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Genetics, Medical Consequences, and Pharmacotherapy of Addiction Andrew J. Saxon, M.D. Psychiatry & Behavioral Sciences Addiction Treatment Center, VA Puget Sound Health Care System Addictions are Complex Disorders The genetic contribution to vulnerability for addiction (generally, or to a specific substance) is hypothesized to involve multiple polymorphisms, including single nucleotide polymorphisms (SNPs) in different genes. Factors Contributing to Vulnerability to Develop a Specific Addiction use of the drug of abuse essential (100%) Genetic (25-60%) Environmental (very high) • DNA • SNPs • other polymorphisms • prenatal • postnatal • contemporary • cues • comorbidity • stress-responsivity • mRNA levels • peptides • proteomics • neurochemistry • synaptogenesis • behaviors Drug-Induced Effects (very high) Kreek et al., 2000; 2005 Phenotyping in Addiction No blood, tissue, radiologic test to make firm Dx Gold Standard for Dx=structured interview using DSM-IV criteria BUT DSM-IV criteria expert consensus, not scientifically validated; ongoing controversy over criteria Conflicting evidence on whether inheritance is substance specific Understanding Genetic and Environmental Influences Using Twin Studies MZ Twins 100% genes 100% home environment DZ Twins 50% genes 100% home environment If MZs > DZs → Additive Genetic Influence (A) If DZs = MZs → Common Environmental Influence (C) If MZs < 1 → Unique Environmental Influence (E) Selected Twin Studies Author Year Heath True Subs. N (Twin Pairs) %Herita 95% CI bility 1997 ETOH 5889 64% 32-73% 1999 Nicotine 3356 60.3% 55-65% Lynskey 2002 Cannabis 6265 44% 15-72% Kendler 2000 Cocaine 79% 59-90% 1198 Schuckit et al., 1994 Potential Alcohol Dependence Genes Alcohol Dehydrogenase Aldehyde Dehydrogenase CYP450 2E1 Dopamine D1, D2, D3 Receptors Dopamine Transporter Serotonin Transporter GABA Receptor Subunits -,-, -Opioid Receptors Cholinergic, Muscarinic Receptor Subunit (CHMR2) Potential Tobacco Dependence Genes CYP450 2A6 CYP450 2D6 CYP450 2E1 Dopamine D1, D2, D3 Receptors Dopamine Transporter GABA Receptor Subunits Nicotinic Cholinergic Receptor Subunits 2 and 3 Src homology 2 domain-containing transforming protein C3 (SHC3) Beta-arrestins 1 and 2 Catechol-O Methyl Transferase Monoamine Oxidase Potential Opioid Dependence Genes CYP450 2D6 Dopamine D2, D4 Receptors Dopamine Transporter Proenkephalin -,-Opioid Receptors Catechol-O Methyl Transferase Potential Cocaine Dependence Genes Dopamine D2, D3 Receptors Dopamine β-hydroxylase (cocaine paranoia) Dopamine Transporter Prodynorphin Cannabinoid CB1 receptor Chronic Alcohol Dependence Causes Disease Primary Diseases Alcoholic health disease (cardiomyopathy) Alcoholic gastritis Alcoholic liver cirrhosis Alcoholic nerve disease (polyneuropathy) Alcoholic psychoses Sources: NIAAA (1993); Stinson (1993); NHTSA (2002) Secondary Diseases Cancer (lip, mouth, pharynx, esophagus, larynx, liver, stomach) Diabetes GI disease Heart disease (hypertension, stroke) Liver disease Pancreatitis (acute, chronic) Pneumonia/influenza Tuberculosis Antecubital Fossa Injection Drug Abuse MEDICAL COMPLICATIONS OF DRUG ADDICTION FROM UNSTERILE NEEDLE USE AND SHARING HIV Hepatitis Sepsis FROM SMOKING Decreased diffusing capacity Bronchospasm FROM LIFESTYLE STDs TB Substance Use and Mortality Total U.S. Mortality 1995=2,312,132 Illicit Drugs 2% Tobacco 19% ETOH 5% Other Causes 74% McGinnis & Foege, 1999 Outpatient Care & Subsequent Hospitalization of Illicit Drug Users Retrospective cohort study of 58,243 illicit drug users covered by NY State Medicaid Program Laine et al., JAMA, 2001 55.6% of HIV-positive, 37.5 of HIV-negative hospitalized VA Costs per Subject Onsite (n=358) Mean Total Costs Total Medical/Surgical Costs Total Mental Health Costs Outpatient Laboratory Costs Outpatient Pharmacy Costs SD Referral (n=362) Mean SD 15,194.27 16,123.63 16,035.04 18,869.39 p-value ns 2,309.79 4,473.49 2,835.47 7,963.29 ns 6,798.10 7,368.62 6,570.24 6,620.10 ns 674.38 685.02 699.24 737.91 ns 1,003.69 1,485.77 904.10 1,396.11 ns Medications for Alcohol Dependence • Disulfiram (Antabuse) • Naltrexone (ReVia) • Acamprosate (Campral) Disulfiram H5C2 C2H5 N H5C2 C S S S C S N C2H5 Tetraethylthiuram - Synthesized by Danish scientists in the 1930’s as an antihelminthic; a non-specific inhibitor of sulfhydryl-containing enzymes Disulfiram Disulfiram-Alcohol Reaction • • • • • • • • Related to acetaldehyde buildup Flushing Sweating Nausea and Vomiting Headache Tachycardia Sometimes hypotension Sometimes dyspnea Possible Medication for Cocaine Dependence Disulfiram – FDA approved for ETOH dependence – 80% of cocaine dependent patients have ETOH dependence. Can disulfiram in ETOH use cocaine use? – Inhibits dopamine -hydroxylase, enzyme which catalyzes the rate limiting step in conversion of dopamine to norepinephrine – In the human laboratory disulfiram elevates cocaine plasma levels through an unknown mechanism Disulfiram Disulfiram and Cognitive Behavior Therapy in Cocaine-Dependent Outpatients Carroll et al., 2004 • 121 cocaine dependent subjects randomized to – – – – Disulfiram + Cognitive Behavioral Tx Disulfiram + Interpersonal Psychotherapy Placebo + Cognitive Behavioral Tx Placebo + Interpersonal Psychotherapy Carroll et al., 2004 Heinz et al., 2005 Meta-Analysis Oral Naltrexone vs. Placebo: Relapse to Heavy Drinking Srisurapanont & Jarusuraisin, 2006 A+118G (Asn40Asp) Asparagine asn – amide (neutral) H2N-CO-CH2-CH(NH2)-COOH Aspartic acid asp – (negatively charged) HOOC-CH2-CH(NH2)-COOH Asp40 allele frequency of 13-20% (24.3 – 36% of European Americans have at least one copy) Pharmacogenetics of Naltrexone Alcohol-Induced "High" "High" Score 6 4 AA 2 AG/GG 0 BAC=.02 BAC=.04 BAC=.06 Breath Alcohol Concentration Analyses indicated that carriers of the G allele reported greater increases in alcohol-induced “High” across rising levels of BrAC, F(2,76)=4.30, p<.05. Ray & Hutchison, 2007 Cumulative Survival (time to relapse) Genetic Polymorphisms and Alcohol Treatment Naltrexone / Asp40 Allele (A/G, G/G) Naltrexone Asn40 Allele (A/A) Placebo / Asp40 Allele (A/G, G/G) Placebo / Asn40 Allele (A/A) Days Oslin DW, et. al. 2003 COMBINE Study Good Clinical Outcome (%) Asn40/Asn40 Asp40 Naltrexone 73 96 Placebo 63 51 Asn40/Asn40 Asp40 Naltrexone 21 4 Placebo 29 12 Relapsed (%) Acamprosate Acamprosate Pre-clinical Effects • Boismaire et al., 1984 – Acamprosate reduces rodent alcohol consumption – This effect blocked by bicucilline (GABAA Antagonist) • Grant & Woolverton, 1989 – Acamprosate does not substitute for alcohol or pentobarital in animals trained to self-administer them – Animals will not self-administer acamprosate • Zeise et al., 1993 – Acamprosate attenuates post-synaptic responses induced by Excitatory Amino Acid agonists thereby decreasing generalized neuronal excitability Acamprosate for Maintaining Abstinence Mann et al., 2004 Medications for Opioid Dependence • Naltrexone • Methadone • Buprenorphine Naltrexone for Opioid Dependence Most ideal pharmacologic treatment Requires detoxification before initiation or severe withdrawal will be precipitated Requires Naloxone challenge test Risk of OD if medication stopped In general poor patient compliance but superb treatment for selected patients Depot Naltrexone to Block Heroin Effect Comer et al., 2002 Methadone Pharmacology Rapidly absorbed orally Peak Levels in 4 hours Half-life=24 hours Metabolized in liver Doses should be individualized but higher doses generally more effective Kyle et al., 1999 Swedish Methadone Study Experimental Group (Methadone) Gunne & Gronbladh, 1981 Before Control Group (No Methadone) Swedish Methadone Study Experimental Group (Methadone) After 2 Years Control Group (No Methadone) a b c d d d Gunne & Gronbladh, 1981 a b c d Sepsis Sepsis and Endocarditis Leg Amputation In Prison Buprenorphine 45 Partial Agonist Activity Levels 100 Full Agonist (e.g. heroin) 90 80 At higher doses, even when partial agonist drug completely binds all mu receptors 70 60 % Mu Receptor 50 Intrinsic 40 Activity Maximum opioid agonist effect is never achieved Partial Agonist (e.g. buprenorphine) 30 20 Like full agonists, partial agonist drugs produce increasing mu opioid receptor specific activity at lower doses 10 0 no drug low dose DRUG DOSE high dose Fentanyl vs. Buprenorphine: Effect of Increasing doses on respiration; n=5-8 per dose group*; drugs infused over 90 sec. *n=1 for highest fentanyl dose Dahan, 2006 Zubieta et al., 2000 Buprenorphine, Methadone, LAAM: Opioid Urine Results 100 All Subjects Mean % Negative 80 LAAM 49% 60 Bup Hi Meth 40% 40 39% 20 Lo Meth 19% 0 1 3 5 7 9 11 Study Week 13 15 17 Adapted from Johnson, et al., 2000 Nicotine Replacement for Smoking Cessation All forms OR 1.77 (95%CI 1.66-1.88)* Gum OR 1.66 (95%CI 1.52-1.81) Patches OR 1.81 (95%CI 1.63-2.02) Spray OR 2.35 (95%CI 1.63-3.38) Inhaler OR 2.14 (95%CI 1.44-3.18) Lozenge OR 2.05 (95%CI 1.62-2.59) *17% vs. 10% 1 year quit rates Antidepressants for Smoking Cessation Bupropion OR 2.06 (95%CI 1.77-2.40) Nortriptyline OR 2.79 (95%CI 1.70-4.59) Pharmacogenetics of Smoking Cessation Lerman et al., 2006 Varenicline – A Designer Drug New molecular entity Selective partial agonist of 42 nicotinic receptor Effects Partial receptor activation (up to 60%) mimics dopamine agonist effects of nicotine, reduces post-cessation craving and nicotine withdrawal sx Blocks nicotine binding and therefore effects of nicotine if smoking – reduces reinforcing effects of nicotine Nicotine Receptors Each receptor composed of 5 subunits Functional properties are determined by subunit composition – 3 main types 42 concentration related to nicotine dependence Repeated nicotine exposure functional nicotine receptors in the brain leads to dopamine activation Withdrawal sx relate to up-regulated nAChRs w/o nicotine Effects of Varenicline on Dopamine Release Coe et al., 2005 Continuous Abstinence Rates Gonzales, D. et al. JAMA 2006;296:47-55. Copyright restrictions may apply. Jorenby, D. E. et al. JAMA 2006;296:56-63. Genetics, Medical Consequences, Pharmacotherapy Conclusions • We have started the search for the genetics of addiction, but we are a long way from the answer • The medical consequences of addiction are extreme • We need a wider range of better pharmacotherapies, and neurobiology and genetics may help us find them