Addiction and chronic pain management - Mayo School … patients with chronic low back pain: an...

©2015 MFMER | slide-1

Buprenorphine Addiction and chronic pain management Markus Bendel, M.D.


Disclosures

Relevant Financial Relationships None

Off-label Investigational Uses

None


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


Outline

• Introduction • Indications • Dosing and titration • Weaning • Side effects • Effectiveness • Conclusion


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

Presenter

Presentation Notes

1985 – schedule V 2002 – Suboxone and subutex – All formulations moved to schedule III


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

Presenter

Presentation Notes

And there are no signs of this trend slowing.


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

Presenter

Presentation Notes

Nociceptin agonism is about 500 times weaker than the binding of the opioid receptors. Norbuprenorphine is the only known active metabolite with about 4000% decreased analgesic effects. Half life – there is no structural change to the receptors after the drug has disengaged from the opioid receptor. Thus, after the analgesic effect of buprenorphine has abated, the receptors are available for binding to other opioid medications. Obviously, this has important implications in managing peri-operative patients in which stronger opioids are required. Half can vary up to 70 hours.


Buprenorphine • Formulations

• US availability • Buprenorphine alone

• Subutex (sublingual tab – generic only) • ___________ (transdermal patch) • ___________ (buccal film) • ___________ (injectable) • ___________ (implantable)

• Formulations combined with naloxone • __________,___________, ________

Presenter

Presentation Notes

Subutex – pure buprenorphine for addiction maintenance has been discontinued in favor of combination products. Suboxone – sublingual film Bunavail – buccal film – citrus taste Zubsolv – sublingual tablet Probuphine – implantable buprenorphine


Outline



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

Presenter

Presentation Notes

SAMHSA = Substance Abuse and Mental Health Services Administration DATA 2000 = Drug Addiction Treatment Act Training is in the form of dedicated residency training in addiction medicine or an 8 hour online course for about $200 30 patients first year, can apply for an increase to 100 patients in second year.


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

Presenter

Presentation Notes

Recommend 8 mg per day of buprenorphine or less. Stable dose. No dependence on full agonists.


Implantable Buprenorphine

Probuphine Full Prescribing Information

Presenter

Presentation Notes

Included for informational purposes. I have not implanted this system. Formal training is required.


Implantable Buprenorphine

Probuphine Full Prescribing Information

Presenter

Presentation Notes

All good things must come to an end. The Probuphine system does require surgical removal after 6 months.


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.

Presenter

Presentation Notes

Benefit of a non-inferior therapy that requires minor surgery to implant and explant? Questionable overall benefit. May have a use for patients that cannot be relied upon to take their medications?


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


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

Presenter

Presentation Notes

Theoretically less addiction = partial agonist = analgesic plateau with higher doses and then acts like an antagonist QTc – mean increase of 9 ms at a dosage of 40 mcg/hr. Only approved to 20 mcg/hr. Other countries up to 140 mcg/hr. Not a clinically significant concern. Cost for 1 month supply 5 mcg/hr (4): $224.08 7.5 mcg/hr (4): $313.70 10 mcg/hr (4): $336.11 15 mcg/hr (4): $484.85 20 mcg/hr (4): $595.03


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


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

Presenter

Presentation Notes

Educate patient on this problem. They will be the one suffering. They need to be able to advocate to peri-operative providers as well.


Outline



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

Presenter

Presentation Notes

Recommended strategy to wean opioids to 30 OME and start a 10 mcg/hr patch. Patients will likely require continued short acting opioids as steady state is not achieved with the patch for approximately 72 hours. Doses should not be titrated within 72 hours. OK to titrate from 5 mcg/hr to 10 mcg/hr and 10 mcg/hr to 20 mcg/hr pending patient selection and comorbid disease.


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

Presenter

Presentation Notes

75, 150, 300, 450, 600, 750, 900 mcg dosing films Greater than 160 mg – CONSIDER alternatives Recommend tapering to 30 OME


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.

Presenter

Presentation Notes

No manufacturer recommendations for any dose adjustments based on age, renal disease or hepatic dysfunction. No evidence to support any recommendations.


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

Presenter

Presentation Notes

Same site can effectively double the dose. Heating can increase release of medication by 55% Areas without any subcutaneous tissue – elbows, knees – lead to very poor absorption. Sounds silly, but patients often times expect to put the patch where the pain is.


Outline



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.

Presenter

Presentation Notes

Study shows slow wean is better.


Presenter

Presentation Notes

.005 mg/hr = .12 mg day = small percentage of receptors are activated = easier to wean medication .020 mg/hr = .48 mg day = 10% receptors are activated = relatively easy to wean, but still step down over weeks 2 mg (oral bup tab) = half of receptors are activated = much harder to wean in a short time frame without significant withdrawal


Outline



Side Effects

Common

• Nausea

• Headache

• Dizziness

• Drowsiness

Uncommon

• Respiratory depression

• Hypotension

The peri-operative conundrum

Presenter

Presentation Notes

Respiratory depression – almost always combined with CNS depressants


Outline



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.


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.

Presenter

Presentation Notes

2 - There was no statistical benefit with the intention-to-treat analysis. There was benefit outside of this analysis. High drop out rates were principally due to nausea.


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.


Outline



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


Thank You

Questions?

[email protected]

Addiction and chronic pain management - Mayo School … patients with chronic low back pain: an...

Documents

Transcript of Addiction and chronic pain management - Mayo School … patients with chronic low back pain: an...