1. Chronic Diseases Treatments but no simple cure, persisting for a long time DiabetesDiabetes EpilepsyEpilepsy AsthmaAsthma HypertensionHypertension AddictionAddiction Acute Diseases Cure, no residual Pneumonia Appendicitis

2. Resultant of interacting variables Agent (Drug) HostEnvironment + - + - - Outcomes: No use UseAbuseAddiction +

3. Risk of Addiction Source: Anthony et al, 1994. Ever Used (%) Addiction (%) Risk(%) Tobacco75.6 24.1 24.131.9 Cocaine16.22.716.7 Heroin 1.5 1.50.423.1 Alcohol 91.5 91.514.115.4 Cannabis46.34.2 9.1 9.1

4. Rat model Addiction – 20% of exposed 1. Continue bar pressing long after drug terminated – stopping difficult 2. High motivation – break point 3. Continue despite punishment

5. “Unseen” Reward Cues “Unseen” Reward Cues activate activate amygdala amygdala v. striatum v. striatum v. pallidum v. pallidumInsula

6. Types of Genetic Studies Family Twin Adoption Large population: COGA Candidate gene studies

7. ASTHMA (adult only).35 -.70 DIABETES (insulin dep).70 -.95 (males) HYPERTENSION.25 -.50 (males) Heritability Estimates Twin Studies ALCOHOL (dependence).55 -.65 (males) OPIATE (dependence).35 -.50 (males) Eye Color1.00

8. The Alcohol Pyramid In Spec Treatment – 1,800,000 Abuse/Dependent – 18,000,000 “Harmful Users” – ??,000,000

9. Results at 5-7 Years Practicing Medicine Completers92% Continuers73% Non-Completers28%

10. Health care reform for addiction treatment Not limited to acute care Early identification Long term care Medications when indicated

11. Level Of Response To Alcohol Observe less response when tested with alcohol Self-report of more drinks for an effect IV alcohol clamp to control level

12. Response Genetically influenced (heritability  40%) Low LR in animals, twins, 1° relatives, 40% offspring of alcoholics

13. Low response Predicts Alcoholism 4-20 Years Later If response low at age 20 And FH positive 60% men developed alcohol use disorder by age 30

14. Frontal Inhibitory Systems Inability to resist craving Unable to “Just say NO!” Impulsive behavior Poor performance on frontal lobe tests, e.g., gambling Possible DSM V spectrum Dx OCD, ADHD, ASP, ?

15. PET O-15 HypoactivityReduced Gray Matter Cocaine Patients Peoples, 2002

16. Brain Reward System Prefrontal Cortex Nucleus Accumbens Arcuate Nucleus Ventral Tegmental Area Nestler and Malenka. The Addicted Brain. Scientific American. March, 2004.

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

20. Amygdala Nature Video Cocaine Video Anterior Cingulate 1.5 0.5 1.0 2.0 2.5 Pt. 30023 Childress ‘97

21. Pt. Op_1.1 Nature Video Opiate Video Anterior Cingulate 1.5 0.5 1.0 2.0 2.5 Orbitofrontal

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

24. Bmax/Kd Cocaine Craving 30 20 10 0 -10 -20 -30 -40 2.5 2.0 1.5 1.0 0.50 0.0 -0.50 2.5 2.0 1.5 1.0 0.50 0.0 -0.50 Change in Craving (Post-Pre) % Change Bmax/kd Caudate % Change Bmax/kd Putamen * **

25. Dopamine D2 Receptors are Lower in Addiction DA D2 Receptor Availability Cocaine Alcohol DA Reward Circuits DA Reward Circuits DA Drug Abuser Non-Drug Abuser Heroin Meth control addicted Adapted from Volkow et al., Neurobiology of Learning and Memory 78:610-624, 2002.

26. Volkow ND and Wise RA: How can drug addiction help us understand obesity? Nature Neuroscience, May 2005

27. Alcohol: desired drink Humans since recorded history Animals from insects to elephants Animals from insects to elephants popular literature monkeys engage in spontaneous alcohol-seeking Animal models are predictive of human drug taking

28. Ethanol: a drug with complex effects on multiple neurotransmitter systems

29. Alcohol reward Partial list GABA Serotonin AMPA, Glu-rec NMDA Neuropeptide Y Glycine Opioid- µ, k, ∂

30. Sedating drug, facilitates GABAergic meds, no specific receptor “dirty” drug- affects numerous receptor systems, directly or indirectly

31. FDA Approved Medications Disulfiram (Antabuse) Naltrexone (generic) Acamprosate (Campral) Depot Naltrexone (Vivitrol)

32. Arguments against medications They are just a “crutch” You have to work the program yourself – no chemical aids They get in the way of the 12 steps I’ve been sober for 10 years and I never took medication They have side effects You’ll become addicted to them Etc…

33. True Translational Story: Naltrexone for Alcoholism Animal lab to Randomized clinical trials to FDA approval for clinical practice to ?? Standard practice

34. Endogenous Opioid System Opiate Receptors Simon 1973 Pert & Snyder 1973 Terenius 1973 Enkephalin 1975 ∂ B-Endorphin µ Dynorphin k Nociceptin OFQ/NOC 1990s

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

40. Post-Shock Drinking Change in % Ethanol Consumption 0 5 10 15 20 25 Placebo Naltrexone -5 1-2 3-4 5-6 Days Post-Shock

41. Saline.25 mg/kg Naltrexone Ethanol Responses Time (min)

42. Variable response to alcohol Alcohol seeking 10 of 22 Rhesus (Altshuler) 15% Vervets 10-15% H. sapiens Less variable in rodents µ receptor knock outs will not self administer alcohol

43. Assumption: alcohol releases endogenous opioids In vivo evidence: only indirect evidence in brain, direct evidence in plasma In vitro evidence: direct measures in lymphocyte cultures, HIV effects of alcohol blocked by naltrexone. Wen Ze Ho et al, 2006 Molecular mechanism unknown

44. Naltrexone Concurrently Antagonizes EtOH-Induced Accumbal DA Release and EtOH Self-Administration Gonzales & Weiss (2002) J Neurosci 18:10663-10671

45. Assumption: alcohol causes the release of endogenous opioids which are “required” for DA release in response to alcohol?

46. Brain Reward System Prefrontal Cortex Nucleus Accumbens Arcuate Nucleus Ventral Tegmental Area Nestler and Malenka. The Addicted Brain. Scientific American. March, 2004.

47. – GABA Ventral Tegmental Area Arcuate Nucleus Dopamine  -Endorphin Neuron Long Loop Nucleus Accumbens Dopamine – Alcohol Gianoulakis. Alcohol-Seeking Behavior: The Roles of the Hypothalamic-Pituitary-Adrenal Axis and the Endogenous Opioid System. Alcohol Health and Research World. 1998;22(3).

48. Dopamine Opioid Antagonism – GABA Ventral Tegmental Area Arcuate Nucleus  -Endorphin Neuron Nucleus Accumbens – Alcohol Dopamine Gianoulakis. Alcohol-Seeking Behavior: The Roles of the Hypothalamic-Pituitary-Adrenal Axis and the Endogenous Opioid System. Alcohol Health and Research World. 1998;22(3).

49. Alcohol effects become conditioned to environmental cues Naltrexone blocks cue induced relapse better than stress induced

50. Pre-Alcohol “Craving”

51. Alcohol - Beverage Condition Insula Cingulate Nucleus Accumbens Z=1.645 Ex.05 Alcoholics (n=10)Controls (n=10)

52. Ventral Tegmental Area Cingulate Z=1.645 Ex.05 Alcohol - Beverage Condition Alcoholics (n=10)Controls (n=10)

53. Propose an RCT of an opiate antagonist in human alcoholics because of animal data ?? IND 1983 Begin open studies 50 mg dose based on experience with heroin Philadelphia VA Hospital

54. Post-Synaptic Neuron Kappa Mu Delta Affinity for Opiate Receptor TX TX TX TX Opiate Receptors Kappa Mu Delta Naltrexone 406 108 54 Naltrexone 406 108 54 Morphine 1 1 1 Morphine 1 1 1 MOR MOR MOR MOR.. NOC N

55. 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

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

57. Cue-induced increases in DA were associated with craving P < 0.002 % Change Bmax/Kd -0.50 0.0 0.50 1.0 1.5 2.0 2.5 -40 -30-20-100102030 Putamen Change in Craving (Pre - Post) Relationship between Cue-Induced Decreases in [11C]raclopride Binding and Cocaine Craving Caudate Putamen 2.00 2.50 3.00 3.50 Neutral Cocaine-Cues Bmax/Kd P < 0.05 P < 0.01 Volkow et al J Neuroscience 2006

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

59. A.coming to treatment appointment with a blood alcohol concentration > 100 mg% > 100 mg% or B.self report of drinking five or more days within one week or C.self report of five or more drinks during one drinking occasion Alcohol Relapse

60. Non-relapse “Survival” Volpicelli et al, Arch Gen Psychiatry, 1992; 49: 876-880 No. of Weeks Receiving Medication 1023 4 56789101112 0.0 0.1 0.2 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0.3 Naltrexone HCL (N=35) Placebo (N=35) Cummulative Proportion with No Relapse

61. Rates of Never Relapsing According to Treatment Group (n=97) O’Malley et al, Arch of Gen Psychiatry, Vol 49, Nov 1992 Naltrexone/coping skills Naltrexone/supportive therapy Placebo/coping skills Placebo/supportive therapy Days 0 20 40 60 80 100 n=97 020408060

62. Alcohol “PRIMING” in human, non- treatment seeking Alcoholics O’Malley et al From the animal laboratory back to the clinic

63. 0 0.02 0.04 0.06 0.08 0.1 01020304080110150180 Placebo, n = 8 Naltrexone, n = 10 Blood Alcohol levels (g/dl) 0 5 10 15 20 25 30 35 40 01020304080110150180 Placebo, n = 7 Naltrexone, n = 9 Craving Priming DoseFirst ChoiceSecond Block

64. Addiction Therapy may be related to activation of Frontal Cortex (Boettiger, et.al. 2009) (Crews and Boettiger et.al. 2009)

65. Possible mechanisms of naltrexone effects 1.Block reward via endogenous opioid system - alcohol activates E.O. - Extinction of alcohol self-administration 2. Reduction in craving does not require extinction some treated alcoholics do not test by drinking 3.Direct effect of naltrexone on frontal executive fx Inc activity in r.lat.orbital gyrus during decision making (delay of reward) & decreased selection of immediate reward. (Boettiger et al 2009)

66. Studies supporting efficacy Studies not supporting efficacy Study# SsNotes Study# SsNotes Volpicelli, et al 199270NoneKranzler, et al 1999 183 None O’Malley, et al 199297NoneKrystal, et al 2002627 None Mason, et al 1994 [Nalmefene] 21None Oslin, et al 199744Elderly Volpicelli, et al 199797None Mason, et al 1999 [Nalmefene] 105None Kranzler, et al 199820Depot Anton, et al 2000131None Chick, et al 2000 (UK)169Adherence Monterosso, et al 2001183None Morris, et al 2001 (Australia) 111None Heinala, et al 2001 (Finland) 121Nonabstine nt Lee, et al 2001 (Singapore) Kiefer et al 2003 (Germany) 53 160 None

67. Studies supporting efficacyStudies not supporting efficacy Study# SsNotesStudy# SsNotes Latt et al 2002107Family Prac Balldin et al 2003118None Feeney et al 200150Hist. cont Rubio et al 2001157v. Acamp. Rubio et al 200230Cont. Drink. Gastpar et al 2002105Neg. in self report Pos. GGT Gastpar et al 2002105Neg. in self report Pos. GGT Guardia et al 2002202Relapse Kranzler et al 2003153Heavy drinkers O’Malley et al 200218Human lab Anton et al 20061383RCT, depot

68. Results: Heavy Drinking Days Baseline Placebo Vivitrex 190 mg Vivitrex 380 mg 75 th Percentile 25 th Percentile Median Heavy Drinking Days per Month 0 5 10 15 20 25 30 OverallMaleFemale 19.3 7.0 5.6 4.9 4.0 2.1 5.4 19.3 3.1 5.9 4.4 21.5

69. Why do many alcoholics respond to naltrexone, but others show no response?

70. % Days Heavy Drinking (PACS 15) 0 2 4 6 8 10 12 14 16 Low CraveMod CraveHigh Crave NTX PLA n = 44 n = 72 n = 57 PACS = Penn Alcohol Craving Scale Baseline Craving Scores

71. Family History and Naltrexone Efficacy % Days Heavy Drinking 0 2 4 6 8 10 12 14 16 NXT PLA 50% Alc Problem Density of Familial Alcohol Problems n = 77 n = 73 n = 29

72. Baseline b- Levels in Low- and High-Risk, and Abstinent Alcoholic Patients Baseline b-Endorphin Levels in Low- and High-Risk, and Abstinent Alcoholic Patients Plasma  -Endorphin Levels (pg/ml Plasma  -Endorphin Levels (pg/ml) Gianoulakis. Eur J Pharmacol. 1990;180:21-29 Gianoulakis. Eur J Pharmacol. 1990;180:21-29.

73. Minutes after alcohol consumption % change in plasma b-endorphin levels Change in b- Endorphin Levels after Alcohol Consumption

74. BAES Stimulation Scores Among FH+ and FH Subjects Placebo Naltrexone Base 2 30 min 60 min 120 min

75. Possible Families of Risk Factors Level of response (LR) P3/disinhibition/ASPD/type 2/B Independent axis II disorders Endogenous Opioid System Alcohol metabolizing enzymes

76. Key effect: Sensitivity of Endogenous Opioid system to alcohol One source of individual variability in response to ethyl alcohol

77. OPRM1 PROTEIN STRUCTURE LIGAND BINDING EXTRACELLULAR NH 2 TERMINUS A118G COOH TERMINUS N40D, N is an N-glycosylation site

78. Human Mu Opioid Receptor Gene PROMOTOR 5’UTR EXON 1 EXON 2 EXON 3 EXON 4 3’UTR 10 variants 4 5’UTR SNPs 2 SNPs 1 SNP 6 INTRON 2 SNPs 1 INTRON 3 SNP 1 3’UTR SNP 6.6 kb of OPRM1 gene sequence was determined in ~200 persons; 25 variants occurred at a frequency >1%. The 118 A>G exon 1 SNP increases OPRM1 affinity for beta- endorphin. The functional significance of other variants remains unknown.

79. Functional Allele Increase and Decrease

80. Self-reported Stimulation (SHAS) Breath Alcohol Concentration Alcohol effects by genotype

81. Wand et al, Neuropsychopharm 26:106–114, 2002

82. Ethnicity & A118G Allele Frequency Based on multiple studies, allele frequencies differ markedly across ethnicities for the A118G SNP in the mu opioid receptor gene. It arose after the out-of-Africa migration. Crowley et al, 2003 Gelernter et al, 1999 Tan et al, 2003 Bart et al, 2004 African1%Koreans31% African- American 3%Chinese35% Swedish17%Malaysian45% European- origin US 15%Indian47% ETHNICITY f(G)

83. Self-reported Stimulation (SHAS) Breath Alcohol Concentration Alcohol effects by genotype

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

85. OPRM1 A118G and Opioid Dependence Bart et al (Mol Psychiatry 9:547, 2004) studied opioid addicts in Sweden for A118G. There was a significant (Chi squared = 13, p = 0.00025) increase in A/G, G/G genotype among opioid addicts. The attributable risk for the G allele is ~ 18%, suggesting that ~ 18% of Swedish opioid addicts have disease in part due to the G allele.

86. OPRM1 A118G and Alcoholism Bart et al (Neuropsychopharmacol, 2005) studied alcoholics in Sweden for the A118G. There was a significant (Chi squared = 7.2, p = 0.007) increase in A/G, G/G genotype among alcoholics. In this study the attributable risk for the G allele is ~ 11%, suggesting that ~ 11% of Swedish alcoholics have disease in part due to the G allele.

87. Relapse Rate by Genotype Days

88. COMBINE Study N = 1383; 9 randomized groups –MM + Placebo –MM + Naltrexone –MM + Acamprosate –MM + Naltrexone + Acamprosate CBI only At least 4 days abstinence at baseline Endpoints –Percent days abstinent –Time to first heavy drinking day +/- CBI CBI = cognitive behavioral intervention; MM = medical management Anton et al. JAMA. 2006;295:2003.

89. Combine: NIAAA Good Outcome Nalt A/G, GG95%N = 28 Nalt A/A73%N = 86 Plac. A/G, GG63%N = 60 Plac. A/A65%N = 205 Odds ratio, nalt good regs, GVA = 10.25 (95% CI 1.31 - 80.0 P=.03) *VA multi-site study: sample size with G allele small

90. Rhesus model Ortholog of A118G allele in humans (OPRM1C77G) increased sensitivity to alcohol increased alcohol preference greater effect in males (Barr et al)

91. Sub-sample of VA coop. study Those who gave blood for DNA Naltrexone sig. better than placebo, but no genetic association. Finnish study with Nalmefene- Naltrexone superior to placebo, but no genetic association PROSPECTIVE study in progress Slow release version of naltrexone

92. Genetic Variables RiskIncreaseDecrease Low LR+ High LR- ASP+ ALDH2- G-Allele-µ op. (Stimulation) + Environment+-

93. genome scans - Phenotype association Genotype- Behavior, (DSM IV) 1940s categories - Endophenotype – biological- alcohol response, imaging

94. Endophenotype Endorphin Dependent Alcoholism Alcohol Endogenous OpioidsAlcohol Endogenous Opioids Euphoria/StimulationEuphoria/Stimulation Sensitive µ ReceptorsSensitive µ Receptors Family HistoryFamily History Alcohol CravingAlcohol Craving

95. Best Treatment Medications Plus Psychosocial Intervention

96. Penn/VA Center Team Joe VolpicelliJames McKay Wade BerrettiniA. Thomas McLellan John CacciolaDavid Metzger Anna Rose ChildressDavid Oslin James CornishHelen Pettinati Charles DackisMichael Stromberg Ronald EhrmanElmer Yu Teresa FranklinGeorge Woody Kyle KampmanArthur Alterman

97. FOR MORE INFORMATION http://www.med.upenn.edu/csa/o r obrien@mail.trc.upenn.edu

98. Possible Gender Effect Males more responsive in only study with large number of women

99. Medications Nicotine Nicotine patch, gum, nasal spray Bupropion Varenicline Rimonabant* Opiates Methadone Buprenorphine Naltrexone Stimulants Modafinil Topiramate Baclofen Disulfiram Propranolol Vigabatrin (clinical trials) Alcohol Disulfiram Naltrexone Acamprosate Topiramate

100. 0 100 200 300 400 500 600 700 800 900 1000 1100 012345 hr Time After Amphetamine % of Basal Release DA DOPAC HVA Accumbens AMPHETAMINE 0 100 200 300 400 012345 hr Time After Cocaine % of Basal Release DA DOPAC HVA Accumbens COCAINE 0 100 150 200 250 012345hr Time After Morphine % of Basal Release Accumbens 0.5 1.0 2.5 10 Dose (mg/kg) MORPHINE 0 100 150 200 250 0 123 hr Time After Nicotine % of Basal Release Accumbens Caudate NICOTINE Effects of Drugs on Dopamine Levels Source: Di Chiara and Imperato

101. Learning Objectives Describe the data supporting a new subtype or endophenotype of alcoholism. Describe the relative merits of the various medications available for the treatment of alcoholism. Describe the range of specific psychosocial treatments for alcoholism.

102. Dependence (Addiction) Tolerance Tolerance Withdrawal Withdrawal More use than intended More use than intended Unsuccessful efforts to cut down Unsuccessful efforts to cut down Spends excessive time in acquisition Spends excessive time in acquisition Activities given up because of use Activities given up because of use Uses despite negative effects Uses despite negative effects DSM-IV

103. Possible Changes Addiction instead of Dependence? Addiction instead of Dependence? Abuse? necessary Abuse? necessary Severity? Severity? Substance and non-substance addictions Substance and non-substance addictions Gambling addiction Internet gaming? Food? Sex? Shopping? DSM-V

104. Risk of Addiction Source: Anthony et al, 1994. Ever Used (%) Dependence (%) Risk (%) Tobacco75.6 24.1 24.131.9 Cocaine16.22.716.7 Heroin 1.5 1.50.423.1 Alcohol 91.5 91.514.115.4 Cannabis46.34.2 9.1 9.1

105. Drugs of Abuse all Activate Reward System Cues associated with drugs become conditioned stimuli become conditioned stimuli

106. From: Koob G, Everitt, B and Robbins T, Reward, motivation and addiction. In: Fundamental Neuroscience, in press. Key Elements of the Neurocircuitry of Addiction

107. From: Koob G, Everitt, B and Robbins T, Reward, motivation and addiction. In: Fundamental Neuroscience, in press.

108. [ 11 C]Raclopride Binding In Cocaine Abusers (n=18) Viewing a Neutral and a Cocaine-Cue Video Viewing a video of cocaine scenes decreased specific binding of [11C]raclopride presumably from DA increases Neutral video Volkow et al J Neuroscience 2006

109. Cue-induced increases in DA were associated with craving P < 0.002 % Change Bmax/Kd -0.50 0.0 0.50 1.0 1.5 2.0 2.5 -40 -30-20-100102030 Putamen Change in Craving (Pre - Post) Relationship between Cue-Induced Decreases in [11C]raclopride Binding and Cocaine Craving Caudate Putamen 2.00 2.50 3.00 3.50 Neutral Cocaine-Cues Bmax/Kd P < 0.05 P < 0.01 Volkow et al J Neuroscience 2006

110. “Unseen” Cue Paradigm 33 msec targets 33 msec targets 467 msec “masks”

111. “Unseen” Reward Cues “Unseen” Reward Cues activate activate amygdala amygdala v. striatum v. striatum v. pallidum v. pallidumInsula

113. Alcoholism: FDA Approved Medications Disulfiram Naltrexone Naltrexone Depot naltrexone Depot naltrexone Acamprosate Acamprosate

114. Specific Meds can block reward GABA enhancers Receptor antagonists Receptor antagonists

115. Baclofen blunts Amygdala Connectivity during 500 msec “SEEN” Cocaine Cues Placebo Baclofen Second half of the task [Drug 2; placebo n = 9; baclofen n =10]

116. Pre-Alcohol “Craving”

117. What is Transducer? Alcohol releases Beta endorphin in –Plasma (pituitary) –Lymphocyte cultures (HIV infectivity blocked by naltrexone –? CNS

118. Post-Docs Tom Aronson, MD Joseph Volpicelli, MD, PhD

119. Any Alcohol Drinking Naltrexone Placebo Percent of Subjects

120. Days Drinking Naltrexone Placebo Average Drinking Days per week