1. Buprenorphine in the treatment of addiction Matthew A. Torrington MD Clinical Research Physician UCLA: Integrated Substance Abuse Programs Matrix Institute on Addictions Addiction Medicine Clinic November 4, 2004

2. Scope of this Talk What are we talking about? Addiction then buprenorphine…. Buprenorphine: For the treatment of opioid dependence Buprenorphine: As an analgesic Buprenorphine: On the horizon

3. AAPainMed,APainS, ASAM defined ADDICTON in 2001 Addiction is a primary, chronic, neurobiologic disease, with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving Savage et al., 2001

4. DSM 4 criteria for opiate abuse Significant impairment or distress resulting from use Failure to fulfill roles at work, home, or school Persistent use in physically hazardous situations Recurrent legal problems related to use Continued use despite interpersonal problems

5. DSM 4 criteria for Opiate Depend. ≥ 3 of the following occurring in the same 12- month period 1. Desire or unsuccessful efforts to cut down on opiate use 2. Large amount of time spent obtaining opiates, using opiates, or recovering from opiate effects 3. Social, occupational, or recreational activities reduced because of opiate use 4. Opiate use continued despite knowledge that a physical or psychological problem is being caused or exacerbated by use

6. 5. Tolerance Need for increased amounts of opiates to achieve desired effect; or Diminished effect with continued use of the same amount of opiate –Tolerance develops normally with repeated use –Tolerance to sedating effect develops quickly –Tolerance to respiratory depression can be marked

7. 6. Withdrawal withdrawal syndrome with cessation of use, reduction of use, or use of opiate antagonist Opiates or related substance taken to relieve or avoid withdrawal symptoms

8. Pseudoaddiction operationally defined as aberrant drug- related behaviors that make patients with chronic pain look like addicts. these behaviors stop if opioid doses are increased and pain improves (Weissman and Haddox, 1989). This indicates that the aberrant drug-related behaviors were actually a search for relief Little data on the subject, but evidence in rats

9. Magnitude of the Problem There are ~ 1,110 licensed OTPs in the U.S. ~225,000 patients in methadone treatment 800,000+ persons addicted to heroin 4.7 million prescription opioid users First time users are on the increase

10. Treatment Admissions

11. Schematic of Opiate Receptor Source: Goodman and Gillman 9 th ed, p. 526

12. Effect of Common Opiates at mu receptor Heroin, morphine, methadone Buprenorphine Naltrexone (Revia, Vixo) Naloxone (Narcan) Nalmefene Agonist Partial Agonist Antagonist

13. Receptor Binding at Mu receptor Agonist: Opens door Partial Agonist Opens door with safety chain Antagonists Dummy key Morphine like effect Weak morphine like effects with strong receptor affinity No effect in absence of an opiate or opiate dependence

14. Buprenorphine

15. Buprenorphine pharmacology contd. “Less bounce to the ounce” Ceiling effect on respiratory depression Less physical dependence capacity Blocks withdrawal in mildly dependent people Precipitates withdrawal in moderate to severely dependent people

16. Good Effect

17. Respiration

18. Intensity of abstinence 60 50 40 30 20 10 0 Himmelsbach scores 012345678910111213141516171819202122 Buprenorphine Morphine Days after drug withdrawal

19. Buprenorphine for Opiate Dependence: Suppresses withdrawal Substitutes for street opiates Blocks subsequently administered opiates Safety in long term use

20. Overview to the Drug Addiction Treatment Act of 2000 – An Amendment to the Controlled Substances Act (October, 2000)

21. Narcotic drug: Approved by the FDA for use in maintenance or detoxification treatment of opioid dependence Schedule III, IV, or V Drugs or combinations of drugs Amended Controlled Substances Act

22. Practitioner requirements: “Qualifying physician” Has capacity to refer patients for appropriate counseling and ancillary services No more than 30 patients (individual or group practice) Amended Controlled Substances Act

23. “Qualifying physician”: A licensed physician who meets one or more of the following: 1. Board certified in Addiction Psychiatry 2. Certified in Addiction Medicine by ASAM 3. Certified in Addiction Medicine by AOA 4. Investigator in buprenorphine clinical trials Amended Controlled Substances Act

24. “Qualifying physician” (continued): Meets one or more of the following: 5. Has completed 8 hours training provided by ASAM, AAAP, AMA, AOA, APA (or other organizations which may be designated by HHS) 6. Training/experience as determined by state medical licensing board 7. Other criteria established through regulation by the Secretary of Health and Human Services Amended Controlled Substances Act

25. Buprenorphine: Potent Analgesic 20-50 times potency of morphine Available worldwide for pain treatment Injectable formulation available in U.S. Usual analgesic dose:.2-.4 mg sl Higher dose for opiate dependence

26. Buprenorphine and Pain Animal data don’t predict human data Good potent analgesic No ceiling effect or inverted U curve Mild CVS effect, mild G-I effect Limited dependence, slow mild withdrawal Ceiling on respiratory depression Analgesia not compromised by ceiling. Effective for long term use mos. to yrs.

28. Buprenorphine: Analgesic Profile Rapid onset of action Long duration of peak effect (60-120 min) Long half life (3.5 hrs) Analgesic action up to 8 hrs. Ceiling effect on respiratory depression Low physical dependence profile

29. Buprenorphine – Clinical Analgesic Use Surgical pain –Intra-operative, peri-operative, post- operative Labor pain Back pain Phantom pain Post-herpetic neuralgia Cancer pain

30. Buprenorphine for Pain Good for trans-dermal application –Lipophilic –High level analgesia –Low adverse effects Patch –Consistent delivery, desirable time course –Flexible dosing and compliance

31. Myths about buprenorphine and pain Partial agonist, limited clinical effects Not reversible by naloxone Can’t be given after other opioids. Reality High affinity, mod intrinsic activity, slow dissociation from mu, highly lipophilic

32. Treating Acute pain in buprenorphine patients Keep on buprenorphine –Increase buprenorphine dose –Add high potency opioid—fentanyl –Add or switch to methadone (Caution) Regional analgesia PCA Non-opioids

33. Treating Chronic pain in buprenorphine patients Keep on sublingual buprenorphine Consider buprenorphine patches (when available) Switch to morphine Switch to methadone (CAUTION) Use opioid rotation High potency opioids for “break thru” pain Non-opioid analgesics Adjunct medications and local anesthetics Non-pharmacological treatments

34. Issues on the horizon: Buprenorphine access: 30 pt rule, inability of NTPs to use buprenorphine, cost Buprenorphine abuse liability Studies underway: –Bup 3, CTN, outpatient detox schedules