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Review

Pharmacotherapy of alcoholism – an update on approved and off-label medications

&
Pages 1187-1199 | Received 14 Feb 2017, Accepted 27 Jun 2017, Published online: 24 Jul 2017

References

  • World Health Organization. International classification of diseases, 10th revision (ICD-10). 2010 [cited 2013 Dec 16]. Available from: http://apps.who.int/classifications/icd10/browse/2010/en
  • American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed. Washington (DC): American Psychiatric Publishing; 2000. Text Revision
  • American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 5th ed. Arlington (VA): American Psychiatric Publishing; 2013.
  • Grant BF, Goldstein RB, Saha TD, et al. Epidemiology of DSM-5 alcohol use disorder: results from the national epidemiologic survey on alcohol and related conditions III. JAMA Psychiatry. 2015 Aug 1;72(8):757–766.
  • Gowing LR, Ali RL, Allsop S, et al. Global statistics on addictive behaviours: 2014 status report. Addiction. 2015 Jun;110(6):904–919.
  • Grant BF, Stinson FS, Dawson DA, et al. Co-occurrence of 12-month alcohol and drug use disorders and personality disorders in the United States: results from the national epidemiologic survey on alcohol and related conditions. Arch Gen Psychiatry. 2004 Apr;61(4):361–368.
  • Hasin DS, Stinson FS, Ogburn E, et al. Prevalence, correlates, disability, and comorbidity of DSM-IV alcohol abuse and dependence in the United States: results from the national epidemiologic survey on alcohol and related conditions. Arch Gen Psychiatry. 2007 Jul;64(7):830–842.
  • Kessler RC, Chiu WT, Demler O, et al. Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the national comorbidity survey replication. Arch Gen Psychiatry. 2005 Jun;62(6):617–627.
  • Pirkola SP, Poikolainen K, Lonnqvist JK. Currently active and remitted alcohol dependence in a nationwide adult general population–results from the finnish health 2000 study. Alcohol Alcohol. 2006 May–Jun;41(3):315–320.
  • Soyka M, Kranzler HR, Hesselbrock V, et al. Guidelines for biological treatment of substance use and related disorders, part 1: alcoholism, first revision. World J Biol Psychiatry. 2016 Dec;23:1–34.
  • Donoghue K, Elzerbi C, Saunders R, et al. The efficacy of acamprosate and naltrexone in the treatment of alcohol dependence, Europe versus the rest of the world: a meta-analysis. Addiction. 2015 Jun;110(6):920–930.
  • Jonas DE, Amick HR, Feltner C, et al. Pharmacotherapy for adults with alcohol use disorders in outpatient settings: a systematic review and meta-analysis. JAMA. 2014 May 14;311(18):1889–1900.
  • Maisel NC, Blodgett JC, Wilbourne PL, et al. Meta-analysis of naltrexone and acamprosate for treating alcohol use disorders: when are these medications most helpful? Addiction. 2013 Feb;108(2):275–293.
  • Rosner S, Hackl-Herrwerth A, Leucht S, et al. Acamprosate for alcohol dependence. Cochrane Database Syst Rev. 2010;9:CD004332.
  • Rosner S, Hackl-Herrwerth A, Leucht S, et al. Opioid antagonists for alcohol dependence. Cochrane Database Syst Rev. 2010;12:CD001867.
  • Heilig M, Epstein DH, Nader MA, et al. Time to connect: bringing social context into addiction neuroscience. Nat Rev Neurosci. 2016 Sep;17(9):592–599.
  • Johnson BA, Ait-Daoud N. Neuropharmacological treatments for alcoholism: scientific basis and clinical findings. Psychopharmacology (Berl). 2000 May;149(4):327–344.
  • Koob GF, Le Moal M. Neurobiology of addiction. London: Academic Press; 2006.
  • Noronha ABC, Cui C, Harris RA, et al., editors. Neurobiology of alcohol dependence. London: Academic Press ; 2014.
  • Nutt D, Nestor L. Addiction. Kettering: Oxford University Press; 2013.
  • Petrakis IL. A rational approach to the pharmacotherapy of alcohol dependence. J Clin Psychopharmacol. 2006 Dec;26(Suppl 1):S3–12.
  • Spanagel R. Alcoholism: a systems approach from molecular physiology to addictive behavior. Physiol Rev. 2009 Apr;89(2):649–705.
  • Spanagel R, Vengeliene V. New pharmacological treatment strategies for relapse prevention. Curr Top Behav Neurosci. 2013;13:583–609.
  • Hillemacher T, Leggio L, Heberlein A. Investigational therapies for the pharmacological treatment of alcoholism. Expert Opin Investig Drugs. 2015 Jan;24(1):17–30.
  • Kwako LE, Spagnolo PA, Schwandt ML, et al. The corticotropin releasing hormone-1 (CRH1) receptor antagonist pexacerfont in alcohol dependence: a randomized controlled experimental medicine study. Neuropsychopharmacology. 2015 Mar 13;40(5):1053–1063.
  • Augier E, Dulman RS, Damadzic R, et al. The GABAB positive allosteric modulator ADX71441 attenuates alcohol self-administration and relapse to alcohol seeking in rats. Neuropsychopharmacology. 2017 Apr 12.
  • Koob GF. Alcoholism: allostasis and beyond. Alcohol Clin Exp Res. 2003 Feb;27(2):232–243.
  • Weiss F, Porrino LJ. Behavioral neurobiology of alcohol addiction: recent advances and challenges. J Neurosci. 2002 May 1;22(9):3332–3337.
  • Bassareo V, Musio P, Di Chiara G. Reciprocal responsiveness of nucleus accumbens shell and core dopamine to food- and drug-conditioned stimuli. Psychopharmacology (Berl). 2011 Apr;214(3):687–697.
  • Di Chiara G, Bassareo V. Reward system and addiction: what dopamine does and doesn’t do. Curr Opin Pharmacol. 2007 Feb;7(1):69–76.
  • Ciccocioppo R, Martin-Fardon R, Weiss F. Effect of selective blockade of mu(1) or delta opioid receptors on reinstatement of alcohol-seeking behavior by drug-associated stimuli in rats. Neuropsychopharmacology. 2002 Sep;27(3):391–399.
  • Jarjour S, Bai L, Gianoulakis C. Effect of acute ethanol administration on the release of opioid peptides from the midbrain including the ventral tegmental area. Alcohol Clin Exp Res. 2009 Jun;33(6):1033–1043.
  • Gianoulakis C. Endogenous opioids and addiction to alcohol and other drugs of abuse. Curr Top Med Chem. 2004;4(1):39–50.
  • Marcinkiewcz CA, Lowery-Gionta EG, Kash TL. Serotonin’s complex role in alcoholism: implications for treatment and future research. Alcohol Clin Exp Res. 2016 Jun;40(6):1192–1201.
  • Goodwani S, Saternos H, Alasmari F, et al. Metabotropic and ionotropic glutamate receptors as potential targets for the treatment of alcohol use disorder. Neurosci Biobehav Rev. 2017 Jun;77:14–31.
  • Hopf FW. Do specific NMDA receptor subunits act as gateways for addictive behaviors? Genes Brain Behav. 2017 Jan;16(1):118–138.
  • Costa ET, Soto EE, Cardoso RA, et al. Acute effects of ethanol on kainate receptors in cultured hippocampal neurons. Alcohol Clin Exp Res. 2000 Feb;24(2):220–225.
  • Crowder TL, Ariwodola OJ, Weiner JL. Ethanol antagonizes kainate receptor-mediated inhibition of evoked GABA(A) inhibitory postsynaptic currents in the rat hippocampal CA1 region. J Pharmacol Exp Ther. 2002 Dec;303(3):937–944.
  • Krystal JH, Tabakoff B. Ethanol abuse, dependence, and withdrawal: neurobiology and clinical implications. In: Davis K, Charney D, Coyle JT, et al., editors. Psychopharmacology: a fifth generation of progress. Philadelphia: Lippincott Williams & Wilkins; 2002. p. 1425–1443.
  • Moghaddam B, Bolinao ML. Biphasic effect of ethanol on extracellular accumulation of glutamate in the hippocampus and the nucleus accumbens. Neurosci Lett. 1994 Aug 29;178(1):99–102.
  • EMA. Guideline on the development of medicinal products for the treatment of alcohol dependence. London: European Medicines Agency; 2010.
  • Ferri M, Amato L, Davoli M. Alcoholics anonymous and other 12-step programmes for alcohol dependence. Cochrane Database Syst Rev. 2006;3:CD005032.
  • Kaner EF, Beyer F, Dickinson HO, et al. Effectiveness of brief alcohol interventions in primary care populations. Cochrane Database Syst Rev. 2007;2:CD004148.
  • Klimas J, Tobin H, Field CA, et al. Psychosocial interventions to reduce alcohol consumption in concurrent problem alcohol and illicit drug users. Cochrane Database Syst Rev. 2014;12:CD009269.
  • Lui S, Terplan M, Smith EJ. Psychosocial interventions for women enrolled in alcohol treatment during pregnancy. Cochrane Database Syst Rev. 2008;3:CD006753.
  • McQueen J, Howe TE, Allan L, et al. Brief interventions for heavy alcohol users admitted to general hospital wards. Cochrane Database Syst Rev. 2009;3:CD005191.
  • Huber CA, Maierhofer K, Wiesbeck GA. Chancen für psychosoziale und psychotherapeutische Interventionsmöglichkeiten durch eine multiprofessionelle Versorgungsumgebung. Suchtmed. 2015;17:179–184.
  • Smedslund G, Berg RC, Hammerstrom KT, et al. Motivational interviewing for substance abuse. Cochrane Database Syst Rev. 2011;5:CD008063.
  • Magill M, Ray LA. Cognitive-behavioral treatment with adult alcohol and illicit drug users: a meta-analysis of randomized controlled trials. J Stud Alcohol Drugs. 2009 Jul;70(4):516–527.
  • Anton RF, O’Malley SS, Ciraulo DA, et al. Combined pharmacotherapies and behavioral interventions for alcohol dependence: the COMBINE study: a randomized controlled trial. JAMA. 2006 May 3;295(17):2003–2017.
  • Mann K, Lemenager T, Hoffmann S, et al. Results of a double-blind, placebo-controlled pharmacotherapy trial in alcoholism conducted in Germany and comparison with the US COMBINE study. Addict Biol. 2013 Nov;18(6):937–946.
  • Litten RZ, Wilford BB, Falk DE, et al. Potential medications for the treatment of alcohol use disorder: an evaluation of clinical efficacy and safety. Substance Abuse. 2016 Apr–Jun;37(2):286–298.
  • Sinclair JM, Chambers SE, Shiles CJ, et al. Safety and tolerability of pharmacological treatment of alcohol dependence: comprehensive review of evidence. Drug Safety. 2016 Jul;39(7):627–645.
  • Mutschler J, Abbruzzese E, Witt SH, et al. Functional polymorphism of the dopamine beta-hydroxylase gene is associated with increased risk of disulfiram-induced adverse effects in alcohol-dependent patients. J Clin Psychopharmacol. 2012 Aug;32(4):578–580.
  • Suh JJ, Pettinati HM, Kampman KM, et al. The status of disulfiram: a half of a century later. J Clin Psychopharmacol. 2006 Jun;26(3):290–302.
  • Skinner MD, Lahmek P, Pham H, et al. Disulfiram efficacy in the treatment of alcohol dependence: a meta-analysis. PLoS One. 2014;9(2):e87366.
  • Fuller RK, Branchey L, Brightwell DR, et al. Disulfiram treatment of alcoholism. A veterans administration cooperative study. JAMA. 1986 Sep 19;256(11):1449–1455.
  • Garbutt JC, West SL, Carey TS, et al. Pharmacological treatment of alcohol dependence: a review of the evidence. JAMA. 1999 Apr 14;281(14):1318–1325.
  • Hughes JC, Cook CC. The efficacy of disulfiram: a review of outcome studies. Addiction. 1997 Apr;92(4):381–395.
  • Krampe H, Stawicki S, Wagner T, et al. Follow-up of 180 alcoholic patients for up to 7 years after outpatient treatment: impact of alcohol deterrents on outcome. Alcohol Clin Exp Res. 2006 Jan;30(1):86–95.
  • Sellers EM, Naranjo CA, Harrison M, et al. Diazepam loading: simplified treatment of alcohol withdrawal. Clin Pharmacol Ther. 1983 Dec;34(6):822–826.
  • Brewer C, Streel E, Skinner M. Supervised disulfiram’s superior effectiveness in alcoholism treatment: ethical, methodological, and psychological aspects. Alcohol Alcohol. 2017 Mar;52(2):213–219.
  • Littleton J. Acamprosate in alcohol dependence: how does it work? Addiction. 1995 Sep;90(9):1179–1188.
  • Spanagel R, Zieglgansberger W. Anti-craving compounds for ethanol: new pharmacological tools to study addictive processes. Trends Pharmacol Sci. 1997 Feb;18(2):54–59.
  • Spanagel R, Pendyala G, Abarca C, et al. The clock gene Per2 influences the glutamatergic system and modulates alcohol consumption. Nat Med. 2005 Jan;11(1):35–42.
  • Frye MA, Hinton DJ, Karpyak VM, et al. Anterior cingulate glutamate is reduced by acamprosate treatment in patients with alcohol dependence. J Clin Psychopharmacol. 2016 Dec;36(6):669–674.
  • Harris BR, Gibson DA, Prendergast MA, et al. The neurotoxicity induced by ethanol withdrawal in mature organotypic hippocampal slices might involve cross-talk between metabotropic glutamate type 5 receptors and N-methyl-D-aspartate receptors. Alcohol Clin Exp Res. 2003 Nov;27(11):1724–1735.
  • Cano-Cebrian MJ, Zornoza-Sabina T, Guerri C, et al. Acamprosate blocks the increase in dopamine extracellular levels in nucleus accumbens evoked by chemical stimulation of the ventral hippocampus. Naunyn Schmiedebergs Arch Pharmacol. 2003 Oct;368(4):324–327.
  • Spanagel R, Vengeliene V, Jandeleit B, et al. Acamprosate produces its anti-relapse effects via calcium. Neuropsychopharmacology. 2014 Mar;39(4):783–791.
  • Schuster R, Koopmann A, Grosshans M, et al. Association of plasma calcium concentrations with alcohol craving: new data on potential pathways. Eur Neuropsychopharmacol. 2017 Jan;27(1):42–47.
  • Mann K, Hoffmann S, Pawlak CR. Does acamprosate really produce its anti-relapse effects via calcium? No support from the PREDICT study in human alcoholics. Neuropsychopharmacology. 2016 Feb;41(3):659–660.
  • Sass H, Soyka M, Mann K, et al. Relapse prevention by acamprosate. Results from a placebo-controlled study on alcohol dependence. Arch Gen Psychiatry. 1996 Aug;53(8):673–680.
  • Mason BJ, Goodman AM, Chabac S, et al. Effect of oral acamprosate on abstinence in patients with alcohol dependence in a double-blind, placebo-controlled trial: the role of patient motivation. J Psychiatr Res. 2006 Aug;40(5):383–393.
  • COMBINE Study Research Group. Testing combined pharmacotherapies and behavioral interventions for alcohol dependence (the COMBINE study): a pilot feasibility study. Alcohol Clin Exp Res. 2003 Jul;27(7):1123–1131.
  • Roos CR, Witkiewitz K. Adding tools to the toolbox: the role of coping repertoire in alcohol treatment. J Consult Clin Psychol. 2016 Jul;84(7):599–611.
  • Glockner-Rist A, Lemenager T, Mann K. Reward and relief craving tendencies in patients with alcohol use disorders: results from the PREDICT study. Addict Behav. 2013 Feb;38(2):1532–1540.
  • Nutt DJ. The role of the opioid system in alcohol dependence. J Psychopharmacol. 2014 Jan;28(1):8–22.
  • Dai X, Thavundayil J, Gianoulakis C. Differences in the peripheral levels of beta-endorphin in response to alcohol and stress as a function of alcohol dependence and family history of alcoholism. Alcohol Clin Exp Res. 2005 Nov;29(11):1965–1975.
  • Marinelli PW, Bai L, Quirion R, et al. A microdialysis profile of Met-enkephalin release in the rat nucleus accumbens following alcohol administration. Alcohol Clin Exp Res. 2005 Oct;29(10):1821–1828.
  • Marinelli PW, Lam M, Bai L, et al. A microdialysis profile of dynorphin A(1-8) release in the rat nucleus accumbens following alcohol administration. Alcohol Clin Exp Res. 2006 Jun;30(6):982–990.
  • Marinelli PW, Quirion R, Gianoulakis C. An in vivo profile of beta-endorphin release in the arcuate nucleus and nucleus accumbens following exposure to stress or alcohol. Neuroscience. 2004;127(3):777–784.
  • Oswald LM, Wand GS. Opioids and alcoholism. Physiol Behav. 2004 Apr;81(2):339–358.
  • Adcock RA, Thangavel A, Whitfield-Gabrieli S, et al. Reward-motivated learning: mesolimbic activation precedes memory formation. Neuron. 2006 May 4;50(3):507–517.
  • Bencherif B, Wand GS, McCaul ME, et al. Mu-opioid receptor binding measured by [11C]carfentanil positron emission tomography is related to craving and mood in alcohol dependence. Biol Psychiatry. 2004 Feb 1;55(3):255–262.
  • Heinz A, Reimold M, Wrase J, et al. Correlation of stable elevations in striatal mu-opioid receptor availability in detoxified alcoholic patients with alcohol craving: a positron emission tomography study using carbon 11-labeled carfentanil. Arch Gen Psychiatry. 2005 Jan;62(1):57–64.
  • Hubbell CL, Czirr SA, Hunter GA, et al. Consumption of ethanol solution is potentiated by morphine and attenuated by naloxone persistently across repeated daily administrations. Alcohol. 1986 Jan–Feb;3(1):39–54.
  • O’Malley SS, Jaffe AJ, Rode S, et al. Experience of a “slip” among alcoholics treated with naltrexone or placebo. Am J Psychiatry. 1996 Feb;153(2):281–283.
  • Volpicelli JR, Alterman AI, Hayashida M, et al. Naltrexone in the treatment of alcohol dependence. Arch Gen Psychiatry. 1992 Nov;49(11):876–880.
  • Kranzler HR, Wesson DR, Billot L. Naltrexone depot for treatment of alcohol dependence: a multicenter, randomized, placebo-controlled clinical trial. Alcohol Clin Exp Res. 2004 Jul;28(7):1051–1059.
  • Garbutt JC, Kranzler HR, O’Malley SS, et al. Efficacy and tolerability of long-acting injectable naltrexone for alcohol dependence: a randomized controlled trial. JAMA. 2005 Apr 6;293(13):1617–1625.
  • Anton RF. Genetic basis for predicting response to naltrexone in the treatment of alcohol dependence. Pharmacogenomics. 2008 Jun;9(6):655–658.
  • Oslin DW, Berrettini W, Kranzler HR, et al. A functional polymorphism of the mu-opioid receptor gene is associated with naltrexone response in alcohol-dependent patients. Neuropsychopharmacology. 2003 Aug;28(8):1546–1552.
  • Oslin DW, Leong SH, Lynch KG, et al. Naltrexone vs placebo for the treatment of alcohol dependence: a randomized clinical trial. JAMA Psychiatry. 2015 May;72(5):430–437.
  • Hermann D, Hirth N, Reimold M, et al. Low mu-opioid receptor status in alcohol dependence identified by combined positron emission tomography and post-mortem brain analysis. Neuropsychopharmacology. 2017 Feb;42(3):606–614.
  • Kiefer F, Jahn H, Tarnaske T, et al. Comparing and combining naltrexone and acamprosate in relapse prevention of alcoholism: a double-blind, placebo-controlled study. Arch Gen Psychiatry. 2003 Jan;60(1):92–99.
  • Fitzgerald N, Angus K, Elders A, et al. Weak evidence on nalmefene creates dilemmas for clinicians and poses questions for regulators and researchers. Addiction. 2016 Aug;111(8):1477–1487.
  • Mann K, Torup L, Sorensen P, et al. Nalmefene for the management of alcohol dependence: review on its pharmacology, mechanism of action and meta-analysis on its clinical efficacy. Eur Neuropsychopharmacol. 2016 Dec;26(12):1941–1949.
  • Naudet F, Palpacuer C, Boussageon R, et al. Evaluation in alcohol use disorders - insights from the nalmefene experience. BMC Med. 2016 Aug 18;14(1):119.
  • Soyka M, Friede M, Schnitker J. Comparing nalmefene and naltrexone in alcohol dependence: are there any differences? Results from an indirect meta-analysis. Pharmacopsychiatry. 2016 Nov;49(6):261–262.
  • Soyka M. Nalmefene for the treatment of alcohol use disorders: recent data and clinical potential. Expert Opin Pharmacother. 2016 Mar;17(4):619–626.
  • Walker BM, Koob GF. Pharmacological evidence for a motivational role of kappa-opioid systems in ethanol dependence. Neuropsychopharmacology. 2008 Feb;33(3):643–652.
  • Walker BM, Valdez GR, McLaughlin JP, et al. Targeting dynorphin/kappa opioid receptor systems to treat alcohol abuse and dependence. Alcohol. 2012 Jun;46(4):359–370.
  • Walker BM, Zorrilla EP, Koob GF. Systemic κ-opioid receptor antagonism by nor-binaltorphimine reduces dependence-induced excessive alcohol self-administration in rats. Addict Biol. 2011 Jan;16(1):116–119.
  • EMA. Selincro (nalmefene): summary of product characteristics. London: European Medicines Agency; 2014.
  • Charlet K, Heinz A. Harm reduction-a systematic review on effects of alcohol reduction on physical and mental symptoms. Addict Biol. 2016 Jun 29.
  • Mason BJ, Salvato FR, Williams LD, et al. A double-blind, placebo-controlled study of oral nalmefene for alcohol dependence. Arch Gen Psychiatry. 1999 Aug;56(8):719–724.
  • Anton RF, Pettinati H, Zweben A, et al. A multi-site dose ranging study of nalmefene in the treatment of alcohol dependence. J Clin Psychopharmacol. 2004 Aug;24(4):421–428.
  • Karhuvaara S, Simojoki K, Virta A, et al. Targeted nalmefene with simple medical management in the treatment of heavy drinkers: a randomized double-blind placebo-controlled multicenter study. Alcohol Clin Exp Res. 2007 Jul;31(7):1179–1187.
  • Gual A, He Y, Torup L, et al. A randomised, double-blind, placebo-controlled, efficacy study of nalmefene, as-needed use, in patients with alcohol dependence. Eur Neuropsychopharmacol. 2013 Nov;23(11):1432–1442.
  • Mann K, Bladstrom A, Torup L, et al. Extending the treatment options in alcohol dependence: a randomized controlled study of as-needed nalmefene. Biol Psychiatry. 2013 Apr 15; 73(8):706–713.
  • van den Brink W, Sorensen P, Torup L, et al. Long-term efficacy, tolerability and safety of nalmefene as-needed in patients with alcohol dependence: a 1-year, randomised controlled study. J Psychopharmacol. 2014 Mar 26; 28(8):733–744.
  • van den Brink W, Aubin HJ, Bladstrom A, et al. Efficacy of as-needed nalmefene in alcohol-dependent patients with at least a high drinking risk level: results from a subgroup analysis of two randomized controlled 6-month studies. Alcohol Alcohol. 2013 Sep–Oct;48(5):570–578.
  • Lynch WJ, Bond C, Breslin FJ, et al. Severity of drinking as a predictor of efficacy of the combination of ondansetron and topiramate in rat models of ethanol consumption and relapse. Psychopharmacology (Berl). 2011 Sep;217(1):3–12.
  • Moore CF, Lycas MD, Bond CW, et al. Acute and chronic administration of a low-dose combination of topiramate and ondansetron reduces ethanol’s reinforcing effects in male alcohol preferring (P) rats. Exp Clin Psychopharmacol. 2014 Feb;22(1):35–42.
  • Johnson BA, Roache JD, Javors MA, et al. Ondansetron for reduction of drinking among biologically predisposed alcoholic patients: a randomized controlled trial. JAMA. 2000 Aug 23–30;284(8):963–971.
  • Kranzler HR, Pierucci-Lagha A, Feinn R, et al. Effects of ondansetron in early-versus late-onset alcoholics: a prospective, open-label study. Alcohol Clin Exp Res. 2003 Jul;27(7):1150–1155.
  • Muller CA, Geisel O, Banas R, et al. Current pharmacological treatment approaches for alcohol dependence. Expert Opin Pharmacother. 2014 Mar;15(4):471–481.
  • Thompson MD, Kenna GA. Variation in the serotonin transporter gene and alcoholism: risk and response to pharmacotherapy. Alcohol Alcohol. 2016 Mar;51(2):164–171.
  • Bauer IE, Graham DP, Soares JC, et al. Serotonergic gene variation in substance use pharmacotherapy: a systematic review. Pharmacogenomics. 2015;16(11):1307–1314.
  • Johnson BA, Ait-Daoud N, Seneviratne C, et al. Pharmacogenetic approach at the serotonin transporter gene as a method of reducing the severity of alcohol drinking. Am J Psychiatry. 2011 Mar;168(3):265–275.
  • Johnson BA, Seneviratne C, Wang XQ, et al. Determination of genotype combinations that can predict the outcome of the treatment of alcohol dependence using the 5-HT(3) antagonist ondansetron. Am J Psychiatry. 2013 Sep;170(9):1020–1031.
  • Cunningham MO, Woodhall GL, Thompson SE, et al. Dual effects of gabapentin and pregabalin on glutamate release at rat entorhinal synapses in vitro. Eur J Neurosci. 2004 Sep;20(6):1566–1576.
  • Dooley DJ, Mieske CA, Borosky SA. Inhibition of K(+)-evoked glutamate release from rat neocortical and hippocampal slices by gabapentin. Neurosci Lett. 2000 Feb 18;280(2):107–110.
  • Bonnet U, Banger M, Leweke FM, et al. Treatment of alcohol withdrawal syndrome with gabapentin. Pharmacopsychiatry. 1999 May;32(3):107–109.
  • Bozikas V, Petrikis P, Gamvrula K, et al. Treatment of alcohol withdrawal with gabapentin. Prog Neuropsychopharmacol Biol Psychiatry. 2002 Jan;26(1):197–199.
  • Mariani JJ, Rosenthal RN, Tross S, et al. A randomized, open-label, controlled trial of gabapentin and phenobarbital in the treatment of alcohol withdrawal. Am J Addict. 2006 Jan–Feb;15(1):76–84.
  • Myrick H, Malcolm R, Brady KT. Gabapentin treatment of alcohol withdrawal. Am J Psychiatry. 1998 Nov;155(11):1632.
  • Rustembegovic A, Sofic E, Tahirovic I, et al. A study of gabapentin in the treatment of tonic-clonic seizures of alcohol withdrawal syndrome. Med Arh. 2004;58(1):5–6.
  • Voris J, Smith NL, Rao SM, et al. Gabapentin for the treatment of ethanol withdrawal. Subst Abus. 2003 Jun;24(2):129–132.
  • Leung JG, Hall-Flavin D, Nelson S, et al. The role of gabapentin in the management of alcohol withdrawal and dependence. Ann Pharmacother. 2015 Aug;49(8):897–906.
  • Pani PP, Trogu E, Pacini M, et al. Anticonvulsants for alcohol dependence. Cochrane Database Syst Rev. 2014;2:CD008544.
  • Mason BJ, Quello S, Goodell V, et al. Gabapentin treatment for alcohol dependence: a randomized clinical trial. JAMA Intern Med. 2014 Jan;174(1):70–77.
  • Anton RF, Myrick H, Baros AM, et al. Efficacy of a combination of flumazenil and gabapentin in the treatment of alcohol dependence: relationship to alcohol withdrawal symptoms. J Clin Psychopharmacol. 2009 Aug;29(4):334–342.
  • Lyon J. More treatments on deck for alcohol use disorder. JAMA. 2017 Jun 13;317(22):2267–2269.
  • Gibbs JW 3rd, Sombati S, DeLorenzo RJ, et al. Cellular actions of topiramate: blockade of kainate-evoked inward currents in cultured hippocampal neurons. Epilepsia. 2000;41(Suppl 1):S10–6.
  • Skradski S, White HS. Topiramate blocks kainate-evoked cobalt influx into cultured neurons. Epilepsia. 2000;41(Suppl 1):S45–7.
  • Gryder DS, Rogawski MA. Selective antagonism of GluR5 kainate-receptor-mediated synaptic currents by topiramate in rat basolateral amygdala neurons. J Neurosci. 2003 Aug 6;23(18):7069–7074.
  • Kaminski RM, Banerjee M, Rogawski MA. Topiramate selectively protects against seizures induced by ATPA, a GluR5 kainate receptor agonist. Neuropharmacology. 2004 Jun;46(8):1097–1104.
  • Leggio L, Schwandt ML. Topiramate for alcoholism treatment: novel pharmacogenetic evidence for the journey to personalized medicine? Int J Neuropsychopharmacol. 2014 Oct;17(10):1541–1544.
  • Ait-Daoud N, Malcolm RJ Jr., Johnson BA. An overview of medications for the treatment of alcohol withdrawal and alcohol dependence with an emphasis on the use of older and newer anticonvulsants. Addict Behav. 2006 Sep;31(9):1628–1649.
  • Farook JM, Morrell DJ, Lewis B, et al. Topiramate (Topamax) reduces conditioned abstinence behaviours and handling-induced convulsions (HIC) after chronic administration of alcohol in Swiss-Webster mice. Alcohol Alcohol. 2007 Jul–Aug;42(4):296–300.
  • Gabriel KI, Cunningham CL. Effects of topiramate on ethanol and saccharin consumption and preferences in C57BL/6J mice. Alcohol Clin Exp Res. 2005 Jan;29(1):75–80.
  • Hargreaves GA, McGregor IS. Topiramate moderately reduces the motivation to consume alcohol and has a marked antidepressant effect in rats. Alcohol Clin Exp Res. 2007 Nov;31(11):1900–1907.
  • Nguyen SA, Malcolm R, Middaugh LD. Topiramate reduces ethanol consumption by C57BL/6 mice. Synapse. 2007 Mar;61(3):150–156.
  • Johnson BA, Ait-Daoud N, Bowden CL, et al. Oral topiramate for treatment of alcohol dependence: a randomised controlled trial. Lancet. 2003 May 17;361(9370):1677–1685.
  • Johnson BA, Rosenthal N, Capece JA, et al. Topiramate for treating alcohol dependence: a randomized controlled trial. JAMA. 2007 Oct 10;298(14):1641–1651.
  • Blodgett JC, Del Re AC, Maisel NC, et al. A meta-analysis of topiramate’s effects for individuals with alcohol use disorders. Alcohol Clin Exp Res. 2014 Jun;38(6):1481–1488.
  • Martinotti G, Di Nicola M, De Vita O, et al. Low-dose topiramate in alcohol dependence: a single-blind, placebo-controlled study. J Clin Psychopharmacol. 2014 Dec;34(6):709–715.
  • Ray LA, Miranda R Jr., MacKillop J, et al. A preliminary pharmacogenetic investigation of adverse events from topiramate in heavy drinkers. Exp Clin Psychopharmacol. 2009 Apr;17(2):122–129.
  • Kranzler HR, Wetherill R, Feinn R, et al. Posttreatment effects of topiramate treatment for heavy drinking. Alcohol Clin Exp Res. 2014 Dec;38(12):3017–3023.
  • Kranzler HR, Armeli S, Wetherill R, et al. Self-efficacy mediates the effects of topiramate and GRIK1 genotype on drinking. Addict Biol. 2016 Mar;21(2):450–459.
  • Knapp CM, Ciraulo DA, Sarid-Segal O, et al. Zonisamide, topiramate, and levetiracetam: efficacy and neuropsychological effects in alcohol use disorders. J Clin Psychopharmacol. 2015 Feb;35(1):34–42.
  • Crunelle CL, Miller ML, Booij J, et al. The nicotinic acetylcholine receptor partial agonist varenicline and the treatment of drug dependence: a review. Eur Neuropsychopharmacol. 2010 Feb;20(2):69–79.
  • Froehlich JC, Fischer SM, Dilley JE, et al. Combining varenicline (Chantix) with naltrexone decreases alcohol drinking more effectively than does either drug alone in a rodent model of alcoholism. Alcohol Clin Exp Res. 2016 Sep;40(9):1961–1970.
  • Gowin JL, Vatsalya V, Westman JG, et al. The effect of varenicline on the neural processing of fearful faces and the subjective effects of alcohol in heavy drinkers. Alcohol Clin Exp Res. 2016 May;40(5):979–987.
  • Mitchell JM, Teague CH, Kayser AS, et al. Varenicline decreases alcohol consumption in heavy-drinking smokers. Psychopharmacology (Berl). 2012 Oct;223(3):299–306.
  • Crunelle CL, Schulz S, de Bruin K, et al. Dose-dependent and sustained effects of varenicline on dopamine D2/3 receptor availability in rats. Eur Neuropsychopharmacol. 2011 Feb;21(2):205–210.
  • Nocente R, Vitali M, Balducci G, et al. Varenicline and neuronal nicotinic acetylcholine receptors: a new approach to the treatment of co-occurring alcohol and nicotine addiction? Am J Addict. 2013 Sep–Oct;22(5):453–459.
  • Ray LA, Courtney KE, Ghahremani DG, et al. Varenicline, naltrexone, and their combination for heavy-drinking smokers: preliminary neuroimaging findings. Am J Drug Alcohol Abuse. 2015 Jan;41(1):35–44.
  • Schacht JP, Anton RF, Randall PK, et al. Varenicline effects on drinking, craving and neural reward processing among non-treatment-seeking alcohol-dependent individuals. Psychopharmacology (Berl). 2014 Sep;231(18):3799–3807.
  • Erwin BL, Slaton RM. Varenicline in the treatment of alcohol use disorders. Ann Pharmacother. 2014 Nov;48(11):1445–1455.
  • Childs E, Roche DJ, King AC, et al. Varenicline potentiates alcohol-induced negative subjective responses and offsets impaired eye movements. Alcohol Clin Exp Res. 2012 May;36(5):906–914.
  • Hays JT, Croghan IT, Schroeder DR, et al. Varenicline for tobacco dependence treatment in recovering alcohol-dependent smokers: an open-label pilot study. J Subst Abuse Treat. 2011 Jan;40(1):102–107.
  • Litten RZ, Ryan ML, Fertig JB, et al. A double-blind, placebo-controlled trial assessing the efficacy of varenicline tartrate for alcohol dependence. J Addict Med. 2013 Jul–Aug;7(4):277–286.
  • McKee SA, Harrison EL, O’Malley SS, et al. Varenicline reduces alcohol self-administration in heavy-drinking smokers. Biol Psychiatry. 2009 Jul 15;66(2):185–190.
  • Meszaros ZS, Abdul-Malak Y, Dimmock JA, et al. Varenicline treatment of concurrent alcohol and nicotine dependence in schizophrenia: a randomized, placebo-controlled pilot trial. J Clin Psychopharmacol. 2013 Apr;33(2):243–247.
  • Plebani JG, Lynch KG, Rennert L, et al. Results from a pilot clinical trial of varenicline for the treatment of alcohol dependence. Drug Alcohol Depend. 2013 Dec 1;133(2):754–758.
  • Fucito LM, Toll BA, Wu R, et al. A preliminary investigation of varenicline for heavy drinking smokers. Psychopharmacology (Berl). 2011 Jun;215(4):655–663.
  • de Bejczy A, Lof E, Walther L, et al. Varenicline for treatment of alcohol dependence: a randomized, placebo-controlled trial. Alcohol Clin Exp Res. 2015 Nov;39(11):2189–2199.
  • Falk DE, Castle IJ, Ryan M, et al. Moderators of varenicline treatment effects in a double-blind, placebo-controlled trial for alcohol dependence: an exploratory analysis. J Addict Med. 2015 Jul–Aug;9(4):296–303.
  • ANSM. Recommandation Temporaire d’Utilisation (RTU) du baclofène dans le traitement de l’alcoolo-dépendance. 2014 [cited 2014 Aug 18]. Available from: http://ansm.sante.fr/var/ansm_site/storage/original/application/2976e3c2bb5c0e5265a35955df5e8de0.pdf
  • Colombo G, Agabio R, Carai MA, et al. Ability of baclofen in reducing alcohol intake and withdrawal severity: i–preclinical evidence. Alcohol Clin Exp Res. 2000 Jan;24(1):58–66.
  • Addolorato G, Caputo F, Capristo E, et al. Baclofen efficacy in reducing alcohol craving and intake: a preliminary double-blind randomized controlled study. Alcohol Alcohol. 2002 Sep–Oct;37(5):504–508.
  • Addolorato G, Leggio L, Ferrulli A, et al. Effectiveness and safety of baclofen for maintenance of alcohol abstinence in alcohol-dependent patients with liver cirrhosis: randomised, double-blind controlled study. Lancet. 2007 Dec 8;370(9603):1915–1922.
  • Garbutt JC, Kampov-Polevoy AB, Gallop R, et al. Efficacy and safety of baclofen for alcohol dependence: a randomized, double-blind, placebo-controlled trial. Alcohol Clin Exp Res. 2010 Nov;34(11):1849–1857.
  • Colombo G, Addolorato G, Agabio R, et al. Role of GABA(B) receptor in alcohol dependence: reducing effect of baclofen on alcohol intake and alcohol motivational properties in rats and amelioration of alcohol withdrawal syndrome and alcohol craving in human alcoholics. Neurotox Res. 2004;6(5):403–414.
  • Ameisen O. Complete and prolonged suppression of symptoms and consequences of alcohol-dependence using high-dose baclofen: a self-case report of a physician. Alcohol Alcohol. 2005 Mar–Apr;40(2):147–150.
  • Muller CA, Geisel O, Pelz P, et al. High-dose baclofen for the treatment of alcohol dependence (BACLAD study): a randomized, placebo-controlled trial. Eur Neuropsychopharmacol. 2015 Aug;25(8):1167–1177.
  • Beraha EM, Salemink E, Goudriaan AE, et al. Efficacy and safety of high-dose baclofen for the treatment of alcohol dependence: a multicentre, randomised, double-blind controlled trial. Eur Neuropsychopharmacol. 2016 Dec;26(12):1950–1959.
  • Reynaud M, Aubin HJ, Trinquet F, et al. A randomized, placebo-controlled study of high-dose baclofen in alcohol-dependent patients-the ALPADIR study. Alcohol Alcohol. 2017;19:1–8.
  • Hauser P, Fuller B, Ho SB, et al. The safety and efficacy of baclofen to reduce alcohol use in veterans with chronic hepatitis C: a randomized controlled trial. Addiction. 2017 Jul;112(7):1173–1183.
  • Pignon B, Labreuche J, Auffret M, et al. The dose-effect relationship of baclofen in alcohol dependence: a 1-year cohort study. Hum Psychopharmacol. 2017 May 18.
  • Farokhnia M, Schwandt ML, Lee MR, et al. Biobehavioral effects of baclofen in anxious alcohol-dependent individuals: a randomized, double-blind, placebo-controlled, laboratory study. Transl Psychiatry. 2017 Apr 25;7(4):e1108.
  • Chick J, Nutt DJ. Substitution therapy for alcoholism: time for a reappraisal? J Psychopharmacol. 2012 Feb;26(2):205–212.
  • Fadda P, Scherma M, Fresu A, et al. Baclofen antagonizes nicotine-, cocaine-, and morphine-induced dopamine release in the nucleus accumbens of rat. Synapse. 2003 Oct;50(1):1–6.
  • Cabrera EA, Wiers CE, Lindgren E, et al. Neuroimaging the effectiveness of substance use disorder treatments. J Neuroimmune Pharmacol. 2016 Sep;11(3):408–433.
  • Kamal RM, van Noorden MS, Franzek E, et al. The neurobiological mechanisms of gamma-hydroxybutyrate dependence and withdrawal and their clinical relevance: a review. Neuropsychobiology. 2016;73(2):65–80.
  • Bay T, Eghorn LF, Klein AB, et al. GHB receptor targets in the CNS: focus on high-affinity binding sites. Biochem Pharmacol. 2014 Jan 15;87(2):220–228.
  • Caputo F, Vignoli T, Tarli C, et al. A brief up-date of the use of sodium oxybate for the treatment of alcohol use disorder. Int J Environ Res Public Health. 2016 Mar;13(3):290.
  • Gallimberti L, Ferri M, Ferrara SD, et al. gamma-Hydroxybutyric acid in the treatment of alcohol dependence: a double-blind study. Alcohol Clin Exp Res. 1992 Aug;16(4):673–676.
  • Caputo F, Addolorato G, Lorenzini F, et al. Gamma-hydroxybutyric acid versus naltrexone in maintaining alcohol abstinence: an open randomized comparative study. Drug Alcohol Depend. 2003 May 01;70(1):85–91.
  • Caputo F, Addolorato G, Stoppo M, et al. Comparing and combining gamma-hydroxybutyric acid (GHB) and naltrexone in maintaining abstinence from alcohol: an open randomised comparative study. Eur Neuropsychopharmacol. 2007 Dec;17(12):781–789.
  • Nava F, Premi S, Manzato E, et al. Comparing treatments of alcoholism on craving and biochemical measures of alcohol consumptionst. J Psychoactive Drugs. 2006 Sep;38(3):211–217.
  • Leone MA, Vigna-Taglianti F, Avanzi G, et al. Gamma-hydroxybutyrate (GHB) for treatment of alcohol withdrawal and prevention of relapses. Cochrane Database Syst Rev. 2010 Feb;17(2):CD006266.
  • Dom G, Moggi F. Co-occurring addictive and psychiatric disorders. Heidelberg (NY): Springer; 2015.
  • Fehr C, Coste F, Rahhali N, et al. Die Behandlungswirklichkeit alkoholabhängiger Patienten in der täglichen medizinischen Praxis in Deutschland. Suchtmed. 2015;17(5):233–246.
  • Nalpas B, Perney P. Use of psychoactive medication in short- and long-term abstainers from alcohol. Alcohol Alcohol. 2017 Apr;04:1–6.
  • Foulds JA, Adamson SJ, Boden JM, et al. Depression in patients with alcohol use disorders: systematic review and meta-analysis of outcomes for independent and substance-induced disorders. J Affect Disord. 2015 Oct;01(185):47–59.
  • Iovieno N, Tedeschini E, Bentley KH, et al. Antidepressants for major depressive disorder and dysthymic disorder in patients with comorbid alcohol use disorders: a meta-analysis of placebo-controlled randomized trials. J Clin Psychiatry. 2011 Aug;72(8):1144–1151.
  • Nunes EV, Levin FR. Treatment of depression in patients with alcohol or other drug dependence: a meta-analysis. JAMA. 2004 Apr 21;291(15):1887–1896.
  • Torrens M, Fonseca F, Mateu G, et al. Efficacy of antidepressants in substance use disorders with and without comorbid depression. A systematic review and meta-analysis. Drug Alcohol Depend. 2005 Apr 4;78(1):1–22.
  • Cornelius JR, Chung T, Douaihy AB, et al. Mirtazapine in comorbid major depression and an alcohol use disorder: a double-blind placebo-controlled pilot trial. Psychiatry Res. 2016 Aug;30(242):326–330.
  • Kishi T, Sevy S, Chekuri R, et al. Antipsychotics for primary alcohol dependence: a systematic review and meta-analysis of placebo-controlled trials. J Clin Psychiatry. 2013 Jul;74(7):e642–54.
  • Anton RF, Kranzler H, Breder C, et al. A randomized, multicenter, double-blind, placebo-controlled study of the efficacy and safety of aripiprazole for the treatment of alcohol dependence. J Clin Psychopharmacol. 2008 Feb;28(1):5–12.
  • Brunetti M, Di Tizio L, Dezi S, et al. Aripiprazole, alcohol and substance abuse: a review. Eur Rev Med Pharmacol Sci. 2012 Oct;16(10):1346–1354.
  • Martinotti G, Orsolini L, Fornaro M, et al. Aripiprazole for relapse prevention and craving in alcohol use disorder: current evidence and future perspectives. Expert Opin Investig Drugs. 2016 Jun;25(6):719–728.
  • Ray LA, Heydari A, Zorick T. Quetiapine for the treatment of alcoholism: scientific rationale and review of the literature. Drug Alcohol Rev. 2010 Sep;29(5):568–575.
  • Guardia J, Roncero C, Galan J, et al. A double-blind, placebo-controlled, randomized pilot study comparing quetiapine with placebo, associated to naltrexone, in the treatment of alcohol-dependent patients. Addict Behav. 2011 Mar;36(3):265–269.
  • Katz DA, Locke C, Liu W, et al. Single-dose interaction study of the arginine vasopressin type 1B receptor antagonist ABT-436 and alcohol in moderate alcohol drinkers. Alcohol Clin Exp Res. 2016 Apr;40(4):838–845.
  • Ryan ML, Falk DE, Fertig JB, et al. A phase 2, double-blind, placebo-controlled randomized trial assessing the efficacy of ABT-436, a novel V1b receptor antagonist, for alcohol dependence. Neuropsychopharmacology. 2017 Apr;42(5):1012–1023.
  • Malcolm R, Myrick H, Roberts J, et al. The effects of carbamazepine and lorazepam on single versus multiple previous alcohol withdrawals in an outpatient randomized trial. J Gen Intern Med. 2002 May;17(5):349–355.
  • Mueller TI, Stout RL, Rudden S, et al. A double-blind, placebo-controlled pilot study of carbamazepine for the treatment of alcohol dependence. Alcohol Clin Exp Res. 1997 Feb;21(1):86–92.
  • Brady KT, Myrick H, Henderson S, et al. The use of divalproex in alcohol relapse prevention: a pilot study. Drug Alcohol Depend. 2002 Aug 1;67(3):323–330.
  • Longo LP, Campbell T, Hubatch S. Divalproex sodium (Depakote) for alcohol withdrawal and relapse prevention. J Addict Dis. 2002;21(2):55–64.
  • Thompson A, Ashcroft DM, Owens L, et al. Drug therapy for alcohol dependence in primary care in the UK: a clinical practice research datalink study. PLoS One. 2017;12(3):e0173272.

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