Evidence-Based Treatment of Alcohol Use Disorder: A Focused Examination of Naltrexone s Role

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2 Evidence-Based Treatment of Alcohol Use Disorder: A Focused Examination of Naltrexone s Role Charles P. O Brien, MD, PhD Professor of Psychiatry University of Pennsylvania Philadelphia, Pennsylvania

3 Faculty Disclosure Dr. O Brien: Research Consultant Alkermes, AstraZeneca, Embera.

4 Disclosure The faculty have been informed of their responsibility to disclose to the audience if they will be discussing off-label or investigational use(s) of drugs, products, and/or devices (any use not approved by the US Food and Drug Administration). Applicable CME staff have no relationships to disclose relating to the subject matter of this activity. This activity has been independently reviewed for balance.

5 Learning Objectives Review the role of naltrexone in the treatment of alcohol use disorder Prescribe anti-craving medication to provide psychopharmacologic effects that reduce alcohol craving Identify which patients respond to naltrexone Identify and treat accompanying mental disorders (eg, depression) complicating the alcoholism

6 Treatment of Alcoholism in the United States 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 30 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.; 2016.

7 FDA Approved Medications Disulfiram Naltrexone (generic) Acamprosate Depot Naltrexone Nalmefene (approved in Europe) Topiramate (used off-label) DETOXIFICATION and referral to AA IS NOT TREATMENT!!

8 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. 2006;79(6): Molecular mechanism unknown

9 Naltrexone: Investigational New Drug License 1983 Open studies Range of doses Minimal side effects Institutional review board approval O Brien CP, et al. In: Spanagel R, et al (Eds). Drugs for Relapse Prevention of Alcoholism. Basel, Switzerland: Birkhäuser Verlag; 2005.

10 Protocol 1986 Self report + breathalyzer 5 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; 2005.

11 Naltrexone Decreases Alcohol Preference % Change from Saline Pretreatment Response Levels (10-day mean) Naltrexone 1.0 mg/kg Naltrexone 3.0 mg/kg Naltrexone 5.0 mg/kg 1 to 5 5 to to 15 Altshuler HL, et al. Life Sci. 1980;26(9):

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16 Post-Shock Drinking Change in % Ethanol Consumption Placebo Naltrexone Days Post-Shock Volpicelli JR, et al. Life Sci. 1986;38(9):

17 Series of Lucky Coincidences 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; 2005.

18 Any Alcohol Drinking Naltrexone Placebo Volpicelli JR, et al. Arch Gen Psychiatry. 1992;49(11):

19 Days Drinking Naltrexone Placebo Volpicelli JR, et al. Arch Gen Psychiatry. 1992;49(11):

20 Subjective High in Naltrexone and Placebo Participants * Naltrexone *P <.05. Volpicelli JR, et al. Arch Gen Psychiatry. 1992;49(11): Placebo

21 Pharmacologic Treatments for Alcoholism 5 Craving Scores by Week Placebo Naltrexone Weeks on Medication Volpicelli JR, et al. Arch Gen Psychiatry. 1992;49(11):

22 Alcohol Relapse A. Coming to treatment appointment with a blood alcohol concentration > 100 mg% OR B. Self-report of drinking 5 days within 1 week OR C. Self-report of 5 drinks during 1 drinking occasion Volpicelli JR, et al. Arch Gen Psychiatry. 1992;49(11):

23 Non-Relapse Survival Cumulative Proportion with No Relapse Naltrexone HCL (n = 35) Placebo (n = 35) No. of Weeks Receiving Medication Volpicelli JR, et al. Arch Gen Psychiatry. 1992;49(11):

24 Rates of Never Relapsing According to Treatment Group Naltrexone/coping skills Naltrexone/supportive therapy Placebo/coping skills Placebo/supportive therapy Percent without Relapse Days N = 97. O Malley SS, et al. Arch Gen Psychiatry. 1992;49(11):

25 Studies Supporting Efficacy Studies Not Supporting Efficacy Study N Notes Study N Notes Volpicelli, et al (1992) 70 None Kranzler, et al (2000) 183 None OMalley, et al (1992) 97 None Krystal, et al (2002) 627 None Mason, et al (1994) [Nalmefene] 21 None Oslin, et al (1997) 44 Elderly Volpicelli, et al (1997) 97 None Mason, et al (1999) [Nalmefene] 105 None Kranzler, et al (1998) 20 Depot Anton, et al (2000) 131 None Chick, et al (2000) [UK] 169 Adherence Monterosso, et al (2001) 183 None Morris, et al (2001) [Australia] Heinala, et al (2001) [Finland] 111 None 121 Nonabstinent Lee, et al (2001) [Singapore] Kiefer et al (2003) [Germany] None None

26 Studies Supporting Efficacy Studies Not Supporting Efficacy Study N Notes Study N Notes Latt, et al (2002) 107 Family Pract Balldin, et al (2003) 118 None Feeney, et al (2001) 50 Hist cont Rubio, et al (2001) 157 vs Acamp Rubio, et al (2002) 30 Cont drink Gastpar, et al (2002) in self- report + GGT Gastpar, et al (2002) in selfreport + GGT Guardia, et al (2002) 202 Relapse Kranzler, et al (2003) 153 Heavy drinkers O Malley, et al (2002) 18 Human lab Anton, et al (2006) 1383 RCT, depot Gual, et al (2013) 711 Nalmefene, DB, PRN > 7000 patients Mann, et al (2013) 604 Nalmefene PRN

27 Adherence Improved Extended-release depot preparation Injection q 30 to 40 days Pharma sets price at $800 per injection Capitated systems (Kaiser, Aetna)

28 Side Effects For alcohol dependence (ie, those occurring in 5% and at least twice as frequently with Depot Naltrexone than placebo): Nausea Vomiting Injection site reactions (including induration, pruritus, nodules and swelling) Muscle cramps, Dizziness or syncope Somnolence or sedation Elevated liver enzymes rare and reversible Decreased appetite or other appetite disorders US Food and Drug Administration.

29 Results: Heavy Drinking Days th Percentile 25 th Percentile 25 Baseline Placebo Median Heavy Drinking Days per Month Naltrexone depot 190 mg Naltrexone depot 380 mg Overall Male Female Garbutt JC, et al. JAMA. 2005;293(13):

30 Europe large clinical trials ~1000 alcoholics each Nalmefene vs placebo PRN All positive Approved 2013: European Medicine Agencies Mann K, et al. Biol Psychiatry. 2013;73(8): Gual A, et al. Eur Neuropsychopharmacol. 2013;23(11): van den Brink W, et al. Alcohol Alcohol. 2013;48(5):

31 Effect size moderate based on heavy drinking days outcome measure NNT 7 to 12 NNT = number needed to treat.

32 Assumption: Alcohol causes the release of endogenous opioids that are required for dopamine release in response to alcohol?

33 Naltrexone Concurrently Antagonizes EtOH-Induced Accumbal Dopamine Release and EtOH Self-Administration Gonzales RA, et al. J Neurosci. 1998;18(24):

34 Brain Reward System Nucleus Accumbens Prefrontal Cortex Arcuate Nucleus Ventral Tegmental Area Nestler EJ, et al. The Addicted Brain. Scientific American. 2004;290:78-85.

35 Dopamine Long Loop Dopamine Nucleus Accumbens Alcohol GABA β-endorphin Neuron Arcuate Nucleus Ventral Tegmental Area Gianoulakis C. Alcohol Health Res World. 1998;22(3):

36 Dopamine Opioid Antagonism Dopamine Nucleus Accumbens Alcohol GABA β-endorphin Neuron Arcuate Nucleus Ventral Tegmental Area Gianoulakis C. Alcohol Health Res World. 1998;22(3):

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

38 Pre-Alcohol Craving Dopamine (% baseline) Time (minutes) Saline, N=13 Naltrexone, N=16 Gonzales RA, et al. J Neurosci. 1998;18(24):

39 Examples of the Various Visual Cues from Normative Appetitive Picture System (NAPS) Alcohol (A) Beverage (B) Visual Control (C) Rest (R) Time Course of the Presentation of Stimuli During fmri Sip of Preferred Beverage R C A B C B A C B A A C B B C A B C A 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. 2001;58(4):

40 Alcohol Beverage Condition Cingulate Insula Nucleus Accumbens Alcoholics (n = 10) Controls (n = 10) Z = Ex.05 Myrick H, et al. Neuropsychopharmacology. 2004;29(2):

41 Alcohol Beverage Condition Cingulate Ventral Tegmental Area Alcoholics (n = 10) Controls (n = 10) Z = Ex.05 Myrick H, et al. Neuropsychopharmacology. 2004;29(2):

42 Drugs to Aid Alcoholics See Little Use, Study Finds Less than one-third of alcoholics receive any treatment Less than 10% are prescribed medications Data from 23,000 patients, 122 randomized trials. For acamprosate and naltrexone, 12 to 20 patients to prevent return to heavy drinking. For statins, 25 to 100 patients to prevent one cardiac event. O Connor A. The New York Times. May 13, Jonas DE, et al. JAMA. 2014;311(18):

43 Cost Benefit Studies Cost of treatment 6 months prior to admission compared to 6 months later Fewer visits to Emergency Department Alanis-Hirsch K, et al. J Subst Abuse Treat. 2016;62:68-73.

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

45 Baseline Craving Scores % Days Heavy Drinking n = 44 PACS = Penn Alcohol Craving Scale. MONTEROSSO, ET AL 2000 n = 72 n = 57 Low Crave Mod Crave High Crave (PACS < 5) (PACS 6 15) (PACS > 15) NTX PLA

46 Family History and Naltrexone Efficacy % Days Heavy Drinking n = 77 n = 73 n = 29 NXT PLA 2 0 < 25% Alc Problem 25%-50% Alc Problem > 50% Alc Problem Density of Familial Alcohol Problems Monterosso JR, et al. Am J Addict. 2001;10(3):

47 Baseline β-endorphin Levels in Low- and High-Risk, and Abstinent Alcoholic Patients 50 Plasma β-endorphin Levels (pg/ml) Low Risk High Risk Abstinent Gianoulakis C. Eur J Pharmacol. 1990;180(1):21-29.

48 Change in β-endorphin Levels after Alcohol Consumption High Risk Low Risk Minutes after Alcohol Consumption Dai X, et al. Alcohol Clin Exp Res. 2005;29(11):

49 BAES Stimulation Scores Among FH+ and FH Participants 25 Placebo 25 Naltrexone FH+ FH Base 2 30 min 60 min 120 min Base 2 30 min 60 min 120 min 0 BAES = Biphasic Alcohol Effects Scale. King AC, et al. Psychopharmacology. 1997;129(1): Ray LA, et al. Arch Gen Psychiatry. 2007;64(9):

50 Key effect: Sensitivity of endogenous opioid system to alcohol One source of individual variability in response to ethyl alcohol

51 OPRM1 Protein Structure EXTRACELLULAR NH 2 TERMINUS A118G LIGAND BINDING N40D, N is an N-glycosylation site COOH TERMINUS

52 Human μ-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 β- endorphin. The functional significance of other variants remains unknown. SNP = single-nucleotide polymorphism. Oslin DW, et al. Neuropsychopharmacology. 2003;28(8):

53 Functional Allele Increase and Decrease

54 Alcohol Effects by Genotype AA allele AG allele Breath Alcohol Concentration SHAS = Subjective High Assessment Scale. Ray LA, et al. Alcohol Clin Exp Res. 2004;28(12):

55 Cortisol Responses by Naloxone by μ-opioid Receptor Genotype PI = time of placebo (saline) administration; N = times of incremental naloxone administration. Wand GS, et al. Neuropsychopharmacology. 2002;26(1):

56 Ethnicity and A118G Allele Frequency 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- 3% Chinese 35% American Swedish 17% Malaysian 45% Europeanorigin US 15% Indian 47% Crowley JJ, et al. Psychiatr Genet. 2003;13(3): Gelernter J, et al. Mol Psychiatry. 1999;4(5): Tan EC, et al. Neuroreport. 2003;14(4): Bart G, et al. Neuropsychopharmacology. 2005;30(2):

57 OPRM1 A118G Allele Frequency of Ethnic Group Migration of Humans on Planet Earth Native American ~16 % Caucasian ~15 % African-America <5 % European ~11 % Han-Chinese ~36 % Japanese ~50 % Hispanic ~13 % Brazilian ~16 % African <5 % Indian ~44 % Malay ~ 45 % Kreek MJ, et al. Pharm Rev. 2005;57(1):1-26. Daher M, et al. Pain Pract. 2013;13(8); Nikolov MA, et al. Drug Alcohol Depend. 2011;117(1):62-65.

58 OPRM1 A118G and Alcoholism controls alcoholics A/A A/G, G/G There was a significant (Chi squared = 7.2, P =.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. Alcoholics in Sweden for the A118G. Bart G, et al. Neuropsychopharmacology. 2005;30(2):

59 Relapse Rate by Genotype 1.0 Proportion Non-relapsed Naltrexone / Asp40 Allele (A/G, G/G) Naltrexone Asn40 Allele (A/A) Placebo / Asp40 Allele (A/G, G/G) Placebo / Asn40 Allele (A/Al) Days Oslin DW, et al. Neuropsychopharmacology. 2003;28(8):

60 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 RF, et al. JAMA. 2006;295(17):

61 COMBINE: NIAAA Good Outcome Naltrexone A/G, GG 95% N = 28 Naltrexone A/A 73% N = 86 Placebo A/G, GG 63% N = 60 Placebo A/A 65% N = 205 Odds ratio, naltrexone good regs, GVA = (95% CI , P =.03) *VA multi-site study: sample size with G allele small Anton RF, et al. Arch Gen Psychiatry. 2008;65(2):

62 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. 2007;64(3): )

63 Sub-sample of VA Cooperative Study Those who gave blood for DNA Naltrexone 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. 2007;31(4):

64 Alcohol-Induced Dopamine Release in Ventral Striatum is Restricted to OPRM1-118G Carriers (BP alcohol - BP placebo )/BP placebo (%) * * AA (n = 16) GX (n = 12) AVS PVS Caudate Putamen AVS = anterior ventral striatum; PVS = posterior ventral striatum Ramchandani VA, et al. Mol Psychiatry. 2011;16(8):

65 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 5-HT levels in striatum showed no difference between genotypes. P =.005. Ramchandani VA, et al. Mol Psychiatry. 2011;16(8):

66 Increased Alcohol-Induced Dopamine-Release in 118GG Mice is Associated with Increased Voluntary Alcohol Intake Intake (g/kg/24hrs) ** *** ** GG AA 3% 5% 7% 9% 11% 13% 15% 20% 0 Alcohol Concentration 20% end Thorsell A, et al. In preparation.

67 CNN Special Addiction: Life on the Edge 5 patients followed for 1 year Different parts of country Admissions Graduations Relapses Interviews with counselors at famous programs Sanjay Gupta, MD. CNN. April 18 and 19,

68 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,

69 Addiction: Life on the Edge 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,

70 Addiction: Life on the Edge 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. Sanjay Gupta, MD. CNN. April 18 and 19,

71 Comorbidity 2 new placebo controlled trials Alcoholism + Depression Naltrexone + Sertraline Alcoholism + PTSD Naltrexone + Exposure Therapy PTSD = posttraumatic stress disorder. Pettinati HM, et al. Am J Psychiatry. 2010;167(6): Foa EB, et al. JAMA. 2013;310(5):

72 Time to First Heavy Drinking Day and Time to First Drinking Day in Depressed Alcohol-Dependent Patients Randomly Assigned to Medication Treatment or Placebo Pettinati HM, et al. Am J Psychiatry. 2010;167(6):

73 HAM-D Score Change from Baseline Week in Treatment Baseline HAM-D Score Placebo Sertraline Naltrexone Sert & NTX HAM-D = Hamilton Rating Scale for Depression. Pettinati HM, et al. Am J Psychiatry. 2010;167(6):

74 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

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76 Q&A Session