Anti-Craving Medications: A New Class of Psychoactive Meds?? May 4, 2004

1. Anti-Craving Medications:A New Class of Psychoactive Meds??May 4, 2004 Charles P. O’Brien, MD, PhD University of Pennsylvania Philadelphia VA Medical Center

2. What’s really importantabout addiction treatment? • Detoxification-manageable • Relapse: HUGE Problem • Years • ? Lifetime

3. SLIDES NOT AVAILABLE PER AUTHOR, DO NOT POST SLIDE TO THE WEB.

4. Factors Leading to Relapse • Psychiatric problems - Depression - Anxiety • Social Problems - Unemployment - Family problems - Peer influence • Protracted Abstinence • Conditioned Responses

5. Targeted Treatments • Other psychiatric problems Specific medications • Psychotherapy • What about the deeply ingrained learned responses ?

6. Brain Changes • Biochemical effects - Protracted abstinence • Memories- may not be reversible

7. 16 2 14 1.8 12 1.6 10 1.4 8 1.2 6 1 Early Late Detoxification: Partial Recovery p < 0.003 DAT (Bmax/Kd) p = 0.11 Delayed Recall # of Words (14 months detoxification) Early Late

8. Addiction = Memory • Drugs are reinforcers • Pavlov’s lab- 1920s • Wikler- 1940s, Lexington • Proneness to relapse after months to years abstinent

9. Craving • Controversial concept • Predicts use, but not 100% • External and Internal factors • Subjective measurement • Semantic issues

10. Craving • Use without prior craving • Craving but no use • Craving increases probability of relapse • Involuntary brain responses, not always conscious

11. Conditioned Responses • Thousands of pairings of environmental cues with drug effects • Cellular level: changes in gene transcription, receptor sensitivity, transmitter release • Persist long after last use of drug • Can be drug-like or withdrawal-like

12. Conditioned drug effects Craving Autonomic (HR, Skin Temp, GSR) Regional CBF Regional Brain Metabolism Neurotransmitter release (DA) Immediate early genes (cFos)

13. Subject 2 Pre Post Post naloxone naloxone or saline methadone Body Temperature (Fo) Minutes

14. Laboratory Studies of Drug Craving Naturally conditioned responses • Videos • Imagery • Odors

18. PET Session Timeline • PET O-15 • Cocaine Patients • Cocaine-naïve Controls Scan 1 Scans 2 &3 Scan 4 Scans 5 & 6 Baseline Neutral Videos Resting Cocaine Videos 0 Minutes 86

19. Amygdala Nature Video Cocaine Video 2.5 2.0 1.5 Anterior Cingulate 1.0 .5 0 Pt. 30023 Childress ‘97 Cocaine Pt. 30023

20. Orbitofrontal Nature Video Opiate Video 2.5 2.0 1.5 Anterior Cingulate 1.0 .5 0 Opiate Patient 01 Pt. Op_1.1

21. Amygdala Nature Video Sexual Video Anterior Cingulate Pt. SX_4

22. Brain Substrates of Cocaine Cue Reactivity University of Pennsylvania (Childress, et al) NIDA Addiction Research Center (Grant, et al; Bonson et al.) Harvard (McLean; MGH) (Maas, et al) Medical College of Wisconsin (Garavan, et al) Emory University (Kilts, et al) Yale (Wexler, et al) Brookhaven National Laboratories (Wang, et al) Limbic activation:Anterior cingulate, amygdala, insula, ventral striatum (NAc), orbitofrontal cortex Other : DLPFC, cerebellum

23. Learned changes Facilitate relapsePre-existing lack of impulse control?Reduced inhibition Difficult to say “No” Difficult to delay rewards Brain in addiction

24. Cocaine Patients PET O-15 Hypoactivity Reduced Gray Matter (in Peoples, 2002)

25. Conditioned neurotransmitter release Micro dialysis in animal models PET ligand displacement in human subjects

26. Pre-Alcohol “Craving”

27. Evidence for increased endogenous DA (reduced binding potential) in cocaine video vs. neutral condition Pt. RAC_001

28. Cognitive Behavioral Therapy 12 Step Programs (AA)Family TherapyRepeated exposures: Extinction Relapse Prevention Limited success, craving responses persist

29. Agonist Maintenance Blocks craving + withdrawal Nicotine patch Methadone Buprenorphine (partial agonist)

30. Psychoactive medications Anti-psychotics Anti-anxiety Anti-depressants Anti-OCD Are there medications that can help reduce craving?

31. Anti-craving medications Non-agonist Reduce Relapse Reduce desire for drug Suppress conditioned craving

32. Absence of Limbic Activation During Cocaine Cue Exposure in a Cocaine Patient (BAC_07) Taking the GABA B Agonist Baclofen Chronically Limbic Activation During Cue-Induced Cocaine Craving in Unmedicated Cocaine Patients (n=14)

33. “Anti-Craving” Medications(non agonists) Naltrexone - Alcohol Acamprosate - Alcohol Bupropion - Nicotine ---------------------------- Rimonabant - Nicotine, obesity (CB-1 antag) Propranolol - Cocaine Disulfiram - Cocaine Modafinil - Cocaine GABA enhancers - Baclofen, Topiramate, GVG

34. Alcohol effects on brain systems Dopamine Increased release Opioid Increased endogenous opioid activity (endorphin release) and stimulation of opioid receptors Serotonin Decreased release GABA Increased sensitivity to GABA

35. Naltrexone decreases Alcohol preference* % Change from Saline Pretreatment Response Levels (10 day mean) Days Naltrexone *Altshuler 1980

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40. Post-Shock Drinking Change in % Ethanol Consumption -5 1-2 3-4 5-6 Days Post-Shock

41. Skepticism • Alcohol - endogenous opioids • Nicotine - endogenous cannabinoids

42. Double blind design • 70 chronic alcoholics • All received intensive day hospital, AA, psychotherapy • Half received Naltrexone 50 mg/day • Half received identical placebo • Weekly craving scores • “slips” measured (not a relapse) • Relapse defined

43. Pharmacological Treatments for Alcoholism Craving Scores by Week Mean (SEM) Craving Score (0-9) 0 1 2 3 4 5 6 7 8 9 10 11 12 Weeks on Medication

44. Any Alcohol Drinking Percent of Subjects Naltrexone Placebo

45. Days Drinking Average Drinking Days per week Naltrexone Placebo

46. Subjective “high” in Naltrexone and Placebo Subjects 0.1 0 - 0.1 - 0.2 - 0.3 - 0.4 - 0.5 mean “high” rating * Naltrexone Placebo * p<.05

47. Non-relapse “Survival” 1.0 0.9 0.8 0.7 Cumulative Proportion with No Relapse 0.6 0.5 0.4 0.3 Naltrexone HCL (N=35) Placebo (N=35) 0.2 0.1 0.0 0 1 2 3 4 5 6 7 8 9 10 11 12 No. of Weeks Receiving Medication Volpicelli et al, Arch Gen Psychiatry, 1992; 49: 876-880

48. Relapse Curves* Naltrexone Placebo Cumulative proportion with no relapse Number of weeks receiving medication *O’Malley 1992

49. Relapse Survival Rates by Level of Compliance: Naltrexone versus Placebo % of sample who did not relapse Number of weeks on medication