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: 501-406-0076 Event ID:27931-24581

Buprenorphine for Chronic Pain Shona Ray-Griffith, MD Assistant Professor University of Arkansas for Medical Sciences

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

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

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

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

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

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

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?

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?

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

How?

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

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

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

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

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

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

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

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

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

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.

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

Questions about the Topic Continuing Education Credit: TEXT: 501-406-0076 Event ID:27931-24581

Case Conference and Feedback Continuing Education Credit: TEXT: 501-406-0076 Event ID:27931-24581