Recent Developments in Pharmacotherapy of Alcoholism

Abstract

Introduction: Alcohol use disorders are common, but only a small minority of patients receive adequate treatment. Cognitive-behavioural therapies, motivational enhancement interviewing and brief interventions are established treatments, but few pharmacotherapies are available.

Areas Covered: This narrative focuses on the neurobiological basis of alcohol use disorders and on emerging drugs that either have recently been approved or look likely to find their way into clinical practice. To date, acamprosate and the opioid antagonist naltrexone have been approved for treatment of alcohol dependence. Recently, the mu-opioid antagonist and partial kappa agonist nalmefene was approved by the European Medicines Agency for reduction of alcohol consumption. Novel clinical approaches include drugs established for other indications such as the GABA-B receptor agonist baclofen, anticonvulsants such as topiramate and gabapentin, the partial nicotine receptor agonist varenicline, and other drugs. Developments in pharmacogenetics are discussed.

Conclusions: The development of pharmaceutical agents to treat alcohol use disorders has lagged behind that of depression and schizophrenic psychosis and is hampered by an incomplete understanding of the neurobiological background. Pharmacogenetics may improve treatment in the future.

Key words

alcohol - alcoholism - baclofen - gabapentin - nalmefene - opioid antagonists - topiramate - varenicline

• References

• 1 Soyka M. Update Alcohol Dependence. Bremen: Unimed Verlag; 2013
• 2 Soyka M, Kuefner H. Alcoholism – Abuse and Dependence. Heidelberg: Thieme; 2008
• 3 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; 61: 361-368
• 4 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; 62: 617-627
• 5 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; 41: 315-320
• 6 Rehm J, Room R, van den Brink W et al. Alcohol use disorders in EU countries and Norway: an overview of the epidemiology. Eur Neuropsychopharmacol 2005; 15: 377-388
• 7 World Health Organization . Global status report on alcohol and health. Geneva, Switzerland: World Health Organization; 2011
• 8 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; 27: 391-399
• 9 Rosner S, Hackl-Herrwerth A, Leucht S et al. Acamprosate for alcohol dependence. Cochrane Database Syst Rev 2010; CD004332
• 10 Rosner S, Hackl-Herrwerth A, Leucht S et al. Opioid antagonists for alcohol dependence. Cochrane Database Syst Rev 2010; CD001867
• 11 Soyka M, Kranzler HR, van den Brink W et al. The World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the biological treatment of substance use and related disorders. Part 2: Opioid dependence. World J Biol Psychiatry 2011; 12: 160-187
• 12 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; 64: 830-842
• 13 Rehm J, Shield KD, Gmel G et al. Modeling the impact of alcohol dependence on mortality burden and the effect of available treatment interventions in the European Union. Eur Neuropsychopharmacol 2013; 23: 89-97
• 14 World Health Organization . Global status report on alcohol and health. Geneva, Switzerland: World Health Organization; 2014
• 15 Laramee P, Kusel J, Leonard S et al. The economic burden of alcohol dependence in Europe. Alcohol Alcohol 2013; 48: 259-269
• 16 Rehm J, Baliunas D, Borges GL et al. The relation between different dimensions of alcohol consumption and burden of disease: an overview. Addiction 2010; 105: 817-843
• 17 Roerecke M, Gual A, Rehm J. Reduction of alcohol consumption and subsequent mortality in alcohol use disorders: systematic review and meta-analyses. J Clin Psychiatry 2013; 74: e1181-e1189
• 18 Berglund M, Thelander S, Jonsson E. Treating alcohol and drug abuse – an evidence based review. Weinheim: Wiley-VCH; 2003
• 19 Dutra L, Stathopoulou G, Basden SL et al. A meta-analytic review of psychosocial interventions for substance use disorders. Am J Psychiatry 2008; 165: 179-187
• 20 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; 70: 516-527
• 21 Martin GW, Rehm J. The effectiveness of psychosocial modalities in the treatment of alcohol problems in adults: a review of the evidence. Can J Psychiatry 2012; 57: 350-358
• 22 Riper H, Andersson G, Hunter SB et al. Treatment of comorbid alcohol use disorders and depression with cognitive-behavioural therapy and motivational interviewing: a meta-analysis. Addiction 2014; 109: 394-406
• 23 Miller WR, Wilbourne PL. Mesa Grande: a methodological analysis of clinical trials of treatments for alcohol use disorders. Addiction 2002; 97: 265-277
• 24 Prendergast M, Podus D, Finney J et al. Contingency management for treatment of substance use disorders: a meta-analysis. Addiction 2006; 101: 1546-1560
• 25 Smedslund G, Berg RC, Hammerstrom KT et al. Motivational interviewing for substance abuse. Cochrane Database Syst Rev 2011; CD008063
• 26 Berner MM, Wahl S, Brueck R et al. The place of additional individual psychotherapy in the treatment of alcoholism: a randomized controlled study in nonresponders to anticraving medication – results of the PREDICT study. Alcohol Clin Exp Res 2014; 38: 1118-1125
• 27 Hester RK, Miller WR. Handbook of Alcoholism Treatment Approaches: Effective Alternatives. 2^nd ed Boston: Allyn and Bacon; 1995
• 28 Project MATCH Research Group . Project MATCH secondary a priori hypotheses. Addiction 1997; 92: 1671-1698
• 29 Noronha ABC, Cui C, Harris RA. (eds.) Neurobiology of Alcohol Dependence. London, Waltham, San Diego: Academic Press; 2014
• 30 Nutt D, Nestor L. Addiction. Kettering: Oxford University Press; 2013
• 31 Koob GF, Le Moal M. Neurobiology of Addiction. London, Burlington, San Diego: Academic Press; 2006
• 32 Spanagel R. Alcoholism: a systems approach from molecular physiology to addictive behavior. Physiol Rev 2009; 89: 649-705
• 33 Spanagel R, Vengeliene V. New pharmacological treatment strategies for relapse prevention. Curr Top Behav Neurosci 2013; 13: 583-609
• 34 Hillemacher T, Leggio L, Heberlein A. Investigational therapies for the pharmacological treatment of alcoholism. Expert Opin Investig Drugs 2014; 28: 1-14
• 35 Gianoulakis C. Endogenous opioids and addiction to alcohol and other drugs of abuse. Curr Top Med Chem 2004; 4: 39-50
• 36 Hubbell CL, Abelson ML, Burkhardt CA et al. Constant infusions of morphine and intakes of sweetened ethanol solution among rats. Alcohol 1988; 5: 409-415
• 37 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; 33: 1033-1043
• 38 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; 29: 1965-1975
• 39 Koob GF, Roberts AJ, Kieffer BL et al. Animal models of motivation for drinking in rodents with a focus on opioid receptor neuropharmacology. Recent Dev Alcohol 2003; 16: 263-281
• 40 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; 29: 1821-1828
• 41 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; 30: 982-990
• 42 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: 777-784
• 43 Narita M, Funada M, Suzuki T. Regulations of opioid dependence by opioid receptor types. Pharmacol Ther 2001; 89: 1-15
• 44 Oswald LM, Wand GS. Opioids and alcoholism. Physiol Behav 2004; 81: 339-358
• 45 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; 3: 39-54
• 46 Adcock RA, Thangavel A, Whitfield-Gabrieli S et al. Reward-motivated learning: mesolimbic activation precedes memory formation. Neuron 2006; 50: 507-517
• 47 Nutt DJ. The role of the opioid system in alcohol dependence. J Psychopharmacol 2014; 28: 8-22
• 48 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; 55: 255-262
• 49 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; 62: 57-64
• 50 Heilig M, Egli M. Pharmacological treatment of alcohol dependence: target symptoms and target mechanisms. Pharmacol Ther 2006; 111: 855-876
• 51 Soyka M, Rosner S. Emerging drugs to treat alcoholism. Expert Opin Emerg Drugs 2010; 15: 695-711
• 52 Spanagel R, Kiefer F. Drugs for relapse prevention of alcoholism: ten years of progress. Trends Pharmacol Sci 2008; 29: 109-115
• 53 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; 108: 275-293
• 54 Littleton J, Zieglgansberger W. Pharmacological mechanisms of naltrexone and acamprosate in the prevention of relapse in alcohol dependence. Am J Addict 2003; 12 (Suppl. 01) S3-S11
• 55 Spanagel R, Vengeliene V, Jandeleit B et al. Acamprosate produces its anti-relapse effects via calcium. Neuropsychopharmacology 2014; 39: 783-791
• 56 Jarosz J, Miernik K, Wachal M et al. Naltrexone (50 mg) plus psychotherapy in alcohol-dependent patients: a meta-analysis of randomized controlled trials. Am J Drug Alcohol Abuse 2013; 39: 144-160
• 57 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; 18: 937-946
• 58 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; 311: 1889-1900
• 59 Zindel LR, Kranzler HR. Pharmacotherapy of alcohol use disorders: seventy-five years of progress. J Stud Alcohol Drugs Suppl 2014; 75 (Suppl. 17) 79-88
• 60 Knudsen HK, Roman PM. Dissemination, adoption, and implementation of acamprosate for treating alcohol use disorders. J Stud Alcohol Drugs 2014; 75: 467-475
• 61 Davies DL, Bortolato M, Finn DA et al. Recent advances in the discovery and preclinical testing of novel compounds for the prevention and/or treatment of alcohol use disorders. Alcohol Clin Exp Res 2013; 37: 8-15
• 62 Franck J, Jayaram-Lindstrom N. Pharmacotherapy for alcohol dependence: status of current treatments. Curr Opin Neurobiol 2013; 23: 692-699
• 63 Litten RZ, Ryan M, Falk D et al. Alcohol medications development: advantages and caveats of government/academia collaborating with the pharmaceutical industry. Alcohol Clin Exp Res 2014; 38: 1196-1199
• 64 Muller CA, Geisel O, Banas R et al. Current pharmacological treatment approaches for alcohol dependence. Expert Opin Pharmacother 2014; 15: 471-481
• 65 European Medicines Agency . Guideline on the development of medicinal products for the treatment of alcohol dependence. London: European Medicines Agency; 2010
• 66 Swift RM. Naltrexone and nalmefene: any meaningful difference?. Biol Psychiatry 2013; 73: 700-701
• 67 Mason BJ, Salvato FR, Williams LD et al. A double-blind, placebo-controlled study of oral nalmefene for alcohol dependence. Arch Gen Psychiatry 1999; 56: 719-724
• 68 Emmerson PJ, Liu MR, Woods JH et al. Binding affinity and selectivity of opioids at mu, delta and kappa receptors in monkey brain membranes. J Pharmacol Exp Ther 1994; 271: 1630-1637
• 69 Ingman K, Hagelberg N, Aalto S et al. Prolonged central mu-opioid receptor occupancy after single and repeated nalmefene dosing. Neuropsychopharmacology 2005; 30: 2245-2253
• 70 Dixon R, Gentile J, Hsu HB et al. Nalmefene: safety and kinetics after single and multiple oral doses of a new opioid antagonist. J Clin Pharmacol 1987; 27: 233-239
• 71 Gal TJ, DiFazio CA, Dixon R. Prolonged blockade of opioid effect with oral nalmefene. Clin Pharmacol Ther 1986; 40: 537-542
• 72 Osborn MD, Lowery JJ, Skorput AG et al. In vivo characterization of the opioid antagonist nalmefene in mice. Life Sci 2010; 86: 624-630
• 73 DeHaven-Hudkins DL, Brostrom PA, Allen JT et al. Pharmacologic profile of NPC 168 (naltrexone phenyl oxime), a novel compound with activity at opioid receptors. Pharmacol Biochem Behav 1990; 37: 497-504
• 74 Bart G, Kreek MJ, Ott J et al. Increased attributable risk related to a functional mu-opioid receptor gene polymorphism in association with alcohol dependence in central Sweden. Neuropsychopharmacology 2005; 30: 417-422
• 75 Walker BM, Koob GF. Pharmacological evidence for a motivational role of kappa-opioid systems in ethanol dependence. Neuropsychopharmacology 2008; 33: 643-652
• 76 Walker BM, Valdez GR, McLaughlin JP et al. Targeting dynorphin/kappa opioid receptor systems to treat alcohol abuse and dependence. Alcohol 2012; 46: 359-370
• 77 Walker BM, Zorrilla EP, Koob GF. Systemic kappa-opioid receptor antagonism by nor-binaltorphimine reduces dependence-induced excessive alcohol self-administration in rats. Addict Biol 2011; 16: 116-119
• 78 Niciu MJ, Arias AJ. Targeted opioid receptor antagonists in the treatment of alcohol use disorders. CNS Drugs 2013; 27: 777-787
• 79 Schluger JH, Ho A, Borg L et al. Nalmefene causes greater hypothalamic-pituitary-adrenal axis activation than naloxone in normal volunteers: implications for the treatment of alcoholism. Alcohol Clin Exp Res 1998; 22: 1430-1436
• 80 Stephens MAC, McCaul ME, Wand GS. The potential role of glucocorticoids and the HPA axis in alcohol dependence. In: Noronha ABC, Changhai CUI, Harris RA, Crabbe JC. (eds.) Neurobiology of Alcohol Dependence. London: Academic Press; 2014: 429-450
• 81 European Medicines Agency . Selincro (nalmefene): Summary of Product Characteristics. London: European Medicines Agency; 2014
• 82 Mason BJ, Ritvo EC, Morgan RO et al. A double-blind, placebo-controlled pilot study to evaluate the efficacy and safety of oral nalmefene HCl for alcohol dependence. Alcohol Clin Exp Res 1994; 18: 1162-1167
• 83 June HL, Grey C, Warren-Reese C et al. The opioid receptor antagonist nalmefene reduces responding maintained by ethanol presentation: preclinical studies in ethanol-preferring and outbred Wistar rats. Alcohol Clin Exp Res 1998; 22: 2174-2185
• 84 Drobes DJ, Anton RF, Thomas SE et al. A clinical laboratory paradigm for evaluating medication effects on alcohol consumption: naltrexone and nalmefene. Neuropsychopharmacology 2003; 28: 755-764
• 85 Drobes DJ, Anton RF, Thomas SE et al. Effects of naltrexone and nalmefene on subjective response to alcohol among non-treatment-seeking alcoholics and social drinkers. Alcohol Clin Exp Res 2004; 28: 1362-1370
• 86 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; 24: 421-428
• 87 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; 23: 1432-1442
• 88 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; 31: 1179-1187
• 89 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; 73: 706-713
• 90 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; 28: 733-744
• 91 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; 48: 570-578
• 92 Braillon A. Nalmefene in alcohol misuse: junk evaluation by the European Medicines Agency. BMJ 2014; 348: g2017
• 93 Spence D. Bad medicine: nalmefene in alcohol misuse. BMJ 2014; 348: g1531
• 94 French JA, Kanner AM, Bautista J et al. Efficacy and tolerability of the new antiepileptic drugs II: treatment of refractory epilepsy: report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology 2004; 62: 1261-1273
• 95 Wenzel RG, Schwarz K, Padiyara RS. Topiramate for migraine prevention. Pharmacotherapy 2006; 26: 375-387
• 96 Rubio G, Martinez-Gras I, Manzanares J. Modulation of impulsivity by topiramate: implications for the treatment of alcohol dependence. J Clin Psychopharmacol 2009; 29: 584-589
• 97 Bray GA, Hollander P, Klein S et al. A 6-month randomized, placebo-controlled, dose-ranging trial of topiramate for weight loss in obesity. Obes Res 2003; 11: 722-733
• 98 Roy Chengappa KN, Levine J, Rathore D et al. Long-term effects of topiramate on bipolar mood instability, weight change and glycemic control: a case-series. Eur Psychiatry 2001; 16: 186-190
• 99 Alderman CP, McCarthy LC, Condon JT et al. Topiramate in combat-related posttraumatic stress disorder. Ann Pharmacother 2009; 43: 635-641
• 100 McElroy SL, Arnold LM, Shapira NA et al. Topiramate in the treatment of binge eating disorder associated with obesity: a randomized, placebo-controlled trial. Am J Psychiatry 2003; 160: 255-261
• 101 Angehagen M, Ronnback L, Hansson E et al. Topiramate reduces AMPA-induced Ca(2+) transients and inhibits GluR1 subunit phosphorylation in astrocytes from primary cultures. J Neurochem 2005; 94: 1124-1130
• 102 White HS, Brown SD, Woodhead JH et al. Topiramate modulates GABA-evoked currents in murine cortical neurons by a nonbenzodiazepine mechanism. Epilepsia 2000; 41 (Suppl. 01) S17-S20
• 103 Johnson BA, Ait-Daoud N, Akhtar FZ et al. Oral topiramate reduces the consequences of drinking and improves the quality of life of alcohol-dependent individuals: a randomized controlled trial. Arch Gen Psychiatry 2004; 61: 905-912
• 104 Weiss F, Porrino LJ. Behavioral neurobiology of alcohol addiction: recent advances and challenges. J Neurosci 2002; 22: 3332-3337
• 105 Johnson BA, Ait-Daoud N. Topiramate in the new generation of drugs: efficacy in the treatment of alcoholic patients. Curr Pharm Des 2010; 16: 2103-2112
• 106 Garnett WR. Clinical pharmacology of topiramate: a review. Epilepsia 2000; 41 (Suppl. 01) S61-S65
• 107 Perucca E, Bialer M. The clinical pharmacokinetics of the newer antiepileptic drugs. Focus on topiramate, zonisamide and tiagabine. Clin Pharmacokinet 1996; 31: 29-46
• 108 Shank RP, Gardocki JF, Streeter AJ et al. An overview of the preclinical aspects of topiramate: pharmacology, pharmacokinetics, and mechanism of action. Epilepsia 2000; 41 (Suppl. 01) S3-S9
• 109 Johnson BA. Recent advances in the development of treatments for alcohol and cocaine dependence: focus on topiramate and other modulators of GABA or glutamate function. CNS Drugs 2005; 19: 873-896
• 110 Johnson BA. Update on neuropharmacological treatments for alcoholism: scientific basis and clinical findings. Biochem Pharmacol 2008; 75: 34-56
• 111 Batki SL, Pennington DL, Lasher B et al. Topiramate treatment of alcohol use disorder in veterans with posttraumatic stress disorder: a randomized controlled pilot trial. Alcohol Clin Exp Res 2014; 38: 2169-2177
• 112 Biton V, Edwards KR, Montouris GD et al. Topiramate titration and tolerability. Ann Pharmacother 2001; 35: 173-179
• 113 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; 38: 1481-1488
• 114 Likhitsathian S, Uttawichai K, Booncharoen H et al. Topiramate treatment for alcoholic outpatients recently receiving residential treatment programs: a 12-week, randomized, placebo-controlled trial. Drug Alcohol Depend 2013; 133: 440-446
• 115 Pani PP, Trogu E, Pacini M et al. Anticonvulsants for alcohol dependence. Cochrane Database Syst Rev 2014; 2: CD008544
• 116 Dickenson AH, Ghandehari J. Anti-convulsants and anti-depressants. Handb Exp Pharmacol 2007; 145-177
• 117 Landmark CJ. Targets for antiepileptic drugs in the synapse. Med Sci Monit 2007; 13: RA1-RA7
• 118 Rogawski MA, Loscher W. The neurobiology of antiepileptic drugs. Nat Rev Neurosci 2004; 5: 553-564
• 119 Coderre TJ, Kumar N, Lefebvre CD et al. A comparison of the glutamate release inhibition and anti-allodynic effects of gabapentin, lamotrigine, and riluzole in a model of neuropathic pain. J Neurochem 2007; 100: 1289-1299
• 120 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; 20: 1566-1576
• 121 Dooley DJ, Mieske CA, Borosky SA. Inhibition of K(+)-evoked glutamate release from rat neocortical and hippocampal slices by gabapentin. Neurosci Lett 2000; 280: 107-110
• 122 Maneuf YP, Blake R, Andrews NA et al. Reduction by gabapentin of K⁺-evoked release of [³H]-glutamate from the caudal trigeminal nucleus of the streptozotocin-treated rat. Br J Pharmacol 2004; 141: 574-579
• 123 Maneuf YP, McKnight AT. Block by gabapentin of the facilitation of glutamate release from rat trigeminal nucleus following activation of protein kinase C or adenylyl cyclase. Br J Pharmacol 2001; 134: 237-240
• 124 Shimoyama M, Shimoyama N, Hori Y. Gabapentin affects glutamatergic excitatory neurotransmission in the rat dorsal horn. Pain 2000; 85: 405-414
• 125 Bonnet U, Banger M, Leweke FM et al. Treatment of alcohol withdrawal syndrome with gabapentin. Pharmacopsychiatry 1999; 32: 107-109
• 126 Bozikas V, Petrikis P, Gamvrula K et al. Treatment of alcohol withdrawal with gabapentin. Prog Neuropsychopharmacol Biol Psychiatry 2002; 26: 197-199
• 127 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; 15: 76-84
• 128 Martinez-Raga J, Sabater A, Perez-Galvez B et al. Add-on gabapentin in the treatment of opiate withdrawal. Prog Neuropsychopharmacol Biol Psychiatry 2004; 28: 599-601
• 129 Myrick H, Malcolm R, Brady KT. Gabapentin treatment of alcohol withdrawal. Am J Psychiatry 1998; 155: 1632
• 130 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: 5-6
• 131 Voris J, Smith NL, Rao SM et al. Gabapentin for the treatment of ethanol withdrawal. Subst Abus 2003; 24: 129-132
• 132 Watson WP, Robinson E, Little HJ. The novel anticonvulsant, gabapentin, protects against both convulsant and anxiogenic aspects of the ethanol withdrawal syndrome. Neuropharmacology 1997; 36: 1369-1375
• 133 Mason BJ, Quello S, Goodell V et al. Gabapentin treatment for alcohol dependence: a randomized clinical trial. JAMA Intern Med 2014; 174: 70-77
• 134 Ameisen O. The End of My Addiction. New York: Farrar, Straus and Giroux; 2008
• 135 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; 40: 147-150
• 136 Bowery NG. GABAB receptor: a site of therapeutic benefit. Curr Opin Pharmacol 2006; 6: 37-43
• 137 Dario A, Tomei G. A benefit-risk assessment of baclofen in severe spinal spasticity. Drug Saf 2004; 27: 799-818
• 138 Addolorato G, Leggio L, Cardone S et al. Role of the GABA(B) receptor system in alcoholism and stress: focus on clinical studies and treatment perspectives. Alcohol 2009; 43: 559-563
• 139 Addolorato G, Leggio L. Safety and efficacy of baclofen in the treatment of alcohol-dependent patients. Curr Pharm Des 2010; 16: 2113-2117
• 140 Agabio R, Colombo G. GABAB receptor ligands for the treatment of alcohol use disorder: preclinical and clinical evidence. Front Neurosci 2014; 8: 140
• 141 El-Husseini A, Sabucedo A, Lamarche J et al. Baclofen toxicity in patients with advanced nephropathy: proposal for new labeling. Am J Nephrol 2011; 34: 491-495
• 142 Novartis Pharmaceuticals Corporation . Lioresal [package insert]. East Hanover, NJ: Novartis Pharmaceutical Corporation; 1998
• 143 Addolorato G, Caputo F, Capristo E et al. Ability of baclofen in reducing alcohol craving and intake: II – Preliminary clinical evidence. Alcohol Clin Exp Res 2000; 24: 67-71
• 144 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; 37: 504-508
• 145 Addolorato G, Leggio L, Ferrulli A et al. Dose-response effect of baclofen in reducing daily alcohol intake in alcohol dependence: secondary analysis of a randomized, double-blind, placebo-controlled trial. Alcohol Alcohol 2011; 46: 312-317
• 146 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; 370: 1915-1922
• 147 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; 34: 1849-1857
• 148 Morley KC, Baillie A, Leung S et al. Baclofen for the treatment of alcohol dependence and possible role of comorbid anxiety. Alcohol Alcohol 2014; Sep 21. pii: agu062. [Epub ahead of print] PubMed PMID: 25246489
• 149 Gorsane MA, Kebir O, Hache G et al. Is baclofen a revolutionary medication in alcohol addiction management? Review and recent updates. Subst Abus 2012; 33: 336-349
• 150 Pastor A, Lloyd-Jones M, Currie J. Reply to Dr Rolland et al. re: “Baclofen for alcohol-dependence: anticraving or partial substitution?”. J Clin Psychopharmacol 2013; 33: 281-282
• 151 Rolland B, Bordet R, Cottencin O. Alcohol-dependence: the current French craze for baclofen. Addiction 2012; 107: 848-849
• 152 Rolland B, Bordet R, Deheul S et al. Baclofen for alcohol-dependence: anticraving or partial substitution?. J Clin Psychopharmacol 2013; 33: 280-281
• 153 Ait-Daoud N, Lynch WJ, Penberthy JK et al. Treating smoking dependence in depressed alcoholics. Alcohol Res Health 2006; 29: 213-220
• 154 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; 22: 453-459
• 155 Mitchell JM, Teague CH, Kayser AS et al. Varenicline decreases alcohol consumption in heavy-drinking smokers. Psychopharmacology (Berl) 2012; 223: 299-306
• 156 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; 36: 906-914
• 157 Fucito LM, Toll BA, Wu R et al. A preliminary investigation of varenicline for heavy drinking smokers. Psychopharmacology (Berl) 2011; 215: 655-663
• 158 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; 40: 102-107
• 159 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; 7: 277-286
• 160 McKee SA, Harrison EL, O’Malley SS et al. Varenicline reduces alcohol self-administration in heavy-drinking smokers. Biol Psychiatry 2009; 66: 185-190
• 161 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; 33: 243-247
• 162 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; 133: 754-758
• 163 Plebani JG, Lynch KG, Yu Q et al. Results of an initial clinical trial of varenicline for the treatment of cocaine dependence. Drug Alcohol Depend 2012; 121: 163-166
• 164 Erwin BL, Slaton RM. Varenicline in the treatment of alcohol use disorders. Ann Pharmacother 2014; 48: 1445-1455
• 165 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; 20: 69-79
• 166 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; 21: 205-210
• 167 Steensland P, Simms JA, Holgate J et al. Varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, selectively decreases ethanol consumption and seeking. Proc Natl Acad Sci USA 2007; 104: 12518-12523
• 168 Foulds J, Steinberg MB, Williams JM et al. Developments in pharmacotherapy for tobacco dependence: past, present and future. Drug Alcohol Rev 2006; 25: 59-71
• 169 Steinberg MB, Bover MT, Richardson DL et al. Abstinence and psychological distress in co-morbid smokers using various pharmacotherapies. Drug Alcohol Depend 2011; 114: 77-81
• 170 Keating GM. Sodium oxybate: a review of its use in alcohol withdrawal syndrome and in the maintenance of abstinence in alcohol dependence. Clin Drug Investig 2014; 34: 63-80
• 171 Skala K, Caputo F, Mirijello A et al. Sodium oxybate in the treatment of alcohol dependence: from the alcohol withdrawal syndrome to the alcohol relapse prevention. Expert Opin Pharmacother 2014; 15: 245-257
• 172 World Health Organization . Gamma-hydroxybutyric acid (GHB). Critical Review Report. Expert Committee on Drug Dependence 35^th Meeting, Hammamet, Tunisia, 4–8 June 2012. Available from: http://www.who.int/medicines/areas/quality_safety/4.1GHBcritical_review.pdf
• 173 Maccioni P, Colombo G, Carai MA. Blockade of the cannabinoid CB1 receptor and alcohol dependence: preclinical evidence and preliminary clinical data. CNS Neurol Disord Drug Targets 2010; 9: 55-59
• 174 Soyka M, Koller G, Schmidt P et al. Cannabinoid receptor 1 blocker rimonabant (SR 141716) for treatment of alcohol dependence: results from a placebo-controlled, double-blind trial. J Clin Psychopharmacol 2008; 28: 317-324
• 175 Vasiljevik T, Franks LN, Ford BM et al. Design, synthesis, and biological evaluation of aminoalkylindole derivatives as cannabinoid receptor ligands with potential for treatment of alcohol abuse. J Med Chem 2013; 56: 4537-4550
• 176 Edwards S, Kenna GA, Swift RM et al. Current and promising pharmacotherapies, and novel research target areas in the treatment of alcohol dependence: a review. Curr Pharm Des 2011; 17: 1323-1332
• 177 Johnson BA, Roache JD, Javors MA et al. Ondansetron for reduction of drinking among biologically predisposed alcoholic patients: A randomized controlled trial. JAMA 2000; 284: 963-971
• 178 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; 28: 5-12
• 179 Emsley E, Lees R, Lingford-Hughes A et al. A review of stress and endogenous opioid interaction in alcohol addiction. J Neurol Neurosurg Psychiatry 2013; 84: e1
• 180 Heilig M, Koob GF. A key role for corticotropin-releasing factor in alcohol dependence. Trends Neurosci 2007; 30: 399-406
• 181 Voronin K, Randall P, Myrick H et al. Aripiprazole effects on alcohol consumption and subjective reports in a clinical laboratory paradigm – possible influence of self-control. Alcohol Clin Exp Res 2008; 32: 1954-1961
• 182 Zorrilla EP, Heilig M, de Wit H et al. Behavioral, biological, and chemical perspectives on targeting CRF(1) receptor antagonists to treat alcoholism. Drug Alcohol Depend 2013; 128: 175-186
• 183 Caputo F, Vignoli T, Grignaschi A et al. Pharmacological management of alcohol dependence: from mono-therapy to pharmacogenetics and beyond. Eur Neuropsychopharmacol 2014; 24: 181-191
• 184 Bond C, LaForge KS, Tian M et al. Single-nucleotide polymorphism in the human mu opioid receptor gene alters beta-endorphin binding and activity: possible implications for opiate addiction. Proc Natl Acad Sci USA 1998; 95: 9608-9613
• 185 Ashenhurst JR, Bujarski S, Ray LA. Delta and kappa opioid receptor polymorphisms influence the effects of naltrexone on subjective responses to alcohol. Pharmacol Biochem Behav 2012; 103: 253-259
• 186 Schacht JP, Anton RF, Voronin KE et al. Interacting effects of naltrexone and OPRM1 and DAT1 variation on the neural response to alcohol cues. Neuropsychopharmacology 2013; 38: 414-422
• 187 Setiawan E, Pihl RO, Benkelfat C et al. Influence of the OPRM1 A118G polymorphism on alcohol-induced euphoria, risk for alcoholism and the clinical efficacy of naltrexone. Pharmacogenomics 2012; 13: 1161-1172
• 188 Anton RF, Oroszi G, O'Malley S et al. An evaluation of mu-opioid receptor (OPRM1) as a predictor of naltrexone response in the treatment of alcohol dependence: results from the Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence (COMBINE) study. Arch Gen Psychiatry 2008; 65: 135-144
• 189 Anton RF, Voronin KK, Randall PK et al. Naltrexone modification of drinking effects in a subacute treatment and bar-lab paradigm: influence of OPRM1 and dopamine transporter (SLC6A3) genes. Alcohol Clin Exp Res 2012; 36: 2000-2007
• 190 Gelernter J, Gueorguieva R, Kranzler HR et al. Opioid receptor gene (OPRM1, OPRK1, and OPRD1) variants and response to naltrexone treatment for alcohol dependence: results from the VA Cooperative Study. Alcohol Clin Exp Res 2007; 31: 555-563
• 191 Kim SG, Kim CM, Choi SW et al. A micro opioid receptor gene polymorphism (A118G) and naltrexone treatment response in adherent Korean alcohol-dependent patients. Psychopharmacology (Berl) 2009; 201: 611-618
• 192 Koller G, Zill P, Rujescu D et al. Possible association between OPRM1 genetic variance at the 118 locus and alcohol dependence in a large treatment sample: relationship to alcohol dependence symptoms. Alcohol Clin Exp Res 2012; 36: 1230-1236
• 193 Kranzler HR, Armeli S, Covault J et al. Variation in OPRM1 moderates the effect of desire to drink on subsequent drinking and its attenuation by naltrexone treatment. Addict Biol 2013; 18: 193-201
• 194 McGeary JE, Monti PM, Rohsenow DJ et al. Genetic moderators of naltrexone’s effects on alcohol cue reactivity. Alcohol Clin Exp Res 2006; 30: 1288-1296
• 195 Oroszi G, Anton RF, O’Malley S et al. OPRM1 Asn40Asp predicts response to naltrexone treatment: a haplotype-based approach. Alcohol Clin Exp Res 2009; 33: 383-393
• 196 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; 28: 1546-1552
• 197 Anton RF, Oroszi G, O’Malley S et al. An evaluation of mu-opioid receptor (OPRM1) as a predictor of naltrexone response in the treatment of alcohol dependence: results from the Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence (COMBINE) study. Arch Gen Psychiatry 2008; 65: 135-144
• 198 Anton RF, Voronin KK, Randall PK et al. Naltrexone modification of drinking effects in a subacute treatment and bar-lab paradigm: influence of OPRM1 and dopamine transporter (SLC6A3) genes. Alcohol Clin Exp Res 2012; 36: 2000-2007
• 199 Gelernter J, Gueorguieva R, Kranzler HR et al. Opioid receptor gene (OPRM1, OPRK1, and OPRD1) variants and response to naltrexone treatment for alcohol dependence: results from the VA Cooperative Study. Alcohol Clin Exp Res 2007; 31: 555-563
• 200 Kim SG, Kim CM, Choi SW et al. A micro opioid receptor gene polymorphism (A118G) and naltrexone treatment response in adherent Korean alcohol-dependent patients. Psychopharmacology (Berl) 2009; 201: 611-618
• 201 Koller G, Zill P, Rujescu D et al. Possible association between OPRM1 genetic variance at the 118 locus and alcohol dependence in a large treatment sample: relationship to alcohol dependence symptoms. Alcohol Clin Exp Res 2012; 36: 1230-1236
• 202 Kranzler HR, Armeli S, Covault J et al. Variation in OPRM1 moderates the effect of desire to drink on subsequent drinking and its attenuation by naltrexone treatment. Addict Biol 2013; 18: 193-201
• 203 McGeary JE, Monti PM, Rohsenow DJ et al. Genetic moderators of naltrexone’s effects on alcohol cue reactivity. Alcohol Clin Exp Res 2006; 30: 1288-1296
• 204 Oroszi G, Anton RF, O'Malley S et al. OPRM1 Asn40Asp predicts response to naltrexone treatment: a haplotype-based approach. Alcohol Clin Exp Res 2009; 33: 383-393
• 205 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; 28: 1546-1552
• 206 Chamorro AJ, Marcos M, Miron-Canelo JA et al. Association of micro-opioid receptor (OPRM1) gene polymorphism with response to naltrexone in alcohol dependence: a systematic review and meta-analysis. Addict Biol 2012; 17: 505-512
• 207 Arias AJ, Armeli S, Gelernter J et al. Effects of opioid receptor gene variation on targeted nalmefene treatment in heavy drinkers. Alcohol Clin Exp Res 2008; 32: 1159-1166
• 208 Kranzler HR, Armeli S, Feinn R et al. GRIK1 genotype moderates topiramate’s effects on daily drinking level, expectations of alcohol’s positive effects and desire to drink. Int J Neuropsychopharmacol 2014; 17: 1549-1556
• 209 Kranzler HR, Covault J, Feinn R et al. Topiramate treatment for heavy drinkers: moderation by a GRIK1 polymorphism. Am J Psychiatry 2014; 171: 445-452
• 210 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; 168: 265-275