Buprenorphine in the treatment of addiction

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, ASAMdefined 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 9th ed, p. 526

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

13. 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 Receptor Binding at Mu receptor

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 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Buprenorphine Morphine 60 50 40 30 20 10 0 Himmelsbach scores 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 theDrug Addiction Treatment Act of 2000 – An Amendmentto the Controlled Substances Act(October, 2000)

21. Amended Controlled Substances Act 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

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

23. Amended Controlled Substances Act “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

24. Amended Controlled Substances Act “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

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