1. Buprenorphine for Pain and for Addiction David A. Moltz, MD MAPP Clinical Conference April 30, 2010

2. I. Addiction and Dependence

3. DSM IVSubstance Dependence A maladaptive pattern of substance use, with 3 or more of: • Tolerance • Withdrawal • Using larger amounts or for a longer time than intended • Persistent desire or lack of control • A great deal of time spent obtaining, using, recovering from • Important activities given up • Continued use in spite of negative consequences

4. Addiction • A chronic but treatable brain disease characterized by • loss of control • compulsive use • use despite known harm • relapse

5. Dependence vs Addiction • Addiction may occur with or without the presence of physical dependence. • Physical dependence results from the body’s adaptation to a drug or medication and is defined by the presence of • Tolerance and/or • Withdrawal

6. Opioid Use in a Household Survey Population • According to the 2002 National Survey on Drug Use and Health : An estimated 4.4 million persons were current users of pain relievers for nonmedical purposes. • New non-medical pain reliever use more than quadrupled from 1990 (628,000 new users) to 2000 (2.7 million new users). SOURCE: SAMHSA, 2002.

7. Neural circuitry of reward • Present in all animals • Produces pleasure for behaviors needed for survival: • Eating • Drinking • Sex • Nurturing

8. Neural circuitry of reward Altruism activates the same circuitry Meeks TW, Jeste DV. The neurobiology of wisdom. Arch Gen Psychiatry 2009;66(4):355-365

9. II. Buprenorphine

10. Definition of Terms • Agonist • Antagonist • Affinity • Intrinsic Activity • Dissociation

11. Buprenorphine • Novel opioid with both agonist and antagonist properties • Partial agonist at mu opioid receptor • High affinity • Low intrinsic activity • Slow dissociation • Antagonist at kappa receptor

12. Buprenorphine • High affinity for mu receptors  ability to compete with full mu agonists (such as heroin) and to block their effects. • Low intrinsic activity  feeling of well-being without full opioid effects • Very slow dissociation rate  prolonged therapeutic effects. • Ceiling effect

14. Advantages of a Partial Agonist • Lower abuse potential • Lower level of physical dependence • Relative safety if ingested in overdose quantities • Weak opioid effects compared with methadone.

15. Blockade Effect • Buprenorphine has tight binding to and slow dissociation from opioid receptors. It produces a blockade effect at the mu-opioid receptor so that subsequently administered opioids do not produce their full euphoric effect. • It appears to produce less physical dependence than a full opioid agonist (such as methadone), and it may be easier to discontinue at the end of medication treatment.

16. Severity of Opioid-Withdrawal Symptoms after Abrupt Discontinuation of Equivalent Doses of Heroin, Buprenorphine, and Methadone Kosten T and O'Connor P. N Engl J Med 2003;348:1786-1795

17. III. Buprenorphine for Addiction

18. Drug Addiction Treatment Act of 2000 (DATA 2000) • Expands treatment options to include both the general health care system and opioid treatment programs. • Expands number of available treatment slots • Allows opioid treatment in office settings • Sets physician qualifications for prescribing the medication

19. Beneficial Effects • Blocks craving • Blocks opiate withdrawal • Does not produce a ‘high’ • Blocks the effects of other opioids • Milder withdrawal than methadone • Stabilization of brain function • Anti-depressant / anti-anxiety effect

20. Beneficial Effects • Significant enhancement in treatment retention and in the quality of participation • Mainstreaming of opioid dependence treatment with office-based practice • Greater safety • Lower diversion risk

21. ResearchOutcomes • Buprenorphine is as effective as moderate doses of methadone. • Partial agonist effects make it mildly reinforcing, encouraging medication compliance. • After a year of buprenorphine + counseling, 75% of patients were retained in treatment compared to 0% in a placebo + counseling condition.

23. Cognitive Effects • Available evidence in patients maintained on buprenorphine indicates no clinically significant disruption in cognitive and psychomotor performance. • “Long-term use…does not impair driving ability.” Dagtekin O, et al. Assessing cognitive & psychomotor Performance under long-term treatment with transdermal buprenorphine in chronic noncancer pain patients. Anesth Analg 2007;105:1442-8

24. Buprenorphine + naloxone Partial agonist + pure antagonist Naloxone is only active intravenously Will precipitate withdrawal in opioid-dependent individuals Combination decreases diversion risk Suboxone

25. Addiction is not a disease of the synapses alone --Mark Publicker

26. IV. Buprenorphine and Pain

27. Pain Patients vs Addicted Persons

28. Risk Factors • Psychosocial • Genetic • Drug-related

29. Pseudo-addiction • “Drug-seeking behavior” • Consequence of inadequate treatment of pain • May be indistinguishable from addictive behavior

30. Effectiveness in Pain • 30-40 times more potent than morphine • Ceiling effect  high safety profile • Transdermal used extensively in Europe • “…transdermal buprenorphine provides effective, sustained and dose-dependent analgesia, irrespective of age.” Pergolizzi J et al. Opioids & the management of chronic severe pain in the elderly: Consensus statement of an international expert panel. Pain Practice 2008;8(4):287-313

31. Buprenorphine vs Morphine • Chronic cancer pain • More effective than morphine for physical pain, mental health and quality of life. Pace, MC, et al. Buprenorphine in long-term control of chronic pain in cancer patients. Frontiers in Bioscience 2007;(12):1291-1299

32. Buprenorphine vs Methadone • Post-partum, maintained on buprenorphine or methadone, with opioids or ibuprofen as needed • Buprenorphine group decreased ibuprofen use over 5 days • Methadone group increased ibuprofen use Jones HE, et al. Management of acute postpartum pain in patients maintained on methadone or buprenorphine during pregnancy. Am J Drug and Alcohol Abuse, 2009; 35:151-56

33. Managing Pain During Buprenorphine Maintenance • Supplement with NSAIDS • Temporarily replace buprenorphine with opiates • Override buprenorphine with opiates • Divide +/or increase buprenorphine dose Heit HA, Gourlay DL. Buprenorphine: New tricks with an old molecule for pain management. Clin J Pain 2008; 24(2):93-97

34. Hyperalgesia

35. Hyperalgesia • A decrease in the threshold to elicit pain • A state of nociceptive sensitization • Hyperesthesia

36. Allodynia The generation of pain in response to low-intensity stimuli or stimuli that are not normally painful.

37. Mechanisms of Hyperalgesia • NMDA (glutaminergic) • Dynorphin (kappa receptor agonist) • Peripheral, spinal and central sensitization • “More complexity than clarity”

38. Opioid-Induced Hyperalgesia • May be activation of hyperalgesic systems to counteract the analgesic effects of the opioids • Ex: Morphine activates NMDA receptors and spinal dynorphin • In withdrawal, the hyperalgesic system is unopposed

39. Hyperalgesia and Tolerance • May share mechanisms (eg,NMDA), but they are clinically different • Hyperalgesia is increased sensitivity to pain • Tolerance is decreased sensitivity to opioids Chang G, et al. Opioid tolerance & hyperalgesia. Med Clin N Am 2007;91;199-211

40. OIH and Tolerance • Difficult to differentiate clinically • OIH diffuse, generalized pain, often different from pre-existing pain • Stopping the opioid can differentiate • Tolerance  more pain • OIH  less pain

41. Treating OIH • Minimize opioid dose using adjuvant therapies • Opioid rotation • Methadone (NMDA antagonist) • Buprenorphine

42. Pain reduction after detoxification • 23 patients not getting benefit from high-dose opioids • No addictive behaviors • 21 showed marked decrease in pain after detoxification • After weaning, 63% decrease in pain with buprenorphine vs. 47% without Baron MJ, McDonald PW. Significant pain reduction in chronic pain patients after detoxification from high-dose opioids. J Opioid Management 2006;2(5):277-282

43. Neuropathic pain • Buprenorphine relieves allodynia from neuropathic pain • Blocks hyperalgesia due to central hypersensitization • Kappa antagonist (dynorphin) • “Buprenorphine has been shown to have a pronounced antihyperalgesic effect.” Induru RR, Davis MP. Buprenorphine for neuropathic pain – Targeting hyperalgesia. Am J Hospice & Palliative Med 2009:26 (6);470-3 Likar R. Transdermal buprenorphine in the management of persistent pain – Safety aspects. Therapeutics & Clinical Risk Management 2006:2(1):115-125

44. Buprenorphine and OIH • “Resolution of OIH usually follows quickly during the maintenance phase with buprenorphine.” • “Buprenorphine may be unique in its ability to treat chronic pain and possibly OIH” • Silverman SM. Opioid induced hyperalgesia: Clinical implications for the pain practitioner.

45. Prescription Opioid Addiction Treatment Study (POATS) • Opioid dependence • 42% with co-existent chronic pain • Overall, 49% substantially improved after 3 mo of buprenorphine • Of those with chronic pain, 53% substantially improved, and “many had significant improvement in their pain.” Weiss R. NIDA Blending Conference 4/22/10. www.NIDA.NIH.Gov

46. Coexistent Addiction and Pain • Buprenorphine is ideal • Treats addiction • Treats pain • Relieves hyperalgesia

47. Resources • Clinical Guidelines for the Use of Buprenorphine in the Treatment of Opioid Addiction. SAMHSA/CSAT Treatment Improvement Protocols. TIP 40. • http://buprenorphine.samhsa.gov • http://www2.aaap.org/buprenorphine (For DATA training)