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Safety and Tolerability of Pharmacological Treatment of Alcohol Dependence: Comprehensive Review of Evidence

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A Letter to the Editor to this article was published on 08 August 2016

Abstract

Alcohol use disorders (AUD) cause significant morbidity and mortality worldwide, but pharmacological treatments for them are underused, despite evidence of efficacy. Acamprosate, naltrexone, nalmefene and disulfiram are all approved in one or more region for the treatment of AUD. Baclofen currently has a temporary indication in France. Safety considerations for using psychopharmacological treatments in this patient group include the impact of concurrent alcohol consumption at high levels; multiple physical comorbidities that may interfere with pharmacological effects, distribution and metabolism; and concomitant medication for the treatment of comorbid physical and psychiatric conditions. The five drugs, including an extended-release injectable suspension of naltrexone, have different safety profiles that need to be balanced with the treatment objective (initiation or continuation of abstinence, or reduction of drinking), individual patient preferences and comorbid conditions. Appropriate treatment will be based on the unique risk–benefit profile in each case.

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References

  1. WHO. Global status report on alcohol and health-2014. Geneva: World Health Organization; 2014.

    Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  3. Rehm J, Shield K, Gmel G, Rehm M, Frick U. Modeling the impact of alcohol dependence on mortality burden and the effect of available treatment interventions in the European Union. Eur Neuropsychopharmacol. 2013;23(2):89–97.

    Article  CAS  PubMed  Google Scholar 

  4. National Collaborating Centre for Mental Health (UK). Alcohol-use disorders: diagnosis, assessment and management of harmful drinking and alcohol dependence. The British Psychological Society and The Royal College of Psychiatrists Publications; 2011.

  5. Amato L, Minozzi S, Davoli M. Efficacy and safety of pharmacological interventions for the treatment of the Alcohol Withdrawal Syndrome. Cochrane Database Syst Rev. 2011;6:CD008537.

    PubMed  Google Scholar 

  6. Rösner S, Hackl-Herrwerth A, Leucht S, Lehert P, Vecchi S, Soyka M. Acamprosate for alcohol dependence. Cochrane Database Syst Rev. 2010;9:CD004332.

    PubMed  Google Scholar 

  7. Rösner S, Hackl-Herrwerth A, Leucht S, et al. Opioid antagonists for alcohol dependence. Cochrane Database Syst Rev. 2010;12:CD001867.

    PubMed  Google Scholar 

  8. Lingford-Hughes AR, Welch S, Peters L, Nutt DJ. BAP updated guidelines: evidence-based guidelines for the pharmacological management of substance abuse, harmful use, addiction and comorbidity: recommendations from BAP. J Psychopharmacol. 2012;26(7):899–952.

    Article  CAS  PubMed  Google Scholar 

  9. Edwards IR, Aronson JK. Adverse drug reactions: definitions, diagnosis, and management. Lancet. 2000;356(9237):1255–9.

    Article  CAS  PubMed  Google Scholar 

  10. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med. 2009;151(4):264–9.

    Article  PubMed  Google Scholar 

  11. Moher D, Liberati A, Tetzlaff J, Altman DG, Group P. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Int J Surgery. 2010;8(5):336–41.

    Article  Google Scholar 

  12. Talat B, Mayers A, Baldwin DS. Quality of case reports of adverse drug reactions with psychotropic drugs: a 25-year review. Hum Psychopharmacol. 2013;28(5):413–20.

    Article  CAS  PubMed  Google Scholar 

  13. Kalk NJ, Lingford-Hughes AR. The clinical pharmacology of acamprosate. Br J Clin Pharmacol. 2014;77(2):315–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Umhau JC, Momenan R, Schwandt ML, Singley E, Lifshitz M, Doty L, et al. Effect of acamprosate on magnetic resonance spectroscopy measures of central glutamate in detoxified alcohol-dependent individuals: a randomized controlled experimental medicine study. Arch Gen Psychiatry. 2010;67(10):1069–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Donoghue K, Elzerbi C, Saunders R, Whittington C, Pilling S, Drummond C. The efficacy of acamprosate and naltrexone in the treatment of alcohol dependence, Europe versus the rest of the world: a meta-analysis. Addiction. 2015;110(6):920–30.

    Article  PubMed  Google Scholar 

  16. Electronic Medicines Compendium (eMC). Campral EC 2015. http://www.medicines.org.uk/emc/medicine/1042/SPC/Campral+EC/. Accessed 3 Sep 2015.

  17. Besson J, Aeby F, Kasas A, Lehert P, Potgieter A. Combined efficacy of acamprosate and disulfiram in the treatment of alcoholism: a controlled study. Alcohol Clin Exp Res. 1998;22(3):573–9.

    Article  CAS  PubMed  Google Scholar 

  18. Rosenthal RN, Gage A, Perhach JL, Goodman AM. Acamprosate: safety and tolerability in the treatment of alcohol dependence. J Addict Med. 2008;2(1):40–50.

    Article  CAS  PubMed  Google Scholar 

  19. Lhuintre J, Moore N, Tran G, Steru L, Langrenon S, Daoust S, et al. Acamprosate appears to decrease alcohol intake in weaned alcoholics. Alcohol Alcohol. 1990;25(6):613–22.

    CAS  PubMed  Google Scholar 

  20. Poldrugo F. Acamprosate treatment in a long-term community-based alcohol rehabilitation programme. Addiction. 1997;92(11):1537–46.

    Article  CAS  PubMed  Google Scholar 

  21. Grant K, Woolverton WL. Reinforcing and discriminative stimulus effects of ca-acetyl homotaurine in animals. Pharmacol Biochem Behav. 1989;32(3):607–11.

    Article  CAS  PubMed  Google Scholar 

  22. Chick J, Howlett H, Morgan M, Ritson B. United Kingdom Multicentre Acamprosate Study (UKMAS): a 6-month prospective study of acamprosate versus placebo in preventing relapse after withdrawal from alcohol. Alcohol Alcohol. 2000;35(2):176–87.

    Article  CAS  PubMed  Google Scholar 

  23. Mason BJ. Acamprosate and naltrexone treatment for alcohol dependence: an evidence-based risk-benefits assessment. Eur Neuropsychopharmacol. 2003;13(6):469–75.

    Article  CAS  PubMed  Google Scholar 

  24. Lhuintre J-P, Moore N, Saligaut C, Boismare F, Daoust M, Chretien P, et al. Ability of calcium bis acetyl homotaurine, a GABA agonist, to prevent relapse in weaned alcoholics. Lancet. 1985;325(8436):1014–6.

    Article  Google Scholar 

  25. Higuchi S. Efficacy of acamprosate for the treatment of alcohol dependence long after recovery from withdrawal syndrome: a randomized, double-blind, placebo-controlled study conducted in Japan (sunrise study). J Clin Psychiatry. 2015;76(2):181–8.

    Article  PubMed  Google Scholar 

  26. Mann K, Lemenager T, Hoffmann S, Reinhard I, Hermann D, Batra A, 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(6):937–46.

    Article  CAS  PubMed  Google Scholar 

  27. Tempesta E, Janiri L, Bignamini A, Chabac S, Potgieter A. Acamprosate and relapse prevention in the treatment of alcohol dependence: a placebo-controlled study. Alcohol Alcohol. 2000;35(2):202–9.

    Article  CAS  PubMed  Google Scholar 

  28. Gual A, Lehert P. Acamprosate during and after acute alcohol withdrawal: a double-blind placebo-controlled study in Spain. Alcohol Alcohol. 2001;36(5):413–8.

    Article  CAS  PubMed  Google Scholar 

  29. Kampman KM, Pettinati HM, Lynch KG, Xie H, Dackis C, Oslin DW, et al. Initiating acamprosate within-detoxification versus post-detoxification in the treatment of alcohol dependence. Addict Behav. 2009;34(6):581–6.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Paille FM, Guelfi JD, Perkins AC, Royer RJ, Steru L, Parot P. Double-blind randomized multicentre trial of acamprosate in maintaining abstinence from alcohol. Alcohol Alcohol. 1995;30(2):239–47.

    CAS  PubMed  Google Scholar 

  31. Pelc I, Verbanck P, Le Bon O, Gavrilovic M, Lion K, Lehert P. Efficacy and safety of acamprosate in the treatment of detoxified alcohol-dependent patients. A 90-day placebo-controlled dose-finding study. Br J Psychiatry. 1997;171(1):73–7.

    Article  CAS  PubMed  Google Scholar 

  32. Kiefer F, Jahn H, Tarnaske T, Helwig H, Briken P, Holzbach R, et al. Comparing and combining naltrexone and acamprosate in relapse prevention of alcoholism: a double-blind, placebo-controlled study. Arch Gen Psychiatry. 2003;60(1):92–9.

    Article  CAS  PubMed  Google Scholar 

  33. Anton RF, O’Malley SS, Ciraulo DA, Cisler RA, Couper D, Donovan DM, et al. Combined pharmacotherapies and behavioral interventions for alcohol dependence: the COMBINE study: a randomized controlled trial. JAMA. 2006;295(17):2003–17.

    Article  CAS  PubMed  Google Scholar 

  34. Ralevski E, O’Brien E, Jane JS, Dean E, Dwan R, Petrakis I. Effects of acamprosate on cognition in a treatment study of patients with schizophrenia spectrum disorders and comorbid alcohol dependence. J Nerv Ment Dis. 2011;199(7):499–505.

    Article  PubMed  Google Scholar 

  35. Tolliver BK, DeSantis SM, Brown DG, Prisciandaro JJ, Brady KT. A randomized, double-blind, placebo-controlled clinical trial of acamprosate in alcohol-dependent individuals with bipolar disorder: a preliminary report. Bipolar Disord. 2012;14(1):54–63.

    Article  CAS  PubMed  Google Scholar 

  36. Lejoyeux M, Lehert P. Alcohol-use disorders and depression: results from individual patient data meta-analysis of the acamprosate-controlled studies. Alcohol Alcohol. 2011;46(1):61–7.

    Article  PubMed  Google Scholar 

  37. Sun W, Xu X-F, Huang J-Z, Tan Q-R, Deng H-H, Li K-Q, et al. A 12-week randomized, double-blind, placebo-controlled multicenter clinical trial of acamprosate for the treatment of alcohol dependence. Chin Mental Health J. 2012;26(12):927–32.

    Google Scholar 

  38. Mason BJ, Lehert P. Acamprosate for alcohol dependence: a sex-specific meta-analysis based on individual patient data. Alcohol Clin Exp Res. 2012;36(3):497–508.

    Article  PubMed  Google Scholar 

  39. McEvoy GK, editor. AHFS drug information 2000. Bethesda: American Society of Health-System Pharmacists; 2000.

  40. King AC, Volpicelli JR, Gunduz M, O’Brien CP, Kreek MJ. Naltrexone biotransformation and incidence of subjective side effects: a preliminary study. Alcohol Clin Exp Res. 1997;21(5):906–9.

    CAS  PubMed  Google Scholar 

  41. Electronic Medicines Compendium (eMC). Adepend 50 mg filmcoated tablets 2014. http://www.medicines.org.uk/emc/medicine/29642. Accessed 3 Sep 2015.

  42. Kim SW, Grant JE, Adson DE, Remmel RP. A preliminary report on possible naltrexone and nonsteroidal analgesic interactions. J Clin Psychopharmacol. 2001;21(6):632–4.

    Article  CAS  PubMed  Google Scholar 

  43. Mitchell JE, Morley JE, Levine AS, Hatsukami D, Gannon M, Pfohl D. High-dose naltrexone therapy and dietary counseling for obesity. Biol Psychiatry. 1987;22(1):35–42.

    Article  CAS  PubMed  Google Scholar 

  44. Sax DS, Kornetsky C, Kim A. Lack of hepatotoxicity with naltrexone treatment. J Clin Pharmacol. 1994;34(9):898–901.

    Article  CAS  PubMed  Google Scholar 

  45. Marrazzi M, Markham K, Kinzie J, Luby E. Binge eating disorder: response to naltrexone. Int J Obes Relat Metab Disord. 1995;19(2):143–5.

    CAS  PubMed  Google Scholar 

  46. Kim SW, Grant JE, Yoon G, Williams KA, Remmel RP. Safety of high-dose naltrexone treatment: hepatic transaminase profiles among outpatients. Clin Neuropharmacol. 2006;29(2):77–9.

    Article  CAS  PubMed  Google Scholar 

  47. Budzyński J, Rybakowski J, Świątkowski M, Torliński L, Kłopocka M, Kosmowski W, et al. Naltrexone exerts a favourable effect on plasma lipids in abstinent patients with alcohol dependence. Alcohol Alcohol. 2000;35(1):91–7.

    Article  PubMed  Google Scholar 

  48. De Sousa A. A comparative study using disulfiram and naltrexone in alcohol-dependent adolescents. J Subst Use. 2014;19(5):341–5.

    Article  Google Scholar 

  49. Oslin D, Liberto JG, O’Brien J, Krois S, Norbeck J. Naltrexone as an adjunctive treatment for older patients with alcohol dependence. Am J Geriatr Psychiatry. 1997;5(4):324–32.

    Article  CAS  PubMed  Google Scholar 

  50. Pettinati HM, Oslin DW, Kampman KM, Dundon WD, Xie H, Gallis TL, et al. A double-blind, placebo-controlled trial combining sertraline and naltrexone for treating co-occurring depression and alcohol dependence. Am J Psychiatry. 2010;167(6):668–75.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Oslin DW, Lynch KG, Pettinati HM, Kampman KM, Gariti P, Gelfand L, et al. A placebo-controlled randomized clinical trial of naltrexone in the context of different levels of psychosocial intervention. Alcohol Clin Exp Res. 2008;32(7):1299–308.

    Article  CAS  PubMed  Google Scholar 

  52. Monterosso JR, Flannery BA, Pettinati HM, Oslin DW, Rukstalis M, O’Brien CP, et al. Predicting treatment response to naltrexone: the influence of craving and family history. Am J Addict. 2001;10(3):258–68.

    Article  CAS  PubMed  Google Scholar 

  53. Pettinati HM, Kampman KM, Lynch KG, Xie H, Dackis C, Rabinowitz AR, et al. A double blind, placebo-controlled trial that combines disulfiram and naltrexone for treating co-occurring cocaine and alcohol dependence. Addict Behav. 2008;33(5):651–67.

    Article  PubMed  Google Scholar 

  54. Schmitz JM, Lindsay JA, Green CE, Herin DV, Stotts AL, Gerard Moeller F. High-dose naltrexone therapy for cocaine-alcohol dependence. Am J Addict. 2009;18(5):356–62.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Pettinati HM, Kampman KM, Lynch KG, Suh JJ, Dackis CA, Oslin DW, et al. Gender differences with high dose naltrexone in cocaine and alcohol dependent patients. J Subst Abuse Treat. 2008;34(4):378–90.

    Article  PubMed  Google Scholar 

  56. Yoon G, Kim SW, Thuras P, Westermeyer J. Safety, tolerability, and feasibility of high-dose naltrexone in alcohol dependence: an open-label study. Hum Psychopharmacol. 2011;26(2):125–32.

    Article  CAS  PubMed  Google Scholar 

  57. Kim SW, Grant JE, Adson DE, Shin YC. Double-blind naltrexone and placebo comparison study in the treatment of pathological gambling. Biol Psychiatry. 2001;49(11):914–21.

    Article  CAS  PubMed  Google Scholar 

  58. Rubio G, Jimenez-Arriero M, Ponce G, Palomo T. Naltrexone versus acamprosate: one year follow-up of alcohol dependence treatment. Alcohol Alcohol. 2001;36(5):419–25.

    Article  CAS  PubMed  Google Scholar 

  59. Petrakis IL, Poling J, Levinson C, Nich C, Carroll K, Rounsaville B, et al. Naltrexone and disulfiram in patients with alcohol dependence and comorbid psychiatric disorders. Biol Psychiatry. 2005;57(10):1128–37.

    Article  CAS  PubMed  Google Scholar 

  60. Johnson BA, Ait-Daoud N, Prihoda TJ. Combining ondansetron and naltrexone effectively treats biologically predisposed alcoholics: from hypotheses to preliminary clinical evidence. Alcohol Clin Exp Res. 2000;24(5):737–42.

    Article  CAS  PubMed  Google Scholar 

  61. Myrick H, Anton RF, Li X, Henderson S, Randall PK, Voronin K. Effect of naltrexone and ondansetron on alcohol cue-induced activation of the ventral striatum in alcohol-dependent people. Arch Gen Psychiatry. 2008;65(4):466–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Caputo F, Addolorato G, Stoppo M, Francini S, Vignoli T, Lorenzini F, et al. Comparing and combining gamma-hydroxybutyric acid (GHB) and naltrexone in maintaining abstinence from alcohol: an open randomized comparative study. Eur Neuropsychopharmacol. 2007;17(12):781–9.

    Article  CAS  PubMed  Google Scholar 

  63. Stella L, Addolorato G, Rinaldi B, Capuano A, Berrino L, Rossi F, et al. An open randomized study of the treatment of escitalopram alone and combined with γ-hydroxybutyric acid and naltrexone in alcoholic patients. Pharmacol Res. 2008;57(4):312–7.

    Article  CAS  PubMed  Google Scholar 

  64. O’Malley SS, Robin RW, Levenson AL, GreyWolf I, Chance LE, Hodgkinson CA, et al. Naltrexone alone and with sertraline for the treatment of alcohol dependence in Alaska natives and non-natives residing in rural settings: a randomized controlled trial. Alcohol Clin Exp Res. 2008;32(7):1271–83.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Farren CK, Scimeca M, Wu R, Malley SO. A double-blind, placebo-controlled study of sertraline with naltrexone for alcohol dependence. Drug Alcohol Depend. 2009;99(1):317–21.

    Article  CAS  PubMed  Google Scholar 

  66. Guardia J, Roncero C, Galan J, Gonzalvo B, Burguete T, Casas M. 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;36(3):265–9.

    Article  PubMed  Google Scholar 

  67. Schmitz JM, Stotts AL, Sayre SL, DeLaune KA, Grabowski J. Treatment of cocaine-alcohol dependence with naltrexone and relapse prevention therapy. Am J Addict. 2004;13(4):333–41.

    Article  PubMed  Google Scholar 

  68. Hersh D, Van Kirk JR, Kranzler HR. Naltrexone treatment of comorbid alcohol and cocaine use disorders. Psychopharmacology. 1998;139(1–2):44–52.

    Article  CAS  PubMed  Google Scholar 

  69. Suh JJ, Pettinati HM, Kampman KM, O’Brien CP. Gender differences in predictors of treatment attrition with high dose naltrexone in cocaine and alcohol dependence. Am J Addict. 2008;17(6):463–8.

    Article  PubMed  PubMed Central  Google Scholar 

  70. Conner KR, Pinquart M, Gamble SA. Meta-analysis of depression and substance use among individuals with alcohol use disorders. J Subst Abuse Treat. 2009;37(2):127–37.

    Article  PubMed  PubMed Central  Google Scholar 

  71. Davidson KM. Diagnosis of depression in alcohol dependence: changes in prevalence with drinking status. Br J Psychiatry. 1995;166(2):199–204.

    Article  CAS  PubMed  Google Scholar 

  72. Oslin DW. Treatment of late-life depression complicated by alcohol dependence. Am J Geriatr Psychiatry. 2005;13(6):491–500.

    Article  PubMed  PubMed Central  Google Scholar 

  73. Adamson SJ, Sellman JD, Foulds JA, Frampton CMA, Deering D, Dunn A, et al. A randomized trial of combined citalopram and naltrexone for nonabstinent outpatients with co-occurring alcohol dependence and major depression. J Clin Psychopharmacol. 2015;35(2):143–9.

    Article  CAS  PubMed  Google Scholar 

  74. Petrakis I, Ralevski E, Nich C, Levinson C, Carroll K, Poling J, et al. Naltrexone and disulfiram in patients with alcohol dependence and current depression. J Clin Psychopharmacol. 2007;27(2):160–5.

    Article  CAS  PubMed  Google Scholar 

  75. Brown ES, Carmody TJ, Schmitz JM, Caetano R, Adinoff B, Swann AC, et al. A randomized, double-blind, placebo-controlled pilot study of naltrexone in outpatients with bipolar disorder and alcohol dependence. Alcohol Clin Exp Res. 2009;33(11):1863–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Petrakis IL, Nich C, Ralevski E. Psychotic spectrum disorders and alcohol abuse: a review of pharmacotherapeutic strategies and a report on the effectiveness of naltrexone and disulfiram. Schizophr Bull. 2006;32(4):644–54.

    Article  PubMed  PubMed Central  Google Scholar 

  77. Petrakis IL, O’Malley S, Rounsaville B, Poling J, McHugh-Strong C, Krystal JH. Naltrexone augmentation of neuroleptic treatment in alcohol abusing patients with schizophrenia. Psychopharmacology. 2004;172(3):291–7.

    Article  CAS  PubMed  Google Scholar 

  78. Petrakis IL, Poling J, Levinson C, Nich C, Carroll K, Ralevski E, et al. Naltrexone and disulfiram in patients with alcohol dependence and comorbid post-traumatic stress disorder. Biol Psychiatry. 2006;60(7):777–83.

    Article  CAS  PubMed  Google Scholar 

  79. Petrakis IL, Ralevski E, Desai N, Trevisan L, Gueorguieva R, Rounsaville B, et al. Noradrenergic vs serotonergic antidepressant with or without naltrexone for veterans with PTSD and comorbid alcohol dependence. Neuropsychopharmacology. 2012;37(4):996–1004.

    Article  CAS  PubMed  Google Scholar 

  80. Killeen TK, Brady KT, Gold PB, Simpson KN, Faldowski RA, Tyson C, et al. Effectiveness of naltrexone in a community treatment program. Alcohol Clin Exp Res. 2004;28(11):1710–7.

    Article  CAS  PubMed  Google Scholar 

  81. Kranzler HR, Modesto-Lowe V, Van Kirk J. Naltrexone vs. nefazodone for treatment of alcohol dependence: a placebo-controlled trial. Neuropsychopharmacology. 2000;22(5):493–503.

    Article  CAS  PubMed  Google Scholar 

  82. Morris PLP, Hopwood M, Whelan G, Gardiner J, Drummond E. Naltrexone for alcohol dependence: a randomized controlled trial. Addiction. 2001;96(11):1565–73.

    Article  CAS  PubMed  Google Scholar 

  83. O’Malley SS, Sinha R, Grilo CM, Capone C, Farren CK, McKee SA, et al. Naltrexone and cognitive behavioral coping skills therapy for the treatment of alcohol drinking and eating disorder features in alcohol-dependent women: a randomized controlled trial. Alcohol Clin Exp Res. 2007;31(4):625–34.

    PubMed  Google Scholar 

  84. O’Malley SS, Krishnan-Sarin S, Farren C, O’Connor PG. Naltrexone-induced nausea in patients treated for alcohol dependence: clinical predictors and evidence for opioid-mediated effects. J Clin Psychopharmacol. 2000;20(1):69–76.

    Article  PubMed  Google Scholar 

  85. Baros A, Latham P, Anton R. Naltrexone and cognitive behavioral therapy for the treatment of alcohol dependence: do sex differences exist? Alcohol Clin Exp Res. 2008;32(5):771–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Anton RF, Moak DH, Latham P, Waid LR, Myrick H, Voronin K, et al. Naltrexone combined with either cognitive behavioral or motivational enhancement therapy for alcohol dependence. J Clin Psychopharmacol. 2005;25(4):349–57.

    Article  CAS  PubMed  Google Scholar 

  87. Anton RF, Moak DH, Waid RL, Latham PK, Malcolm RJ, Dias JK. Naltrexone and cognitive behavioral therapy for the treatment of outpatient alcoholics: results of a placebo-controlled trial. Am J Psychiatry. 1999;156(11):1758–64.

    CAS  PubMed  Google Scholar 

  88. Ahmadi J, Ahmadi N. A double-blind, placebo-controlled study of naltrexone in the treatment of alcohol dependence. German J Psychiatry. 2002;5(4):85–9.

    Google Scholar 

  89. Huang MC, Chen CH, Yu JM, Chen CC. A double-blind, placebo-controlled study of naltrexone in the treatment of alcohol dependence in Taiwan. Addict Biol. 2005;10(3):289–92.

    Article  CAS  PubMed  Google Scholar 

  90. Lee A, Tan S, Lim D, Winslow RM, Wong KE, Allen J, et al. Naltrexone in the treatment of male alcoholics—an effectiveness study in Singapore. Drug Alcohol Rev. 2001;20(2):193–9.

    Article  Google Scholar 

  91. Chick J, Anton R, Checinski K, Croop R, Drummond DC, Farmer R, et al. A multicentre, randomized, double-blind, placebo-controlled trial of naltrexone in the treatment of alcohol dependence or abuse. Alcohol Alcohol. 2000;35(6):587–93.

    Article  CAS  PubMed  Google Scholar 

  92. Volpicelli JR, Rhines KC, Rhines JS, Volpicelli LA, Alterman AI, O’Brien CP. Naltrexone and alcohol dependence: role of subject compliance. Arch Gen Psychiatry. 1997;54(8):737–42.

    Article  CAS  PubMed  Google Scholar 

  93. Johnson BA, Ait-Daoud N, Aubin H-J, van den Brink W, Guzzetta R, Loewy J, et al. A pilot evaluation of the safety and tolerability of repeat dose administration of long-acting injectable naltrexone (Vivitrex®) in patients with alcohol dependence. Alcohol Clin Exp Res. 2004;28(9):1356–61.

    Article  CAS  PubMed  Google Scholar 

  94. Kranzler HR, Modesto-Lowe V, Nuwayser ES. Sustained-release naltrexone for alcoholism treatment: a preliminary study. Alcohol Clin Exp Res. 1998;22(5):1074–9.

    CAS  PubMed  Google Scholar 

  95. 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;28(7):1051–9.

    Article  CAS  PubMed  Google Scholar 

  96. 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;293(13):1617–25.

    Article  CAS  PubMed  Google Scholar 

  97. Faiman MD, Jensen JC, Lacoursiere RB. Elimination kinetics of disulfiram in alcoholics after single and repeated doses. Clin Pharmacol Ther. 1984;36(4):520–6.

    Article  CAS  PubMed  Google Scholar 

  98. Malcolm R, Olive MF, Lechner W. The safety of disulfiram for the treatment of alcohol and cocaine dependence in randomized clinical trials: guidance for clinical practice. Expert Opin Drug Saf. 2008;7(4):459–72.

    Article  CAS  PubMed  Google Scholar 

  99. Christensen J, Rønsted P, Vaag U. Side effects after disulfiram. Acta Psychiatr Scand. 1984;69(4):265–73.

    Article  CAS  PubMed  Google Scholar 

  100. Frye RF, Branch RA. Effect of chronic disulfiram administration on the activities of CYP1A2, CYP2C19, CYP2D6, CYP2E1, and N-acetyltransferase in healthy human subjects. Br J Clin Pharmacol. 2002;53(2):155–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Electronic Medicines Compendium (eMC). Disulfiram Tablets 200 mg 2012. http://www.medicines.org.uk/emc/medicine/519. Accessed 3 Sep 2015.

  102. Rothstein E, Clancy DD. Combined use of disulfiram and metronidazole in treatment of alcoholism. Q J Stud Alcohol. 1970;31(2):446–7.

    CAS  PubMed  Google Scholar 

  103. Kumaraswamy G, Pundarikaksha H, Ramaiah V, Anjanappa J. A study of cardiovascular complications of disulfiram-ethanol reaction. Natl J Physiol Pharmacy Pharmacol. 2013;3(1):35–42.

    Article  Google Scholar 

  104. Chick J, Gough K, Falkowski W, Kershaw P, Hore B, Mehta B, et al. Disulfiram treatment of alcoholism. Br J Psychiatry. 1992;161(1):84–9.

    Article  CAS  PubMed  Google Scholar 

  105. Fuller RK, Branchey L, Brightwell DR, Derman RM, Emrick CD, Iber FL, et al. Disulfiram treatment of alcoholism: a Veterans Administration cooperative study. JAMA. 1986;256(11):1449–55.

    Article  CAS  PubMed  Google Scholar 

  106. Iber FL, Lee K, Lacoursiere R, Fuller R. Liver toxicity encountered in the Veterans Administration trial of disulfiram in alcoholics. Alcohol Clin Exp Res. 1987;11(3):301–4.

    Article  CAS  PubMed  Google Scholar 

  107. Ulrichsen J, Nielsen MK, Ulrichsen M. Disulfiram in severe alcoholism—an open controlled study. Nordic J Psychiatry. 2010;64(6):356–62.

    Article  Google Scholar 

  108. Mutschler J, Dirican G, Gutzeit A, Grosshans M. Safety and efficacy of long-term disulfiram aftercare. Clin Neuropharmacol. 2011;34(5):195–8.

    Article  CAS  PubMed  Google Scholar 

  109. Palatty PL, Saldanha E. Status of disulfiram in present day alcoholic deaddiction therapy. Indian J Psychiatry. 2011;53(1):25.

    Article  PubMed  PubMed Central  Google Scholar 

  110. Chick J. Safety issues concerning the use of disulfiram in treating alcohol dependence. Drug Saf. 1999;20(5):427–35.

    Article  CAS  PubMed  Google Scholar 

  111. Niederhofer H, Staffen W. Comparison of disulfiram and placebo in treatment of alcohol dependence of adolescents. Drug Alcohol Rev. 2003;22(3):295–7.

    Article  PubMed  Google Scholar 

  112. Goyer PF, Brown GL, Minichiello MD, Major LF. Mood-altering effects of disulfiram in alcoholics. J Stud Alcohol. 1984;45(3):209–13.

    Article  CAS  PubMed  Google Scholar 

  113. Ling W, Weiss DG, Charuvastra VC, O’Brien CP, Blakis M, Wang R, et al. Use of disulfiram for alcoholics in methadone maintenance programs: a Veterans Administration cooperative study. Arch Gen Psychiatry. 1983;40(8):851–4.

    Article  CAS  PubMed  Google Scholar 

  114. Specka M, Heilmann M, Lieb B, Scherbaum N. Use of disulfiram for alcohol relapse prevention in patients in opioid maintenance treatment. Clin Neuropharmacol. 2014;37(6):161–5.

    Article  CAS  PubMed  Google Scholar 

  115. Carroll KM, Nich C, Ball SA, McCance E, Rounsavile BJ. Treatment of cocaine and alcohol dependence with psychotherapy and disulfiram. Addiction. 1998;93(5):713–27.

    Article  CAS  PubMed  Google Scholar 

  116. Benowitz NL. Clinical pharmacology and toxicology of cocaine. Pharmacol Toxicol. 1993;72(1):3–12.

    Article  CAS  PubMed  Google Scholar 

  117. Larson EW, Olincy A, Rummans TA, Morse RM. Disulfiram treatment of patients with both alcohol dependence and other psychiatric disorders: a review. Alcohol Clin Exp Res. 1992;16(1):125–30.

    Article  CAS  PubMed  Google Scholar 

  118. Swift RM. Naltrexone and nalmefene: any meaningful difference? Biol Psychiatry. 2013;73(8):700–1.

    Article  CAS  PubMed  Google Scholar 

  119. Fudala PJ, Heishman SJ, Henningfield JE, Johnson RE. Human pharmacology and abuse potential of nalmefene. Clin Pharmacol Ther. 1991;49(3):300–6.

    Article  CAS  PubMed  Google Scholar 

  120. European Medicines Agency. Selincro 2015. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002583/human_med_001620.jsp&mid=WC0b01ac058001d124. Accessed 3 Sep 2015.

  121. Mason BJ, Salvato FR, Williams LD, Ritvo EC, Cutler RB. A double-blind, placebo-controlled study of oral nalmefene for alcohol dependence. Arch Gen Psychiatry. 1999;56(8):719–24.

    Article  CAS  PubMed  Google Scholar 

  122. Frye RF, Matzke GR, Schade R, Dixon R, Rabinovitz M. Effects of liver disease on the disposition of the opioid antagonist nalmefene. Clin Pharmacol Ther. 1997;61(1):15–23.

    Article  CAS  PubMed  Google Scholar 

  123. Anton RF, Pettinati H, Zweben A, Kranzler HR, Johnson B, Bohn MJ, et al. A multi-site dose ranging study of nalmefene in the treatment of alcohol dependence. J Clin Psychopharmacol. 2004;24(4):421–8.

    Article  CAS  PubMed  Google Scholar 

  124. Drobes DJ, Anton RF, Thomas SE, Voronin K. A clinical laboratory paradigm for evaluating medication effects on alcohol consumption: naltrexone and nalmefene. Neuropsychopharmacology. 2003;28(4):755–64.

    Article  CAS  PubMed  Google Scholar 

  125. Gual A, He Y, Torup L, van den Brink W, Mann K, Group ES. A randomized, double-blind, placebo-controlled, efficacy study of nalmefene, as-needed use, in patients with alcohol dependence. Eur Neuropsychopharmacol. 2013;23(11):1432–42.

    Article  CAS  PubMed  Google Scholar 

  126. Mann K, Bladström A, Torup L, Gual A, van den Brink W. Extending the treatment options in alcohol dependence: a randomized controlled study of as-needed nalmefene. Biol Psychiatry. 2013;73(8):706–13.

    Article  CAS  PubMed  Google Scholar 

  127. van den Brink W, Sørensen P, Torup L, Mann K, Gual A. 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(8):733–44.

    Article  PubMed  CAS  Google Scholar 

  128. van den Brink W, Strang J, Gual A, Sørensen P, Jensen TJ, Mann K. Safety and tolerability of as-needed nalmefene in the treatment of alcohol dependence: results from the Phase III clinical programme. Exp Opin Drug Saf. 2015;14(4):495–504.

    Article  CAS  Google Scholar 

  129. Electronic Medicines Compendium (eMC). Baclofen Tablets BP 10 mg 2012. http://www.medicines.org.uk/emc/medicine/23850. Accessed 3 Sep 2015.

  130. Addolorato G, Caputo F, Capristo E, Domenicali M, Bernardi M, Janiri L, et al. Baclofen efficacy in reducing alcohol craving and intake: a preliminary double-blind randomized controlled study. Alcohol Alcohol. 2002;37(5):504–8.

    Article  CAS  PubMed  Google Scholar 

  131. Addolorato G, Leggio L, Ferrulli A, Cardone S, Vonghia L, Mirijello 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(9603):1915–22.

    Article  CAS  PubMed  Google Scholar 

  132. Müller CA, Geisel O, Pelz P, Higl V, Krüger J, Stickel A, et al. High-dose baclofen for the treatment of alcohol dependence (BACLAD study): a randomized, placebo-controlled trial. Eur Neuropsychopharmacol. 2015;25(8):1167–77.

    Article  PubMed  CAS  Google Scholar 

  133. Gache P, Hadengue A. Baclofen improves abstinence in alcoholic cirrhosis: still better to come? J Hepatol. 2008;49(6):1083–5.

    Article  CAS  PubMed  Google Scholar 

  134. Leggio L, Ferrulli A, Zambon A, Caputo F, Kenna G, Swift R, et al. Baclofen promotes alcohol abstinence in alcohol dependent cirrhotic patients with hepatitis C virus (HCV) infection. Addict Behav. 2012;37(4):561–4.

    Article  CAS  PubMed  Google Scholar 

  135. Saddichha S, Jayaram N, Manjunatha N, Benegal V. Baclofen-induced morbiliform rashes: a case series. J Clin Pharmacol. 2011;51(12):1733–4.

    Article  CAS  PubMed  Google Scholar 

  136. Krupitsky E, Burakov A, Ivanov V, Krandashova G, Lapin I, Grinenko AJ, et al. Baclofen administration for the treatment of affective disorders in alcoholic patients. Drug Alcohol Depend. 1993;33(2):157–63.

    Article  CAS  PubMed  Google Scholar 

  137. Garbutt JC, Kampov-Polevoy AB, Gallop R, Kalka-Juhl L, Flannery BA. Efficacy and safety of baclofen for alcohol dependence: a randomized, double-blind, placebo-controlled trial. Alcohol Clin Exp Res. 2010;34(11):1849–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Morley K, Baillie A, Leung S, Addolorato G, Leggio L, Haber P. Baclofen for the treatment of alcohol dependence and possible role of comorbid anxiety. Alcohol Alcohol. 2014;49(6):654–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Ponizovsky AM, Rosca P, Aronovich E, Weizman A, Grinshpoon A. Baclofen as add-on to standard psychosocial treatment for alcohol dependence: a randomized, double-blind, placebo-controlled trial with 1 year follow-up. J Subst Abuse Treat. 2015;52:24–30.

    Article  PubMed  Google Scholar 

  140. Addolorato G, Leggio L, Ferrulli A, Cardone S, Bedogni G, Caputo F, 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(3):312–7.

    Article  CAS  PubMed  Google Scholar 

  141. De Beaurepaire R. Suppression of alcohol dependence using baclofen: a 2-year observational study of 100 patients. Front Psychiatry. 2012;3:3–7.

    Article  CAS  Google Scholar 

  142. Rolland B, Labreuche J, Duhamel A, Deheul S, Gautier S, Auffret M, et al. Baclofen for alcohol dependence: relationships between baclofen and alcohol dosing and the occurrence of major sedation. Eur Neuropsychopharmacol. 2015;25(10):1631–6.

    Article  CAS  PubMed  Google Scholar 

  143. Rolland B, Jaillette E, Carton L, Bence C, Deheul S, Saulnier F, et al. Assessing alcohol versus baclofen withdrawal syndrome in patients treated with baclofen for alcohol use disorder. J Clin Psychopharmacol. 2014;34(1):153–6.

    Article  CAS  PubMed  Google Scholar 

  144. Rolland B, Valin T, Langlois C, Auffret M, Gautier S, Deheul S, et al. Safety and drinking outcomes among patients with comorbid alcohol dependence and borderline personality disorder treated with high-dose baclofen: a comparative cohort study. Int Clin Psychopharmacol. 2015;30(1):49–53.

    Article  PubMed  Google Scholar 

  145. Franchitto N, Pelissier F, Lauque D, Simon N, Lançon C. Self-intoxication with baclofen in alcohol-dependent patients with co-existing psychiatric illness: an emergency department case series. Alcohol Alcohol. 2014;49(1):79–83.

    Article  CAS  PubMed  Google Scholar 

  146. Leung NY, Whyte IM, Isbister GK. Baclofen overdose: defining the spectrum of toxicity. Emerg Med Australas. 2006;18(1):77–82.

    Article  PubMed  Google Scholar 

  147. Pommier P, Debaty G, Bartoli M, Viglino D, Carpentier F, Danel V, et al. Severity of deliberate acute baclofen poisoning: a nonconcurrent cohort study. Basic Clin Pharmacol Toxicol. 2014;114(4):360–4.

    Article  CAS  PubMed  Google Scholar 

  148. National Health Medical Research Council. Australian guidelines to reduce health risks from drinking alcohol. Canberra: Commonwealth of Australia; 2009.

    Google Scholar 

  149. Suh JJ, Pettinati HM, Kampman KM, O’Brien CP. The status of disulfiram: a half of a century later. J Clin Psychopharmacol. 2006;26(3):290–302.

    Article  CAS  PubMed  Google Scholar 

  150. 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 Int Med. 2008;168(11):1188–99.

    Article  CAS  Google Scholar 

  151. 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.

    Article  CAS  PubMed  Google Scholar 

  152. Jonas DE, Amick HR, Feltner C, Bobashev G, Thomas K, Wines R, et al. Pharmacotherapy for adults with alcohol use disorders in outpatient settings: a systematic review and meta-analysis. JAMA. 2014;311(18):1889–900.

    Article  PubMed  CAS  Google Scholar 

  153. Iovieno N, Papakostas GI. Correlation between different levels of placebo response rate and clinical trial outcome in major depressive disorder: a meta-analysis. J Clin Psychiatry. 2012;73(10):1300–6.

    Article  PubMed  Google Scholar 

  154. Joshi N, McMillan S. Drug safety: case reports. Drug Saf Case Rep. 2014;1(1):1–2.

    Article  Google Scholar 

  155. Leucht S, Hierl S, Kissling W, Dold M, Davis JM. Putting the efficacy of psychiatric and general medicine medication into perspective: review of meta-analyses. Br J Psychiatry. 2012;200(2):97–106.

    Article  PubMed  Google Scholar 

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Acknowledgments

This study was undertaken at and funded by the University of Southampton. The authors would like to thank the following experts for reviewing reference lists: Professor R. F. Anton, Professor H. R. Kranzler, Professor H. J. Aubin and Professor W. van den Brink.

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Correspondence to Julia M. A. Sinclair.

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No sources of funding were used to assist in the preparation of this study.

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David Baldwin has received four grants from Lundbeck A/S for research on two antidepressant compounds and has participated in advisory board meetings hosted by Lundbeck A/S. Julia Sinclair has participated in advisory boards hosted by Lundbeck A/S discussing nalmefene and has received speaker fees for speaking at meetings. Sophia Chambers has a Studentship funded by the Wessex Academic Health Science Network and Lundbeck partnership. Celia Shiles declares that she has no conflicts of interest that are directly relevant to the content of this study.

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Sinclair, J.M.A., Chambers, S.E., Shiles, C.J. et al. Safety and Tolerability of Pharmacological Treatment of Alcohol Dependence: Comprehensive Review of Evidence. Drug Saf 39, 627–645 (2016). https://doi.org/10.1007/s40264-016-0416-y

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