Skip to main content
SpringerLink
Log in

Anticonvulsants for the Treatment of Alcohol Withdrawal Syndrome and Alcohol Use Disorders

  • Review Article
  • Published:
CNS Drugs Aims and scope Submit manuscript

Abstract

Alcoholic patients suffer from harmful allostatic neuroplastic changes in the brain causing an acute withdrawal syndrome upon cessation of drinking followed by a protracted abstinence syndrome and an increased risk of relapse to heavy drinking. Benzodiazepines have long been the treatment of choice for detoxifying patients and managing alcohol withdrawal syndrome (AWS). Non-benzodiazepine anticonvulsants (NBACs) are increasingly being used both for alcohol withdrawal management and for ongoing outpatient treatment of alcohol dependence, with the goal of either abstinence or harm reduction. This expert narrative review summarizes the scientific basis and clinical evidence supporting the use of NBACs in treating AWS and for reducing harmful drinking patterns. There is less evidence in support of NBAC therapy for AWS, with few placebo-controlled trials. Carbamazepine and gabapentin appear to be the most promising adjunctive treatments for AWS, and they may be useful as monotherapy in select cases, especially in outpatient settings and for the treatment of mild-to-moderate low-risk patients with the AWS. The body of evidence supporting the use of the NBACs for reducing harmful drinking in the outpatient setting is stronger. Topiramate appears to have a robust effect on reducing harmful drinking in alcoholics. Gabapentin is a potentially efficacious treatment for reducing the risk of relapse to harmful drinking patterns in outpatient management of alcoholism. Gabapentin’s ease of use, rapid titration, good tolerability, and efficacy in both the withdrawal and chronic phases of treatment make it particularly appealing. In summary, several NBACs appear to be beneficial in treating AWS and alcohol use disorders.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Notes

  1. The term ‘reversibility’ refers to whether the drug binds but is capable of dissociating from the enzyme, or whether it permanently binds the enzyme, thus essentially destroying it. The term ‘selectivity’ refers to whether or not the drug affects either or both MAO-A and MAO-B enzymes.

References

  1. Harwood H. Updating estimates of the economic costs of alcohol abuse in the United States: estimates, update methods, and data. In: National Institute on Alcohol Abuse and Alcoholism (NIAAA), editor. Report prepared by The Lewin Group for the National Institute on Alcohol Abuse and Alcoholism. Rockville: NIAAA; 2000.

  2. Hasin DS, Stinson FS, Ogburn E, Grant BF. 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(7):830–42.

    PubMed  Google Scholar 

  3. World Health Organization, Management of Substance Abuse Team. Global status report on alcohol and health, 2014. http://apps.who.int/iris/bitstream/10665/112736/1/9789240692763_eng.pdf?ua=1. Accessed 20 Aug 2014.

  4. World Health Organization, Management of Substance Abuse Team. Global status report on alcohol and health. Geneva: World Health Organization; 2011.

    Google Scholar 

  5. Koob GF. Alcoholism: allostasis and beyond. Alcohol Clin Exp Res. 2003;27(2):232–43.

    CAS  PubMed  Google Scholar 

  6. Schuckit MA. Alcohol-use disorders. Lancet. 2009;373(9662):492–501.

    PubMed  Google Scholar 

  7. De Witte P, Pinto E, Ansseau M, Verbanck P. Alcohol and withdrawal: from animal research to clinical issues. Neurosci Biobehav Rev. 2003;27(3):189–97.

    PubMed  Google Scholar 

  8. Addolorato G, Leggio L, Hopf FW, Diana M, Bonci A. Novel therapeutic strategies for alcohol and drug addiction: focus on GABA, ion channels and transcranial magnetic stimulation. Neuropsychopharmacology. 2012;37(1):163–77.

    PubMed Central  CAS  PubMed  Google Scholar 

  9. Holmes A, Spanagel R, Krystal JH. Glutamatergic targets for new alcohol medications. Psychopharmacology (Berl). 2013;229(3):539–54.

    CAS  PubMed  Google Scholar 

  10. Niciu MJ, Mason GF. Neuroimaging in alcohol and drug dependence. Curr Behav Neurosci Rep. 2014;1(1):45–54.

    PubMed Central  PubMed  Google Scholar 

  11. Krystal JH, Staley J, Mason G, Petrakis IL, Kaufman J, Harris RA, et al. Gamma-aminobutyric acid type A receptors and alcoholism: intoxication, dependence, vulnerability, and treatment. Arch Gen Psychiatry. 2006;63(9):957–68.

    CAS  PubMed  Google Scholar 

  12. Hermann D, Weber-Fahr W, Sartorius A, Hoerst M, Frischknecht U, Tunc-Skarka N, et al. Translational magnetic resonance spectroscopy reveals excessive central glutamate levels during alcohol withdrawal in humans and rats. Biol Psychiatry. 2012;71(11):1015–21.

    CAS  PubMed  Google Scholar 

  13. Book SW, Myrick H. Novel anticonvulsants in the treatment of alcoholism. Expert Opin Investig Drugs. 2005;14(4):371–6.

    CAS  PubMed  Google Scholar 

  14. White HS, Smith MD, Wilcox KS. Mechanisms of action of antiepileptic drugs. Int Rev Neurobiol. 2007;81:85–110.

    CAS  PubMed  Google Scholar 

  15. Mayo-Smith MF. Pharmacological management of alcohol withdrawal. A meta-analysis and evidence-based practice guideline. American Society of Addiction Medicine Working Group on Pharmacological Management of Alcohol Withdrawal. JAMA. 1997;278(2):144–51.

    CAS  PubMed  Google Scholar 

  16. Miller WR, Wilbourne PL. Mesa Grande: a methodological analysis of clinical trials of treatments for alcohol use disorders. Addiction. 2002;97(3):265–77.

    PubMed  Google Scholar 

  17. Benzer DG. Management of alcohol intoxication and withdrawal. American Society of Addiction Medicine. Principles of Addiction Medicine. Chevy Chase: American Society of Addiction Medicine; 1994.

    Google Scholar 

  18. Becker HC. Kindling in alcohol withdrawal. Alcohol Health ResWorld. 1998;22(1):25–33.

    CAS  Google Scholar 

  19. Minozzi S, Amato L, Vecchi S, Davoli M. Anticonvulsants for alcohol withdrawal. Cochrane Database Syst Rev. 2010;(3):CD005064.

  20. Chance JF. Emergency department treatment of alcohol withdrawal seizures with phenytoin. Ann Emerg Med. 1991;20(5):520–2.

    CAS  PubMed  Google Scholar 

  21. Rathlev NK, D’Onofrio G, Fish SS, Harrison PM, Bernstein E, Hossack RW, et al. The lack of efficacy of phenytoin in the prevention of recurrent alcohol-related seizures. Ann Emerg Med. 1994;23(3):513–8.

    CAS  PubMed  Google Scholar 

  22. Ambrosio AF, Soares-Da-Silva P, Carvalho CM, Carvalho AP. Mechanisms of action of carbamazepine and its derivatives, oxcarbazepine, BIA 2-093, and BIA 2-024. Neurochem Res. 2002;27(1–2):121–30.

    CAS  PubMed  Google Scholar 

  23. Granger P, Biton B, Faure C, Vige X, Depoortere H, Graham D, et al. Modulation of the gamma-aminobutyric acid type A receptor by the antiepileptic drugs carbamazepine and phenytoin. Mol Pharmacol. 1995;47(6):1189–96.

    CAS  PubMed  Google Scholar 

  24. Barrons R, Roberts N. The role of carbamazepine and oxcarbazepine in alcohol withdrawal syndrome. J Clin Pharmacy Ther. 2010;35(2):153–67.

    CAS  Google Scholar 

  25. Stuppaeck CH, Pycha R, Miller C, Whitworth AB, Oberbauer H, Fleischhacker WW. Carbamazepine versus oxazepam in the treatment of alcohol withdrawal: a double-blind study. Alcohol Alcohol. 1992;27(2):153–8.

    CAS  PubMed  Google Scholar 

  26. Ritola E, Malinen L. A double-blind comparison of carbamazepine and clomethiazole in the treatment of alcohol withdrawal syndrome. Acta Psychiatr Scand. 1981;64(3):254–9.

    CAS  PubMed  Google Scholar 

  27. Malcolm R, Myrick H, Roberts J, Wang W, Anton RF, Ballenger JC. The effects of carbamazepine and lorazepam on single versus multiple previous alcohol withdrawals in an outpatient randomized trial. J Gen Intern Med. 2002;17(5):349–55.

    PubMed Central  CAS  PubMed  Google Scholar 

  28. Malcolm R, Ballenger JC, Sturgis ET, Anton R. Double-blind controlled trial comparing carbamazepine to oxazepam treatment of alcohol withdrawal. Am J Psychiatry. 1989;146(5):617–21.

    CAS  PubMed  Google Scholar 

  29. Lucht M, Kuehn KU, Armbruster J, Abraham G, Gaensicke M, Barnow S, et al. Alcohol withdrawal treatment in intoxicated vs non-intoxicated patients: a controlled open-label study with tiapride/carbamazepine, clomethiazole and diazepam. Alcohol Alcohol. 2003;38(2):168–75.

  30. Kalyoncu OA, Beyazyurek M, Kuru L, Solukcu R, Yazman U. Double-blind comparative trial with carbamazepine vs diazepam treatment of alcohol withdrawal. Eur Neuropsychopharmacol. 1996;6(4):1–2.

    Google Scholar 

  31. Hillbom M, Tokola R, Kuusela V, Karkkainen P, Kalli-Lemma L, Pilke A, et al. Prevention of alcohol withdrawal seizures with carbamazepine and valproic acid. Alcohol. 1989;6(3):223–6.

  32. Bjorkqvist SE, Isohanni M, Makela R, Malinen L. Ambulant treatment of alcohol withdrawal symptoms with carbamazepine: a formal multicentre double-blind comparison with placebo. Acta Psychiatr Scand. 1976;53(5):333–42.

    CAS  PubMed  Google Scholar 

  33. Koethe D, Juelicher A, Nolden BM, Braunwarth WD, Klosterkotter J, Niklewski G, et al. Oxcarbazepine–efficacy and tolerability during treatment of alcohol withdrawal: a double-blind, randomized, placebo-controlled multicenter pilot study. Alcohol Clin Exp Res. 2007;31(7):1188–94.

    CAS  PubMed  Google Scholar 

  34. Schik G, Wedegaertner FR, Liersch J, Hoy L, Emrich HM, Schneider U. Oxcarbazepine versus carbamazepine in the treatment of alcohol withdrawal. Addict Biol. 2005;10(3):283–8.

    CAS  PubMed  Google Scholar 

  35. Rosenberg G. The mechanisms of action of valproate in neuropsychiatric disorders: can we see the forest for the trees? Cell Mol LifeSci. 2007;64(16):2090–103.

    CAS  Google Scholar 

  36. Lum E, Gorman SK, Slavik RS. Valproic acid management of acute alcohol withdrawal. Ann Pharmacother. 2006;40(3):441–8.

    CAS  PubMed  Google Scholar 

  37. Reoux JP, Saxon AJ, Malte CA, Baer JS, Sloan KL. Divalproex sodium in alcohol withdrawal: a randomized double-blind placebo-controlled clinical trial. Alcohol Clin Exp Res. 2001;25(9):1324–9.

    CAS  PubMed  Google Scholar 

  38. Sills GJ. The mechanisms of action of gabapentin and pregabalin. Curr Opin Pharmacol. 2006;6(1):108–13.

    CAS  PubMed  Google Scholar 

  39. Bonnet U, Banger M, Leweke FM, Maschke M, Kowalski T, Gastpar M. Treatment of alcohol withdrawal syndrome with gabapentin. Pharmacopsychiatry. 1999;32(3):107–9.

    CAS  PubMed  Google Scholar 

  40. Mariani JJ, Rosenthal RN, Tross S, Singh P, Anand OP. A randomized, open-label, controlled trial of gabapentin and phenobarbital in the treatment of alcohol withdrawal. Am J Addict. 2006;15(1):76–84.

  41. Myrick H, Malcolm R, Randall PK, Boyle E, Anton RF, Becker HC, et al. A double-blind trial of gabapentin versus lorazepam in the treatment of alcohol withdrawal. Alcohol Clin Exp Res. 2009;33(9):1582–8.

    PubMed Central  CAS  PubMed  Google Scholar 

  42. Stock CJ, Carpenter L, Ying J, Greene T. Gabapentin versus chlordiazepoxide for outpatient alcohol detoxification treatment. Ann Pharmacother. 2013;47(7–8):961–9.

  43. Bonnet U, Hamzavi-Abedi R, Specka M, Wiltfang J, Lieb B, Scherbaum N. An open trial of gabapentin in acute alcohol withdrawal using an oral loading protocol. Alcohol Alcohol. 2010;45(2):143–5.

  44. Di Nicola M, Martinotti G, Tedeschi D, Frustaci A, Mazza M, Sarchiapone M, et al. Pregabalin in outpatient detoxification of subjects with mild-to-moderate alcohol withdrawal syndrome. Hum Psychopharmacol. 2010;25(3):268–75.

    PubMed  Google Scholar 

  45. Martinotti G, di Nicola M, Frustaci A, Romanelli R, Tedeschi D, Guglielmo R, et al. Pregabalin, tiapride and lorazepam in alcohol withdrawal syndrome: a multi-centre, randomized, single-blind comparison trial. Addiction. 2010;105(2):288–99.

    PubMed  Google Scholar 

  46. Forg A, Hein J, Volkmar K, Winter M, Richter C, Heinz A, et al. Efficacy and safety of pregabalin in the treatment of alcohol withdrawal syndrome: a randomized placebo-controlled trial. Alcohol Alcohol. 2012;47(2):149–55.

  47. Richter C, Hinzpeter A, Schmidt F, Kienast T, Preuss UW, Plenge T, et al. Levetiracetam for the treatment of alcohol withdrawal syndrome: a multicenter, prospective, randomized, placebo-controlled trial. J Clin Psychopharmacol. 2010;30(6):720–5.

    CAS  PubMed  Google Scholar 

  48. Vogl C, Mochida S, Wolff C, Whalley BJ, Stephens GJ. The synaptic vesicle glycoprotein 2A ligand levetiracetam inhibits presynaptic Ca2+ channels through an intracellular pathway. Mol Pharmacol. 2012;82(2):199–208.

    CAS  PubMed  Google Scholar 

  49. White HS. Mechanism of action of newer anticonvulsants. J Clin Psychiatry. 2003;64(Suppl 8):5–8.

    CAS  PubMed  Google Scholar 

  50. Perucca E. Clinical pharmacology and therapeutic use of the new antiepileptic drugs. Fundam Clin Pharmacol. 2001;15(6):405–17.

    CAS  PubMed  Google Scholar 

  51. McElroy SL, Kotwal R, Hudson JI, Nelson EB, Keck PE. Zonisamide in the treatment of binge-eating disorder: an open-label, prospective trial. J Clin Psychiatry. 2004;65(1):50–6.

    CAS  PubMed  Google Scholar 

  52. Ueda Y, Doi T, Tokumaru J, Willmore LJ. Effect of zonisamide on molecular regulation of glutamate and GABA transporter proteins during epileptogenesis in rats with hippocampal seizures. Brain Res Mol Brain Res. 2003;116(1–2):1–6.

  53. Okada M, Kaneko S, Hirano T, Mizuno K, Kondo T, Otani K, et al. Effects of zonisamide on dopaminergic system. Epilepsy Res. 1995;22(3):193–205.

    CAS  PubMed  Google Scholar 

  54. Okada M, Hirano T, Kawata Y, Murakami T, Wada K, Mizuno K, et al. Biphasic effects of zonisamide on serotonergic system in rat hippocampus. Epilepsy Res. 1999;34(2–3):187–97.

    CAS  PubMed  Google Scholar 

  55. Asanuma M, Miyazaki I, Diaz-Corrales FJ, Kimoto N, Kikkawa Y, Takeshima M, et al. Neuroprotective effects of zonisamide target astrocyte. Ann Neurol. 2010;67(2):239–49.

    CAS  PubMed  Google Scholar 

  56. Sonsalla PK, Wong LY, Winnik B, Buckley B. The antiepileptic drug zonisamide inhibits MAO-B and attenuates MPTP toxicity in mice: clinical relevance. Exp Neurol. 2010;221(2):329–34.

    PubMed Central  CAS  PubMed  Google Scholar 

  57. Krupitsky EM, Rudenko AA, Burakov AM, Slavina TY, Grinenko AA, Pittman B, et al. Antiglutamatergic strategies for ethanol detoxification: comparison with placebo and diazepam. Alcohol Clin Exp Res. 2007;31(4):604–11.

    CAS  PubMed  Google Scholar 

  58. Choi E, Ki SW, Kim SE, Kim JW, Park JK. The efficacy and safety of topiramate in the treatment of alcohol withdrawal. J Korean Neuropsychiatr Assoc. 2005;44(3):328–33.

    Google Scholar 

  59. Rustembegovic A, Sofic E, Kroyer G. A pilot study of Topiramate (Topamax) in the treatment of tonic-clonic seizures of alcohol withdrawal syndromes. Med Arhiv. 2002;56(4):211–2.

    PubMed  Google Scholar 

  60. Rubio G, Lopez-Munoz F, Ponce G, Pascual JM, Martinez-Gras I, Ferre F, et al. Zonisamide versus diazepam in the treatment of alcohol withdrawal syndrome. Pharmacopsychiatry. 2010;43(7):257–62.

    CAS  PubMed  Google Scholar 

  61. Tzschentke TM, Schmidt WJ. Glutamatergic mechanisms in addiction. Mol Psychiatry. 2003;8(4):373–82.

    CAS  PubMed  Google Scholar 

  62. Minuk GY, Rockman GE, German GB, Duerksen DR, Borrett G, Hoeschen L. The use of sodium valproate in the treatment of alcoholism. J Addict Dis. 1995;14(2):67–74.

    CAS  PubMed  Google Scholar 

  63. Brady KT, Myrick H, Henderson S, Coffey SF. The use of divalproex in alcohol relapse prevention: a pilot study. Drug Alcohol Depend. 2002;67(3):323–30.

    CAS  PubMed  Google Scholar 

  64. Brady KT, Myrick H, Henderson S, Coffey SF. The use of divalproex in alcohol relapse prevention: a pilot study. Drug Alcohol Depend. 2002;67(3):323–30.

    CAS  PubMed  Google Scholar 

  65. Salloum IM, Cornelius JR, Daley DC, Kirisci L, Himmelhoch JM, Thase ME. Efficacy of valproate maintenance in patients with bipolar disorder and alcoholism: a double-blind placebo-controlled study. Arch Gen Psychiatry. 2005;62(1):37–45.

    CAS  PubMed  Google Scholar 

  66. Kemp DE, Gao K, Ganocy SJ, Elhaj O, Bilali SR, Conroy C, et al. A 6-month, double-blind, maintenance trial of lithium monotherapy versus the combination of lithium and divalproex for rapid-cycling bipolar disorder and Co-occurring substance abuse or dependence. J Clin Psychiatry. 2009;70(1):113–21.

    PubMed Central  CAS  PubMed  Google Scholar 

  67. Mueller TI, Stout RL, Rudden S, Brown RA, Gordon A, Solomon DA, et al. A double-blind, placebo-controlled pilot study of carbamazepine for the treatment of alcohol dependence. Alcohol Clin Exp Res. 1997;21(1):86–92.

    CAS  PubMed  Google Scholar 

  68. Croissant B, Diehl A, Klein O, Zambrano S, Nakovics H, Heinz A, et al. A pilot study of oxcarbazepine versus acamprosate in alcohol-dependent patients. Alcohol Clin Exp Res. 2006;30(4):630–5.

    CAS  PubMed  Google Scholar 

  69. Martinotti G, Di Nicola M, Romanelli R, Andreoli S, Pozzi G, Moroni N, et al. High and low dosage oxcarbazepine versus naltrexone for the prevention of relapse in alcohol-dependent patients. Hum Psychopharmacol. 2007;22(3):149–56.

    CAS  PubMed  Google Scholar 

  70. Kalyoncu A, Mirsal H, Pektas O, Unsalan N, Tan D, Beyazyurek M. Use of lamotrigine to augment clozapine in patients with resistant schizophrenia and comorbid alcohol dependence: a potent anti-craving effect? J Psychopharmacol. 2005;19(3):301–5.

    CAS  PubMed  Google Scholar 

  71. Pollack MH, Roy-Byrne PP, Van Ameringen M, Snyder H, Brown C, Ondrasik J, et al. The selective GABA reuptake inhibitor tiagabine for the treatment of generalized anxiety disorder: results of a placebo-controlled study. J Clin Psychiatry. 2005;66(11):1401–8.

    CAS  PubMed  Google Scholar 

  72. Paparrigopoulos T, Tzavellas E, Karaiskos D, Malitas P, Liappas I. An open pilot study of tiagabine in alcohol dependence: tolerability and clinical effects. J Psychopharmacol. 2010;24(9):1375–80.

    CAS  PubMed  Google Scholar 

  73. Fehr C, Hohmann N, Grunder G, Dielentheis TF, Buchholz HG, Chechko N, et al. Tiagabine does not attenuate alcohol-induced activation of the human reward system. Psychopharmacology (Berl). 2007;191(4):975–83.

    CAS  PubMed  Google Scholar 

  74. Sarid-Segal O, Piechniczek-Buczek J, Knapp C, Afshar M, Devine E, Sickles L, et al. The effects of levetiracetam on alcohol consumption in alcohol-dependent subjects: an open label study. Am J Drug Alcohol Abuse. 2008;34(4):441–7.

    PubMed  Google Scholar 

  75. Zalewska-Kaszubska J, Bajer B, Czarnecka E, Dyr W, Gorska D. Voluntary alcohol consumption and plasma beta-endorphin levels in alcohol preferring rats chronically treated with levetiracetam: a preliminary study. Physiol Behav. 2011;102(5):538–41.

    CAS  PubMed  Google Scholar 

  76. Mariani JJ, Levin FR. Levetiracetam for the treatment of co-occurring alcohol dependence and anxiety: case series and review. Am J Drug Alcohol Abuse. 2008;34(6):683–91.

    PubMed Central  PubMed  Google Scholar 

  77. Fertig JB, Ryan ML, Falk DE, Litten RZ, Mattson ME, Ransom J, et al. A double-blind, placebo-controlled trial assessing the efficacy of levetiracetam extended-release in very heavy drinking alcohol-dependent patients. Alcohol Clin Exp Res. 2012;36(8):1421–30.

    PubMed Central  CAS  PubMed  Google Scholar 

  78. Mitchell JM, Grossman LE, Coker AR, Messing RO. The anticonvulsant levetiracetam potentiates alcohol consumption in non-treatment seeking alcohol abusers. J Clin Psychopharmacol. 2012;32(2):269–72.

    CAS  PubMed  Google Scholar 

  79. Richter C, Effenberger S, Bschor T, Bonnet U, Haasen C, Preuss UW, et al. Efficacy and safety of levetiracetam for the prevention of alcohol relapse in recently detoxified alcohol-dependent patients: a randomized trial. J Clin Psychopharmacol. 2012;32(4):558–62.

    CAS  PubMed  Google Scholar 

  80. Le Strat Y. Levetiracetam in the treatment of alcohol dependence: toward the end of the story? Alcohol Clin Exp Res. 2012;36(8):1309–10.

    PubMed  Google Scholar 

  81. Knapp CM, Ciraulo DA, Sarid-Segal O, Richardson MA, Devine E, Streeter CC, et al. Zonisamide, topiramate, and levetiracetam: efficacy and neuropsychological effects in alcohol use disorders. J Clin Psychopharmacol. 2015;35(1):34–42.

    PubMed Central  CAS  PubMed  Google Scholar 

  82. Karam-Hage M, Brower KJ. Gabapentin treatment for insomnia associated with alcohol dependence. Am J Psychiatry. 2000;157(1):151.

    CAS  PubMed  Google Scholar 

  83. Karam-Hage M, Brower KJ. Open pilot study of gabapentin versus trazodone to treat insomnia in alcoholic outpatients. Psychiatry Clin Neurosci. 2003;57(5):542–4.

    PubMed Central  CAS  PubMed  Google Scholar 

  84. Brower KJ, Myra Kim H, Strobbe S, Karam-Hage MA, Consens F, Zucker RA. A randomized double-blind pilot trial of gabapentin versus placebo to treat alcohol dependence and comorbid insomnia. Alcohol Clin Exp Res. 2008;32(8):1429–38.

    PubMed Central  CAS  PubMed  Google Scholar 

  85. Bisaga A, Evans SM. The acute effects of gabapentin in combination with alcohol in heavy drinkers. Drug Alcohol Depend. 2006;83(1):25–32.

    CAS  PubMed  Google Scholar 

  86. Myrick H, Anton R, Voronin K, Wang W, Henderson S. A double-blind evaluation of gabapentin on alcohol effects and drinking in a clinical laboratory paradigm. Alcohol Clin Exp Res. 2007;31(2):221–7.

    CAS  PubMed  Google Scholar 

  87. Furieri FA, Nakamura-Palacios EM. Gabapentin reduces alcohol consumption and craving: a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry. 2007;68(11):1691–700.

    CAS  PubMed  Google Scholar 

  88. Mason BJ, Quello S, Goodell V, Shadan F, Kyle M, Begovic A. Gabapentin treatment for alcohol dependence: a randomized clinical trial. JAMA InternMed. 2014;174(1):70–7.

    CAS  Google Scholar 

  89. Anton RF, Myrick H, Baros AM, Latham PK, Randall PK, Wright TM, 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;29(4):334–42.

    CAS  PubMed  Google Scholar 

  90. Anton RF, Myrick H, Wright TM, Latham PK, Baros AM, Waid LR, et al. Gabapentin combined with naltrexone for the treatment of alcohol dependence. Am J Psychiatry. 2011;168(7):709–17.

    PubMed Central  PubMed  Google Scholar 

  91. Martinotti G, Di Nicola M, Tedeschi D, Andreoli S, Reina D, Pomponi M, et al. Pregabalin versus naltrexone in alcohol dependence: a randomised, double-blind, comparison trial. J Psycho pharmacol. 2010;24(9):1367–74.

    CAS  Google Scholar 

  92. Johnson BA, Ait-Daoud N, Bowden CL, DiClemente CC, Roache JD, Lawson K, et al. Oral topiramate for treatment of alcohol dependence: a randomised controlled trial. Lancet. 2003;361(9370):1677–85.

    CAS  PubMed  Google Scholar 

  93. Johnson BA, Ait-Daoud N, Akhtar FZ, Ma JZ. 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(9):905–12.

    CAS  PubMed  Google Scholar 

  94. Johnson BA, Ait-Daoud N, Akhtar FZ, Javors MA. Use of oral topiramate to promote smoking abstinence among alcohol-dependent smokers: a randomized controlled trial. Arch Intern Med. 2005;165(14):1600–5.

    CAS  PubMed  Google Scholar 

  95. Johnson BA, Rosenthal N, Capece JA, Wiegand F, Mao L, Beyers K, et al. Topiramate for treating alcohol dependence: a randomized controlled trial. JAMA. 2007;298(14):1641–51.

    CAS  PubMed  Google Scholar 

  96. Johnson BA, Rosenthal N, Capece JA, Wiegand F, Mao L, Beyers K, et al. Improvement of physical health and quality of life of alcohol-dependent individuals with topiramate treatment: US multisite randomized controlled trial. Arch Intern Med. 2008;168(11):1188–99.

    CAS  PubMed  Google Scholar 

  97. De Sousa AA, De Sousa J, Kapoor H. An open randomized trial comparing disulfiram and topiramate in the treatment of alcohol dependence. J Subst Abuse Treat. 2008;34(4):460–3.

    PubMed  Google Scholar 

  98. Florez G, Garcia-Portilla P, Alvarez S, Saiz PA, Nogueiras L, Bobes J. Using topiramate or naltrexone for the treatment of alcohol-dependent patients. Alcohol Clin Exp Res. 2008;32(7):1251–9.

    CAS  PubMed  Google Scholar 

  99. Baltieri DA, Daro FR, Ribeiro PL, de Andrade AG. Comparing topiramate with naltrexone in the treatment of alcohol dependence. Addiction. 2008;103(12):2035–44.

    PubMed  Google Scholar 

  100. Florez G, Saiz PA, Garcia-Portilla P, Alvarez S, Nogueiras L, Bobes J. Topiramate for the treatment of alcohol dependence: comparison with naltrexone. Eur Addict Res. 2011;17(1):29–36.

    PubMed  Google Scholar 

  101. Johnson BA, Ait-Daoud N. Topiramate in the new generation of drugs: efficacy in the treatment of alcoholic patients. Curr Pharm Des. 2010;16(19):2103–12.

    PubMed Central  CAS  PubMed  Google Scholar 

  102. Paparrigopoulos T, Tzavellas E, Karaiskos D, Kourlaba G, Liappas I. Treatment of alcohol dependence with low-dose topiramate: an open-label controlled study. BMC Psychiatry. 2011;11:41.

    PubMed Central  CAS  PubMed  Google Scholar 

  103. Batki SL, Pennington DL, Lasher B, Neylan TC, Metzler T, Waldrop A, 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(8):2169–77.

    CAS  PubMed  Google Scholar 

  104. Martinotti G, Di Nicola M, De Vita O, Hatzigiakoumis DS, Guglielmo R, Santucci B, et al. Low-dose topiramate in alcohol dependence: a single-blind, placebo-controlled study. J Clin Psychopharmacol. 2014;34(6):709–15.

    CAS  PubMed  Google Scholar 

  105. Miranda R Jr, MacKillop J, Monti PM, Rohsenow DJ, Tidey J, Gwaltney C, et al. Effects of topiramate on urge to drink and the subjective effects of alcohol: a preliminary laboratory study. Alcohol Clin Exp Res. 2008;32(3):489–97.

    CAS  PubMed  Google Scholar 

  106. Rubio G, Martinez-Gras I, Manzanares J. Modulation of impulsivity by topiramate: implications for the treatment of alcohol dependence. J Clin Psychopharmacol. 2009;29(6):584–9.

    CAS  PubMed  Google Scholar 

  107. Likhitsathian S, Saengcharnchai P, Uttawichai K, Yingwiwattanapong J, Wittayanookulluk A, Srisurapanont M. Cognitive changes in topiramate-treated patients with alcoholism: a 12-week prospective study in patients recently detoxified. Psychiatry Clin Neurosci. 2012;66(3):235–41.

    CAS  PubMed  Google Scholar 

  108. Ray LA, Miranda R Jr, MacKillop J, McGeary J, Tidey JW, Rohsenow DJ, et al. A preliminary pharmacogenetic investigation of adverse events from topiramate in heavy drinkers. Exp Clin Psychopharmacol. 2009;17(2):122–9.

    PubMed Central  CAS  PubMed  Google Scholar 

  109. Kranzler HR, Gelernter J, Anton RF, Arias AJ, Herman A, Zhao H, et al. Association of markers in the 3’ region of the GluR5 kainate receptor subunit gene to alcohol dependence. Alcohol Clin Exp Res. 2009;33(5):925–30.

    PubMed Central  CAS  PubMed  Google Scholar 

  110. Kranzler HR, Covault J, Feinn R, Armeli S, Tennen H, Arias AJ, et al. Topiramate treatment for heavy drinkers: moderation by a GRIK1 polymorphism. Am J Psychiatry. 2014;171(4):445–52.

    PubMed Central  PubMed  Google Scholar 

  111. Kranzler HR, Armeli S, Tennen H, Gelernter J, Covault J. GRIK1 genotype and daily expectations of alcohol’s positive effects moderate the reduction of heavy drinking by topiramate. Exp Clin Psychopharmacol. 2014;22(6):494–501.

    CAS  PubMed  Google Scholar 

  112. Kranzler HR, Armeli S, Wetherill R, Feinn R, Tennen H, Gelernter J, et al. Self-efficacy mediates the effects of topiramate and GRIK1 genotype on drinking. Addict Biol. 2014. doi:10.1111/adb.12207

  113. Likhitsathian S, Uttawichai K, Booncharoen H, Wittayanookulluk A, Angkurawaranon C, Srisurapanont M. Topiramate treatment for alcoholic outpatients recently receiving residential treatment programs: a 12-week, randomized, placebo-controlled trial. Drug Alcohol Depend. 2013;133(2):440–6.

    CAS  PubMed  Google Scholar 

  114. Kampman KM, Pettinati HM, Lynch KG, Spratt K, Wierzbicki MR, O’Brien CP. A double-blind, placebo-controlled trial of topiramate for the treatment of comorbid cocaine and alcohol dependence. Drug Alcohol Depend. 2013;133(1):94–9.

    PubMed Central  CAS  PubMed  Google Scholar 

  115. Blodgett JC, Del Re AC, Maisel NC, Finney JW. A meta-analysis of topiramate’s effects for individuals with alcohol use disorders. Alcohol Clin Exp Res. 2014;38(6):1481–8.

    CAS  PubMed  Google Scholar 

  116. Falk D, Wang XQ, Liu L, Fertig J, Mattson M, Ryan M, et al. Percentage of subjects with no heavy drinking days: evaluation as an efficacy endpoint for alcohol clinical trials. Alcohol Clin Exp Res. 2010;34(12):2022–34.

    PubMed  Google Scholar 

  117. Sarid-Segal O, Knapp CM, Burch W, Richardson MA, Bahtia S, DeQuattro K, et al. The anticonvulsant zonisamide reduces ethanol self-administration by risky drinkers. Am J Drug Alcohol Abuse. 2009;35(5):316–9.

    PubMed Central  PubMed  Google Scholar 

  118. Knapp CM, Sarid-Segal O, Richardson MA, Colaneri LS, Afshar M, Devine E, et al. Open label trial of the tolerability and efficacy of zonisamide in the treatment of alcohol dependence. Am J Drug Alcohol Abuse. 2010;36(2):102–5.

    PubMed  Google Scholar 

  119. Rubio G, Lopez-Munoz F, Ferre F, Martinez-Gras I, Ponce G, Pascual JM, et al. Effects of zonisamide in the treatment of alcohol dependence. Clin Neuropharmacol. 2010;33(5):250–3.

  120. Arias AJ, Feinn R, Oncken C, Covault J, Kranzler HR. Placebo-controlled trial of zonisamide for the treatment of alcohol dependence. J Clin Psychopharmacol. 2010;30(3):318–22.

    PubMed Central  CAS  PubMed  Google Scholar 

  121. American Psychiatric Association. Diagnostic and statistical manual of mental disorders, fourth edition (DSM-IV). Washington, DC: Am Psychiatr Assoc; 1994.

    Google Scholar 

  122. American Psychiatric Association. Diagnostic and statistical manual of mental disorders, fifth edition (DSM-5). Washington, DC: Am Psychiatr Assoc; 2013.

    Google Scholar 

  123. American Psychiatric Association. Diagnostic and statistical manual of mental disorders, fourth edition, text revision (DSM-IV-TR). Washington, DC: Am Psychiatr Assoc; 2000.

    Google Scholar 

  124. Ebell MH, Siweck J, Weiss BD, Woolf SH, Ewigman B, Bowman M. Strength of recommendation taxonomy (SORT): a patientcentered approach to grading evidence in medical literature. Am Fam Physician. 2004;69(3):548–56.

    PubMed  Google Scholar 

Download references

Acknowledgments

Funding source: Dr. Niciu receives salary support from the Intramural Research Program at the National Institutes of Health/National Institute of Mental Health (IRP-NIMH-NIH).

Conflict of interest and financial disclosures

Dr. Hammond, Dr. Niciu, Dr. Drew, and Dr. Arias report no conflicts of interest with respect to the content of this manuscript. Dr. Hammond has received support from the American Psychiatric Association Child and Adolescent Fellowship, an unrestricted education grant supported by Shire Pharmaceuticals and the American Academy of Child and Adolescent Psychiatry Pilot Research Award for Junior Investigators supported by Lilly USA, LLC. Dr. Arias has no financial disclosures. He holds (jointly through Yale University School of Medicine) a provisional use-patent on the medication perampanel for use in treating addictive disorders. Dr. Niciu has no financial disclosures to report. Dr. Drew reports no financial disclosures.

Contributor’s statements

All authors have participated in the concept and design, analysis and interpretation of data, and drafting or revising of this manuscript.

Author information

Authors and Affiliations

  1. Yale Child Study Center, Yale University School of Medicine, PO Box 207900, 230 South Frontage Road, New Haven, CT, 06520, USA

    Christopher J. Hammond

  2. Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA

    Christopher J. Hammond & Albert J. Arias

  3. Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health, Bethesda, MD, USA

    Mark J. Niciu

  4. Veterans Affairs Connecticut Healthcare System-West Haven Campus, West Haven, CT, USA

    Shannon Drew & Albert J. Arias

Authors
  1. Christopher J. Hammond
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mark J. Niciu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shannon Drew
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Albert J. Arias
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Albert J. Arias.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hammond, C.J., Niciu, M.J., Drew, S. et al. Anticonvulsants for the Treatment of Alcohol Withdrawal Syndrome and Alcohol Use Disorders. CNS Drugs 29, 293–311 (2015). https://doi.org/10.1007/s40263-015-0240-4

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40263-015-0240-4

Keywords

Search

Navigation