rare in patients treated with opioids’

DON’T FORGET…

• Brain Oxygen is an important homeostatic

parameter

• Electrochemical sensors can examine

fluctuations in brain oxygen

• Fluctuations occur under normal conditions

• All opioids at high doses decrease brain

oxygen secondary to respiratory depression

• Opioids differ in their ability to inhibit

respiration and induce brain hypoxia.

14

• 3 ug/kg maintains self admin in rats

• LD50 1-3 mg/kg

• ”Based on the amplitude of brain oxygen decreases, oxycodone, heroin,

and fentanyl are ~ 4-, 40-, and 400-fold stronger than morphine”

• Rats are much more tolerant to hypoxemia than humans, tolerate up to

6min!

NIDA 2020

NALOXONE

• Life saving medication

• I am trying to get it for EVERYONE

using drugs, even cocaine users

• And educate!

15

CASE AA

• 57 y/o AA presents to ED with unrelieved pain

• Non-specific “my foot keeps painin me”

• Known vasculopathy, heavy smoking history

• Previously requested assistance from vascular surgical team secondary to patient non-

compliance, escalating requests for narcotics, refusal for surgery, reported illicit heroin use

• Attempted outpatient induction bup/nal

• Non-compliance with UDS testing, follow-up visits

CASE AA• UDS (+) CBD only

• ‘using marijuana for my pain’

• Consented to start buprenorphine perioperatively

• 8mg continued perioperatively-fem/pop bypass

• Titrated to 8mg BID with good results

• Discharged home per patient request with 14 day supply buprenorphine on a

Friday, ambulatory w/ walker

• Readmitted following Monday after a fall

• Had only taken one buprenorphine since discharge; UDS(-) OPI

16

CASE AA

• Titrated buprenorphine to 8mg TID which he appeared to be tolerating well,

pleasant with clinicians and staff despite requiring groin exploration and

wound vac application (Friday)

• Monday-veteran requesting dilaudid

• Notes that he had not been taking buprenorphine

• Nurse had been leaving it with him; he pointed out strip on bedside tray and also one in

the pocket of dirty scrub pants in laundry

• Said he was ‘not going to take it anymore’ so it was discontinued

CASE AA

• Transferred to skilled facility

• Refused to speak to me for about a week

• Requested our team speak with him again

• Agreed to restart buprenorphine 8mg TID which he again tolerated until a

Friday then said he ‘wanted to throw something at me’ when I tried to speak

to him on Monday if I mentioned the word ‘buprenorphine’

TAKEAWAYS

17

THANK YOU!

• Don’t forget to take care of YOURSELF!

• George Singletary MD MPH

• gsinglet@tulane.edu

REFERENCES•

Fishman, M. A., & Kim, P. S. (2018). Buprenorphine for Chronic Pain: a Systemic Review. Curr Pain Headache Rep, 22(12), 83.

doi:10.1007/s11916-018-0732-2

• Gress, K., Charipova, K., Jung, J. W., Kaye, A. D., Paladini, A., Varrassi, G., . . . Urits, I. (2020). A comprehensive review of partial opioid

agonists for the treatment of chronic pain. Best Pract Res Clin Anaesthesiol, 34(3), 449-461. doi:10.1016/j.bpa.2020.06.003

• Lee, D. S., Hann, J. E., Klaire, S. S., Nikoo, M., Negraeff, M. D., & Rezazadeh-Azar, P. (2020). Rapid Induction of Buprenorphine/Naloxone for

Chronic Pain Using a Microdosing Regimen: A Case Report. A A Pract, 14(2), 44-47. doi:10.1213/XAA.0000000000001138

• Pergolizzi, J. V., & Raffa, R. B. (2019). Safety And Efficacy Of The Unique Opioid Buprenorphine For The Treatment Of Chronic Pain. J Pain Res,

12, 3299-3317. doi:10.2147/JPR.S231948

• Roy, P. J., & Stein, M. D. (2019). Offering Emergency Buprenorphine Without a Prescription. JAMA. doi:10.1001/jama.2019.8309

• Shulman, M., Luo, S. X., Campbell, A. N. C., Scodes, J., Pavlicova, M., Broffman, A., . . . Nunes, E. V. (2020). Secondary Analysis of Pain Outcomes

in a Large Pragmatic Randomized Trial of Buprenorphine/Naloxone Versus Methadone for Opioid Use Disorder. J Addict Med, 14(5), e188-

e194. doi:10.1097/ADM.0000000000000630

• Weimer, M. B., Guerra, M., Morrow, G., & Adams, K. (2020). Hospital-based Buprenorphine Micro-dose Initiation. J Addict Med.

doi:10.1097/ADM.0000000000000745

• Zimmerman, A., Bikdash, R., & Rauck, R. (2020). Conversion of Schedule II Opioids to Buprenorphine Buccal Film: A Retrospective Analysis. Pain

Med. doi:10.1093/pm/pnaa226