addiction and chronic pain management - mayo school … patients with chronic low back pain: an...
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Buprenorphine Addiction and chronic pain management Markus Bendel, M.D.
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Disclosures
Relevant Financial Relationships None
Off-label Investigational Uses
None
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Learning Objectives • Review the basic formulations, dosing, and
side-effects of buprenorphine
• Identify differences in buprenorphine prescribing between the indications of addiction management and chronic pain
• Understand the evidence for the use of buprenorphine in chronic pain
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Outline
• Introduction • Indications • Dosing and titration • Weaning • Side effects • Effectiveness • Conclusion
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History of buprenorphine in the U.S. 1985 - Initial marketing as analgesic in 1985
2002 – FDA approved for addiction management
2010 – FDA approved transdermal formulation for chronic pain management
2015 – FDA approved buccal buprenorphine for chronic pain management
2016 – FDA approved implantable buprenorphine product for addiction maintenance
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Business is booming
• 2015 – sales of daily oral formulations of buprenorphine totaled $2 Billion1
• Since 2006, more prescriptions of
buprenorphine than methadone1
1 http://www.titanpharm.com/pipeline/probuphine
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Just the facts… • Partial agonist of the mu opioid receptors • Also,
• Weak antagonist of Kappa opioid receptors • Agonist of delta opioid receptors • Partial agonist of ORL-1 (nociceptin)
• Hepatic metabolism • BILIARY and renal excretion • Terminal ½ life ~ 26 hours
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Buprenorphine • Formulations
• US availability • Buprenorphine alone
• Subutex (sublingual tab – generic only) • ___________ (transdermal patch) • ___________ (buccal film) • ___________ (injectable) • ___________ (implantable)
• Formulations combined with naloxone • __________,___________, ________
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Outline
• Introduction • Indications • Dosing and titration • Weaning • Side effects • Effectiveness • Conclusion
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Addiction Maintenance
• Buprenorphine-naloxone formulations – FDA approved 2002
• Buprenorphine CAN be abused • After DATA 2000, special licensure from
SAMHSA and DEA • “X” DEA number issued for this purpose
• Fully searchable online • Special training • Patient quota
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Implantable Buprenorphine • ____________
• Recent approval for addiction maintenance • 4 probuphine implants are inserted
subdermally in the upper arm • Left in place for 6 months • Must be removed
• Not for initial therapy. Patient must have
“sustained prolonged clinical stability on transmucosal buprenorphine.”1
1. Probuphine Full Prescribing Information
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Implantable Buprenorphine
Probuphine Full Prescribing Information
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Implantable Buprenorphine
Probuphine Full Prescribing Information
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Implantable Buprenorphine • Better than traditional sublingual route?
• Trial1
• Randomized • Implantable vs. sublingual • 96.4% vs 87.6% maintained abstinence • Result – Non-inferiority!
1.Rosenthal RN, Lofwall MR, Kim S, et al. Effect of Buprenorphine Implants on Illicit Opioid Use Among Abstinent Adults With Opioid Dependence Treated With Sublingual Buprenorphine: A Randomized Clinical Trial. JAMA 2016;316:282-90.
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Chronic Pain Management • ________ - FDA approval 2010 • ________ - FDA approval 2015
• Moderate to severe pain requiring long term treatment
• Ineffective alternatives
• Contraindications: • Significant respiratory depression • Severe bronchial asthma • Paralytic ileus • Anaphylaxis
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Buprenorphine for Chronic Pain
Advantages
• Less addiction potential?
• Ceiling for respiratory depression?
• Easy administration – improved compliance
• No significant QTc effects
• Reliable elimination
Disadvantages
• There remains opioid abuse potential
• Cost
• Induced withdrawal
• Perioperative concerns
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Perioperative Problem • Highly bound to opioid receptor • Traditional post-operative analgesics don’t have
access to receptors • Long half-life • If present, standard opioid therapy will be less
efficacious • Problem often not addressed pre-operatively
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Perioperative Solutions • Elective
• Stop 3-5 days pre-operatively and replace with traditional opioid agonist
• Cancel/delay case? • Urgent/Emergent
• Stop on arrival (Probuphine?) • Supplement with high dose opioids and
monitoring • Watch for sedation as buprenorphine
dissociates
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Outline
• Introduction • Indications • Dosing and titration • Weaning • Side effects • Effectiveness • Conclusion
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Dosing and Titration - Butrans
• Opioid Naïve • Start with 5 mcg/hr patch
• Opioid Experienced
• Less than 30 OME • 5 mcg/hr patch
• Between 30 and 80 OME • 10 mcg/hr patch
• Greater than 80 OME • Consider alternatives
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Dosing and Titration - Belbuca • Opioid Naïve
• Start with 75 mcg daily (titrating to BID)
• Opioid Experienced • Less than 30 OME
• 75 mcg daily (titrating to BID) • Between 30 and 89 OME
• 150 mcg q 12 hours • Between 90 mg to 160 mg
• 300 mcg q 12 hours
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Special Populations
Renal Disease
• No relationship between CrCl and steady plasma drug concentrations
Hepatic Disease
• No increased exposure to parent drug or metabolites in patients with Child-Pugh A or B liver disease
• There is increased exposure in moderate to severe disease1
• Use with caution
1. Nasser AF, Heidbreder C, Liu YZ, Fudala PJ. Pharmacokinetics of Sublingual Buprenorphine and Naloxone in Subjects with Mild to Severe Hepatic Impairment (Child-Pugh Classes A, B, and C), in Hepatitis C Virus-Seropositive Subjects, and in Healthy Volunteers. Clin Pharmacokinet 2015;54:837-49.
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Things to tell your patient about the patch…
Do
• Rotate application sites
• Apply to upper arm, back, chest
• Discuss possibility of problems with pain control peri-operatively
Don’t
• Repeat application site for 4 weeks
• Heat the patch
• Cut the patch
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Outline
• Introduction • Indications • Dosing and titration • Weaning • Side effects • Effectiveness • Conclusion
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Weaning • Consider indication for medication
• Chronic pain – relatively low doses • Decrease in step-wise fashion
• Addiction
• Need specialized training • Slow wean1
• ~ 25% every 10 days • Likely will experience withdrawal
1. Dunn KE, Saulsgiver KA, Miller ME, Nuzzo PA, Sigmon SC. Characterizing opioid withdrawal during double-blind buprenorphine detoxification. Drug Alcohol Depend 2015;151:47-55.
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Outline
• Introduction • Indications • Dosing and titration • Weaning • Side effects • Effectiveness • Conclusion
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Side Effects
Common
• Nausea
• Headache
• Dizziness
• Drowsiness
Uncommon
• Respiratory depression
• Hypotension
The peri-operative conundrum
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Outline
• Introduction • Indications • Dosing and titration • Weaning • Side effects • Effectiveness • Conclusion
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Low Back Pain • Sublingual for chronic back pain1
• Vs. placebo
• Improved activities of daily living2
• Improved pain and disability scores3
1. Rauck RL, Potts J, Xiang Q, Tzanis E, Finn A. Efficacy and tolerability of buccal buprenorphine in opioid-naive patients with moderate to severe chronic low back pain. Postgrad Med 2016;128:1-11.
2. Miller K, Yarlas A, Wen W, et al. The impact of buprenorphine transdermal delivery system on activities of daily living among patients with chronic low back pain: an application of the international classification of functioning, disability and health. Clin J Pain 2014;30:1015-22.
3. Gordon A, Rashiq S, Moulin DE, et al. Buprenorphine transdermal system for opioid therapy in patients with chronic low back pain. Pain Res Manag 2010;15:169-78.
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Neuropathic Pain • Cochrane Review
• No studies met inclusion criteria1 • Thereby, no recommendation
• Diabetic neuropathy2
• Slight benefit to sham • High drop-out rate
1. Wiffen PJ, Derry S, Moore RA, et al. Buprenorphine for neuropathic pain in adults. Cochrane Database Syst Rev 2015;9:CD011603.
2. Simpson RW, Wlodarczyk JH. Transdermal Buprenorphine Relieves Neuropathic Pain: A Randomized, Double-Blind, Parallel-Group, Placebo-Controlled Trial in Diabetic Peripheral Neuropathic Pain. Diabetes Care 2016.
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Cancer Pain • Cochrane Review
• Mixed results. Very low quality data.1
• Meta-analysis for transdermal delivery and cancer2
1. Schmidt-Hansen M, Bromham N, Taubert M, Arnold S, Hilgart JS. Buprenorphine for treating cancer pain. Cochrane Database Syst Rev 2015;3:CD009596. 2. Naing C, Yeoh PN, Aung K. A meta-analysis of efficacy and tolerability of buprenorphine for the relief of cancer pain. Springerplus 2014;3:87.
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Outline
• Introduction • Indications • Dosing and titration • Weaning • Side effects • Effectiveness • Conclusion
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Conclusions • Transdermal buprenorphine and buccal
buprenorphine is FDA approved for moderate-severe chronic pain
• Patient selection, as with all opioid therapy, is vital
• Limited trials available, but evidence suggests safety and efficacy for select indications