Treatment of Alcoholism in the United States. Evidence-Based Treatment of Alcohol Use Disorder: A Focused Examination of Naltrexone s Role

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1 Treatment of Alcoholism in the United States Evidence-Based Treatment of Alcohol Use Disorder: A Focused Examination of s Role Charles P. O Brien, MD, PhD Professor of Psychiatry University of Pennsylvania Philadelphia, Pennsylvania How to prescribe oral naltrexone Very low dose to begin Try to convince patient to continue at least 3 to 4 months before giving up Duration depends on results years Slow release depot, Q 3 days Most success, few side effects Best continuity of care This is a chronic disease Brunton L, et al. Goodman and Gilman s The Pharmacological Basis of Therapeutics. New York, NY: The McGraw-Hill Companies, Inc.; 216. FDA Approved Medications Disulfiram (generic) Acamprosate Depot Nalmefene (approved in Europe) Topiramate (used off-label) Hypothesis: 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 Wang X, et al. J Leukoc Biol. 26;79(6): Molecular mechanism unknown DETOXIFICATION and referral to AA IS NOT TREATMENT!! : Investigational New Drug License 1983 Open studies Range of doses Minimal side effects Institutional review board approval Protocol 1986 Self report + breathalyzer per week Endpoint = Relapse to heavy drinking Slips recorded, not as endpoint Craving recorded RECRUITMENT OBSTRUCTIONS (counselors against medication) Joe Volpicelli started fellowship O Brien CP, et al. In: Spanagel R, et al (Eds). Drugs for Relapse Prevention of Alcoholism. Basel, Switzerland: Birkhäuser Verlag; 2. O Brien CP, et al. In: Spanagel R, et al (Eds). Drugs for Relapse Prevention of Alcoholism. Basel, Switzerland: Birkhäuser Verlag; 2.

2 Decreases Alcohol Preference Post-Shock Drinking % Change from Saline Pretreatment Response Levels (1-day mean) to to 1 1 to 1 Altshuler HL, et al. Life Sci. 198;26(9): mg/kg 3. mg/kg. mg/kg Change in % Ethanol Consumption Days Post-Shock Volpicelli JR, et al. Life Sci. 1986;38(9): Series of Lucky Coincidences Any Alcohol Drinking 1. Altshuler poster at College on Problems of Drug Dependence 2. Joe Volpicelli decides on Fellowship O Brien CP, et al. In: Spanagel R, et al (Eds). Drugs for Relapse Prevention of Alcoholism. Basel, Switzerland: Birkhäuser Verlag; 2. Volpicelli JR, et al. Arch Gen Psychiatry. 1992;49(11): Days Drinking Subjective High in and Participants Volpicelli JR, et al. Arch Gen Psychiatry. 1992;49(11): * *P <.. Volpicelli JR, et al. Arch Gen Psychiatry. 1992;49(11):

3 Pharmacologic Treatments for Alcoholism Alcohol Relapse Craving Scores by Week A. Coming to treatment appointment with a blood alcohol concentration > 1 mg% Weeks on Medication Volpicelli JR, et al. Arch Gen Psychiatry. 1992;49(11): OR B. Self-report of drinking days within 1 week OR C. Self-report of drinks during 1 drinking occasion Volpicelli JR, et al. Arch Gen Psychiatry. 1992;49(11): Cumulative Proportion with No Relapse Non-Relapse Survival HCL (n = 3) (n = 3) No. of Weeks Receiving Medication Volpicelli JR, et al. Arch Gen Psychiatry. 1992;49(11): Rates of Never Relapsing According to Treatment Group Percent without Relapse /coping skills /supportive therapy /coping skills /supportive therapy Days N = 97. O Malley SS, et al. Arch Gen Psychiatry. 1992;49(11): Studies Supporting Efficacy Studies Not Supporting Efficacy Study N Notes Study N Notes Volpicelli, et al (1992) 7 None Kranzler, et al 183 None (2) OMalley, et al (1992) 97 None Krystal, et al (22) 627 None Mason, et al (1994) 21 None [Nalmefene] Oslin, et al (1997) 44 Elderly Volpicelli, et al (1997) 97 None Mason, et al (1999) 1 None [Nalmefene] Kranzler, et al (1998) 2 Depot Anton, et al (2) 131 None Chick, et al (2) [UK] 169 Adherence Monterosso, et al (21) 183 None Morris, et al (21) [Australia] 111 None Heinala, et al (21) [Finland] Lee, et al (21) [Singapore] Kiefer et al (23) [Germany] 121 Nonabstinent 3 16 None None Studies Supporting Efficacy Studies Not Supporting Efficacy Study N Notes Study N Notes Latt, et al (22) 17 Family Pract Balldin, et al (23) 118 None Feeney, et al (21) Hist cont Rubio, et al (21) 17 vs Acamp Rubio, et al (22) 3 Cont drink Gastpar, et al (22) 1 - in self- report + GGT Guardia, et al (22) 22 Relapse Kranzler, et al (23) 13 Heavy drinkers O Malley, et al (22) 18 Human lab Anton, et al (26) 1383 RCT, depot Gual, et al (213) Mann, et al (213) Nalmefene, DB, PRN Nalmefene PRN Gastpar, et al (22) 1 - in selfreport + GGT > 7 patients

4 Adherence Improved Side Effects Extended-release depot preparation Injection q 3 to 4 days Pharma sets price at $8 per injection Capitated systems (Kaiser, Aetna) For alcohol dependence (ie, those occurring in % and at least twice as frequently with Depot than placebo): Nausea Vomiting Injection site reactions (including induration, pruritus, nodules, and swelling) Muscle cramps Dizziness or syncope Somnolence or sedation Anorexia Decreased appetite or other appetite disorders US Food and Drug Administration. Results: Heavy Drinking Days Europe 212 Median Heavy Drinking Days per Month th Percentile 2 th Percentile Baseline depot 19 mg depot 38 mg large clinical trials ~1 alcoholics each Nalmefene vs placebo PRN All positive Approved 213: European Medicine Agencies Overall Male Female Garbutt JC, et al. JAMA. 2;293(13): Mann K, et al. Biol Psychiatry. 213;73(8): Gual A, et al. Eur Neuropsychopharmacol. 213;23(11): van den Brink W, et al. Alcohol Alcohol. 213;48():7-78. Effect size moderate based on heavy drinking days outcome measure NNT 7 to 12 Assumption: Alcohol causes the release of endogenous opioids that are required for dopamine release in response to alcohol? NNT = number needed to treat.

5 Concurrently Antagonizes EtOH-Induced Accumbal Dopamine Release and EtOH Self-Administration Brain Reward System Prefrontal Cortex Nucleus Accumbens Arcuate Nucleus Ventral Tegmental Area Gonzales RA, et al. J Neurosci. 1998;18(24): Nestler EJ, et al. The Addicted Brain. Scientific American. 24;29:78-8. Dopamine Long Loop Dopamine Dopamine Opioid Antagonism Dopamine Nucleus Accumbens Nucleus Accumbens Alcohol Alcohol GABA GABA β-endorphin Neuron Arcuate Nucleus Ventral Tegmental Area β-endorphin Neuron Arcuate Nucleus Ventral Tegmental Area Gianoulakis C. Alcohol Health Res World. 1998;22(3): Gianoulakis C. Alcohol Health Res World. 1998;22(3): Examples of the Various Visual Cues from Normative Appetitive Picture System (NAPS) Alcohol (A) Beverage (B) Visual Control (C) Rest (R) Alcohol effects become conditioned to environmental cues blocks cue induced relapse better than stress induced Time Course of the Presentation of Stimuli During fmri Sip of Preferred Beverage C A B C B A C B A A C B B C A B C A R R R R R R Time (min) *Craving rated after each block Comparisons: Alcohol - Beverage Beverage - Vis Ctrl Alcohol - Vis Ctrl Beverage - Rest Vis Ctrl - Rest George MS, et al. Arch Gen Psychiatry. 21;8(4):34-32.

6 Alcohol Beverage Condition Alcohol Beverage Condition Cingulate Cingulate Insula Nucleus Accumbens Alcoholics (n = 1) Controls (n = 1) Z = 1.64 Ex. Myrick H, et al. Neuropsychopharmacology. 24;29(2): Ventral Tegmental Area Alcoholics (n = 1) Controls (n = 1) Z = 1.64 Ex. Myrick H, et al. Neuropsychopharmacology. 24;29(2): Drugs to Aid Alcoholics See Little Use, Study Finds Less than one-third of alcoholics receive any treatment Less than 1% are prescribed medications Data from 23, patients, 122 randomized trials. For acamprosate and naltrexone, 12 to 2 patients to prevent return to heavy drinking. For statins, 2 to 1 patients to prevent one cardiac event. Cost Benefit Studies Cost of treatment 6 months prior to admission compared to 6 months later Fewer visits to Emergency Department O Connor A. The New York Times. May 13, 214. Jonas DE, et al. JAMA. 214;311(18): Alanis-Hirsch K, et al. J SubstAbuse Treat. 216;62: Baseline Craving Scores n = 7 Why do many alcoholics respond to naltrexone, but others show no response? % Days Heavy Drinking n = 44 n = 72 NTX PLA Low Crave Mod Crave High Crave (PACS < ) (PACS 6 1) (PACS > 1) PACS = Penn Alcohol Craving Scale.

7 Family History and Efficacy Baseline β-endorphin Levels in Low- and High-Risk, and Abstinent Alcoholic Patients % Days Heavy Drinking 16 n = n = 77 n = < 2% Alc Problem 2%-% Alc Problem > % Alc Problem Density of Familial Alcohol Problems Monterosso JR, et al. Am J Addict. 21;1(3): NXT PLA Plasma β-endorphin Levels (pg/ml) Low Risk High Risk Abstinent Gianoulakis C. Eur J Pharmacol. 199;18(1): Change in β-endorphin Levels after Alcohol Consumption BAES Stimulation Scores Among FH+ and FH Participants FH+ FH High Risk Low Risk Minutes after Alcohol Consumption Dai X, et al. Alcohol Clin Exp Res. 2;29(11): Base 2 3 min 6 min 12 min Base 2 3 min 6 min 12 min BAES = Biphasic Alcohol Effects Scale. King AC, et al. Psychopharmacology. 1997;129(1):1-22. Ray LA, et al. Arch Gen Psychiatry. 27;64(9): OPRM1 Protein Structure Key effect: Sensitivity of endogenous opioid system to alcohol One source of individual variability in response to ethyl alcohol EXTRACELLULAR NH 2 TERMINUS A118G LIGAND BINDING N4D, N is an N-glycosylation site COOH TERMINUS

8 Human μ-opioid Receptor Gene Functional Allele PROMOTOR UTR EXON 1 EXON 2 EXON 3 EXON 4 3 UTR 1 variants 4 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 ~2 persons; 2 variants occurred at a frequency > 1%. The 118 A > G exon 1 SNP increases OPRM1 affinity for β- endorphin. The functional significance of other variants remains unknown. Increase and Decrease SNP = single-nucleotide polymorphism. Oslin DW, et al. Neuropsychopharmacology. 23;28(8): Alcohol Effects by Genotype Cortisol Responses by Naloxone by μ-opioid Receptor Genotype AA allele AG allele Breath Alcohol Concentration SHAS = Subjective High Assessment Scale. Ray LA, et al. Alcohol Clin Exp Res. 24;28(12): PI = time of placebo (saline) administration; N = times of incremental naloxone administration. Wand GS, et al. Neuropsychopharmacology. 22;26(1): Ethnicity and A118G Allele Frequency OPRM1 A118G Allele Frequency of Ethnic Group Migration of Humans on Planet Earth Based on multiple studies, allele frequencies differ markedly across ethnicities for the A118G SNP in the μ-opioid receptor gene. It arose after the out-of-africa migration. Ethnicity f(g) Ethnicity f(g) African 1% Koreans 31% African- American 3% Chinese 3% Swedish 17% Malaysian 4% Europeanorigin US 1% Indian 47% Caucasian ~1 % Native American ~16 % Hispanic ~13 % African-America < % Brazilian ~16 % European ~11 % African < % Indian ~44 % Han-Chinese ~36 % Malay ~ 4 % Japanese ~ % Crowley JJ, et al. Psychiatr Genet. 23;13(3): Gelernter J, et al. Mol Psychiatry. 1999;4(): Tan EC, et al. Neuroreport. 23;14(4): Bart G, et al. Neuropsychopharmacology. 2;3(2): Kreek MJ, et al. Pharm Rev. 2;7(1):1-26. Daher M, et al. Pain Pract. 213;13(8); Nikolov MA, et al. Drug Alcohol Depend. 211;117(1):62-6.

9 OPRM1 A118G and Alcoholism Relapse Rate by Genotype controls alcoholics A/A A/G, G/G Alcoholics in Sweden for the A118G. Bart G, et al. Neuropsychopharmacology. 2;3(2): There was a significant (Chi squared = 7.2, P =.7) 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. Proportion Non-relapsed Days Oslin DW, et al. Neuropsychopharmacology. 23;28(8): / Asp4 Allele (A/G, G/G) Asn4 Allele (A/A) / Asp4 Allele (A/G, G/G) / Asn4 Allele (A/Al) COMBINE Study N = 1383; 9 randomized groups MM + MM + MM + Acamprosate MM + + Acamprosate CBI only At least 4 days abstinence at baseline Endpoints Percent days abstinent Time to first heavy drinking day +/- CBI COMBINE: NIAAA Good Outcome A/G, GG 9% N = 28 A/A 73% N = 86 A/G, GG 63% N = 6 A/A 6% N = 2 Odds ratio, naltrexone good regs, GVA = 1.2 (9% CI , P =.3) *VA multi-site study: sample size with G allele small CBI = cognitive behavioral intervention; MM = medical management. Anton RF, et al. JAMA. 26;29(17): Anton RF, et al. Arch Gen Psychiatry. 28;6(2): Sub-sample of VA Cooperative Study Rhesus model Ortholog of A118G allele in humans (OPRM1C77G) Increased sensitivity to alcohol Increased alcohol preference Greater effect in males (Barr CS, et al. Arch Gen Psychiatry. 27;64(3): ) Those who gave blood for DNA significantly 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 Gelernter J, et al. Alcohol Clin Exp Res. 27;31(4):-63.

10 Alcohol-Induced Dopamine Release in Ventral Striatum is Restricted to OPRM1-118G Carriers Animal Models for A118G: Mouse OPRM 118 AA and GG mice were given ethanol 2 g/kg, during in vivo microdialysis. GG mice showed a significant dopamine elevation in striatum after the ethanol, while AA mice did not. The -HT levels in striatum showed no difference between genotypes. AVS = anterior ventral striatum; PVS = posterior ventral striatum. Ramchandani VA, et al. Mol Psychiatry. 211;16(8): P =.. Ramchandani VA, et al. Mol Psychiatry. 211;16(8): Increased Alcohol-Induced Dopamine-Release in 118GG Mice is Associated with Increased Voluntary Alcohol Intake CNN Special Addiction: Life on the Edge patients followed for 1 year Different parts of country Admissions Graduations Relapses Interviews with counselors at famous programs Thorsell A, et al. In preparation. Sanjay Gupta, MD. CNN. April 18 and 19, Addiction: Life on the Edge Addiction: Life on the Edge GUPTA: And so he tried again. He checked himself into an experimental program run by Brown University. This time he got counseling once a week and a daily pill, a medicine called naltrexone. About 2 months into it, Walter Kent suddenly noticed the world around him looked and felt different. KENT: And I had just turned around and I said, this is really something for the first time in my life that I never had this sensation where I didn t want a drink. And this, to me, was like a godsend because of the fact that for someone who had to have a drink, now all of a sudden I don t need that I don t have that feeling anymore. GUPTA: He hasn t had a drink in more than 8 years. Even after his doctor stopped the medication. He s healthy, back at work, fixing up carburetors. And now he s part of a running debate. Is addiction an illness you can treat with a pill or a character flaw to be tackled with therapy and self-help? Sanjay Gupta, MD. CNN. April 18 and 19, GUPTA: Despite the evidence, most fancy rehab centers use medication only rarely, if at all. The focus is much more on therapy. Head Counselor Minnesota: With the health care professional staff here at Hazelden, our experience tells us having that network of support in recovery is what really makes the difference. GUPTA: More so than medication? CLARK: More so than just medication, exactly. GUPTA: And that s the conventional wisdom. Sanjay Gupta, MD. CNN. April 18 and 19, 29.

11 Addiction: Life on the Edge Comorbidity California Program GUPTA: What about medications? Head Counselor California Program: We do not use them at the Betty Ford Center. No comment from the interviewer, no follow-up questions. 2 new placebo controlled trials Alcoholism + Depression + Sertraline Alcoholism + PTSD + Exposure Therapy Sanjay Gupta, MD. CNN. April 18 and 19, PTSD = posttraumatic stress disorder. Pettinati HM, et al. Am J Psychiatry. 21;167(6): Foa EB, et al. JAMA. 213;31(): Time to First Heavy Drinking Day and Time to First Drinking Day in Depressed Alcohol-Dependent Patients Randomly Assigned to Medication Treatment or HAM-D Score Change from Baseline Pettinati HM, et al. Am J Psychiatry. 21;167(6): HAM-D = Hamilton Rating Scale for Depression. Pettinati HM, et al. Am J Psychiatry. 21;167(6): 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 1 years and I never took medication They have side effects You ll become addicted to them Etc