1. Supported in part by Arkansas Blue Cross and Blue Shield
and the Office of the Arkansas Drug Director and in partnership with the Arkansas Academy of Family Physicians (AAFP), the Arkansas Medical Society (AMS), the Arkansas State Medical Board (ASMB), the Arkansas Department of Health (ADH) and its Division of Substance Misuse and Injury Prevention (Prescription Drug Monitoring Program—PDMP)
Continuing Education Credit: TEXT:
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2. Buprenorphine for Chronic Pain
Shona Ray-Griffith, MD
Assistant Professor
University of Arkansas for Medical Sciences

3. Disclosures I receive clinical trial support from Neuronetics.
I have received clinical trial support from Sage Therapeutics.
Neither will be discussed today.

4. Objectives What? When? How?
Review pharmacological properties of buprenorphine
When?
Discuss use of buprenorphine for chronic pain
How?
Provide overview of Belbuca and Butrans

5. Pharmacology of Buprenorphine
Schedule III controlled substance
Partial mu-opioid agonist
Analgesia and rewards
Partial kappa-opioid antagonist
Dose-ceiling effect
32mg day
Naloxone may not be effective in reversing respiratory depression
High doses (10-35mg/70kg) may be of limited value

6. Pharmacology of Buprenorphine
Metabolized extensively in the liver to norbuprenorphine (major metabolite) via glucuronidation
Renal excretion: no need for alterations in dose
Mean plasma elimination half-life of 27.6±11.2 hours
Studies have revealed no differences in geriatric population or by sex.
Drug Interactions
CYP3A4 inhibitors can increase and inducers can decrease BUP
96% protein bound

7. Buprenorphine Major Contraindications
Addiction, abuse, and misuse
Hepatic Impairment
Severe hepatic impairment: Reduce start and incremental dose by half
Increased risk of hepatotoxicity: Baseline and periodic LFTs
Significant Respiratory Depression
Acute/severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment
Interactions with Benzodiazepines

8. Buprenorphine Minor Contraindications
Adrenal Insufficiency
Serotonin Syndrome
GI obstruction
Hypersensitivity to buprenorphine
Risk of Prolonged QTc Interval
Severe hypotension
NAS/NOWS
Increased risk of seizures

9. Buprenorphine for Chronic Pain
When would you consider buprenorphine for treatment of chronic pain?
What are you positive and negative experiences?
What are your concerns?

10. Buprenorphine for Chronic Pain
Long-acting opioid needed
Defined as daily, around the clock
Alternative treatments failed/inadequate
Not for use as prn
Not able to tolerate po
Concern for abuse of opioids
Concern for overdose potential
Comorbid depression?

12. Buprenorphine Chronic Pain Opioid Use Disorder No DEA waiver needed
No naloxone
Multiple doses daily
Patch or buccal
Specialized training and DEA waiver required
+/- naloxone
Once daily dosing
Sublingual tablets, buccal films, or film; injection

13. How?

14. Belbuca Buccal film Dose (mcg): 75, 150, 300, 450, 600, 750, and 900*
Peppermint flavored
Dose (mcg): 75, 150, 300, 450, 600, 750, and 900*
Frequency: Every 12 hours
Contraindications:
Analgesic requirements greater than 160 oral MME daily
Oral mucositis: Reduce start and incremental dose by half
Doses above 900mcg daily have potential for QTc interval prolongation

15. Belbuca Starting Dose
Taper all other long-term opioids to less than 30 MME
Titrate by 150mcg Q12 hours every 4 days if needed
Original Opioid Dose (MME)
Initial Belbuca Dose
Opioid naïve patients
75mcg once daily or every 12 hours
Less than 30
30-89
150mcg every 12 hours
90-160
300mcg every 12 hours

16. Belbuca Demonstration No food or drink during 30 minutes
Wet the inside of the cheek/area for placement
Applied immediately after removal from package
Yellow side is placed against the inside of the cheek
Held in place for 5 seconds
Dissolves within 30 minutes
No food or drink during 30 minutes
Avoid applying to open sores/lesions
If chewed or swallowed, may result in lower peak concentrations and lower bioavailability

17. Belbuca Discontinuation requires tapering Side Effects
More than 5%: Nausea, vomiting, constipation, headache, dizziness, somnolence, diarrhea, dry mouth, and URI

18. Belbuca Clinical Trials
Three 12 week double-blind, placebo-controlled clinical trials in opioid naïve and opioid experienced patients with moderate to severe chronic low back pain
Pain scores as primary outcome
2 demonstrated efficacy
A higher proportion of Belbuca patients had a 30 and 50% reduction in pain scores

19. Butrans Extended release patch
Doses (mcg/hour): 5, 7.5, 10, 15, and 20*
The proportion of BUP mixed in adhesive matrix is the same for each strength. The amount released is proportional to the active surface area of the system.
Frequency: 7 days
Contraindications
Butrans 20mcg/hour may not provide adequate analgesia for patients receiving more than 80 MME daily

20. Butrans Starting Dose
Taper all other long-term opioids to less than 30 MME
Minimum titration interval is 72 hours
For dose adjustments, use 2 patches of same dose
For dose adjustments, patients should remove patch and replace with 2 patches adjacent to each other at a different site
Do not exceed total dose of 20mcg/hour
Original Opioid Dose (MME)
Initial Butrans Dose
Opioid naïve patients
5mcg/hour every 7 days
Less than 30
30-80
10mcg/hour every 7 days

21. Butrans Patch Application Site Avoid exposure to external heat sources
Locations: upper outer arm, upper chest, upper back, or the side of the chest
Should be dry and hairless (clip hair if needed)
Wait a minimum of 3 weeks before applying to the same site
Avoid exposure to external heat sources
May cause increase in absorption of buprenorphine
Incidental bathing is allowed
First aid tape can secure edges only. Bioclusive or Tegaderm can secure full patch.
If patch falls off before 7 days, place a new patch at different site
Dispose by:
Patch-Disposal Unite
Folding patch on itself and flushing down the toilet
Wash hands after applying

22. Butrans Discontinuation requires tapering every 7 days
After removal of patch, the mean concentration decreases about 50% in 12 hrs with an apparent terminal half-life of about 26 hrs
Side Effects
More than 5%: nausea, dizziness, headache, somnolence, vomiting, constipation, dry mouth
Application site pruritus, erythema, rash
Geriatric Use: More adverse effects reported but no difference in pharmacokinetics
Dispensed as a package of 4 patches

23. Butrans Clinical Trials
Four 12-week double-blind, controlled clinical trials in opioid naïve and opioid experienced patients with moderate to severe chronic low back pain or osteoarthritis
Pain scores as primary outcome
2 demonstrated efficacy in low back pain
Others did not demonstrate efficacy for active drug or placebo
The score for average pain over the last 24 hours at the end of the study was statistically significantly lower for patients treated with butrans in both studies
In study comparing to low dose (5mcg), a higher proportion of 20mcg/hour patients had at least a 30% reduction in pain scores from screening to study endpoint.

24. Treatment of Acute Pain on Buprenorphine
Debated topic
No standard protocol
Present example of cesarean section protocol
Other examples?

25. Questions about the Topic
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26. Case Conference and Feedback
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