Skip to main content
SpringerLink
Log in

Sodium Oxybate: A Review of Its Use in Alcohol Withdrawal Syndrome and in the Maintenance of Abstinence in Alcohol Dependence

  • Adis Drug Evaluation
  • Published:
Clinical Drug Investigation Aims and scope Submit manuscript

Abstract

A liquid formulation of sodium oxybate (Alcover®), the sodium salt of γ-hydroxybutyric acid (GHB), is approved in Italy and Austria for use in alcohol withdrawal syndrome and for the maintenance of abstinence in alcohol dependence. This article reviews the efficacy and tolerability of sodium oxybate in alcohol withdrawal syndrome and in the maintenance of abstinence in alcohol dependence, as well as summarizing its pharmacological properties. Results of randomized controlled trials indicate that sodium oxybate was at least as effective as diazepam and clomethiazole in patients with alcohol withdrawal syndrome, rapidly alleviating symptoms, and was at least as effective as naltrexone or disulfiram in the maintenance of abstinence in alcohol-dependent patients. Sodium oxybate was generally well tolerated. The risk of sodium oxybate abuse is generally low when it is administered to alcohol-dependent patients at its approved dosage, under the supervision of a designated family member and with continuous strict medical surveillance. However, certain patient groups, such as patients with alcohol dependence and borderline personality disorder or who are in remission from heroin or cocaine addiction, may not be suitable candidates for sodium oxybate therapy because of an increased risk of abuse. In conclusion, sodium oxybate is a useful option for the treatment of alcohol withdrawal syndrome and for the maintenance of abstinence in alcohol dependence.

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

Fig. 1

Similar content being viewed by others

References

  1. Rehm J. The risks associated with alcohol use and alcoholism. Alcohol Res Health. 2011;34(2):135–43.

    PubMed Central  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  3. Wittchen HU, Jacobi F, Rehm J, et al. The size and burden of mental disorders and other disorders of the brain in Europe 2010. Eur Neuropsychopharmacol. 2011;21(9):655–79.

    Article  CAS  PubMed  Google Scholar 

  4. Kohn R, Saxena S, Levav I, et al. The treatment gap in mental health care. Bull World Health Organ. 2004;82(11):858–66.

    PubMed Central  PubMed  Google Scholar 

  5. National Institute for Health and Clinical Excllence. Alcohol-use disorders: diagnosis, assessment and management of harmful drinking and alcohol dependence. 2011. http://www.nice.org.uk/nicemedia/live/13337/53191/53191.pdf. Accessed 14 Oct 2013.

  6. Rehm J, Baliunas D, Borges GLG, et al. The relation between different dimensions of alcohol consumption and burden of disease: an overview. Addiction. 2010;105(5):817–43.

    Article  PubMed Central  PubMed  Google Scholar 

  7. Leggio L, Kenna GA, Swift RM. New developments for the pharmacological treatment of alcohol withdrawal syndrome: a focus on non-benzodiazepine GABAergic medications. Prog Neuropsychopharmacol Biol Psychiatry. 2008;32(5):1106–17.

    Article  CAS  PubMed  Google Scholar 

  8. Chick J, Nutt DJ. Substitution therapy for alcoholism: time for a reappraisal? J Psychopharmacol (Oxf). 2012;26(2):205–12.

    Article  CAS  Google Scholar 

  9. Laboratorio Farmaceutico C.T. S.r.l. Alcover® (sodium oxybate; 4-hydroxybutyric acid sodium salt): Italian summary of product characteristics. 2007.

  10. G.L. Pharma GmbH. Alcover® (sodium gamma hydroxybutyric acid): Austrian summary of product characteristics. 2012.

  11. Tabakoff B. Neurobiology of GHB in relation to alcohol dependence [abstract no. SAT2.2]. Alcohol Alcohol. 2011;46(Suppl 1):i24.

    Article  Google Scholar 

  12. June HL, Williams JA, Cason CR, et al. Low doses of gamma-hydroxybutyric acid (GHB) attenuate ethanol intake in alcohol-preferring (P) rats [abstract no. 62]. Alcohol Clin Exp Res. 1995;19(Suppl 2):14A.

    Google Scholar 

  13. Snead OC, Gibson KM. γ-Hydroxybutyric acid. N Engl J Med. 2005;352(26):2721–32.

    Article  CAS  PubMed  Google Scholar 

  14. Benarroch EE. γ-Hydroxybutyric acid and its relevance in neurology. Neurology. 2009;72(3):282–6.

    Article  PubMed  Google Scholar 

  15. Nicholson KL, Balster RL. GHB: a new and novel drug of abuse. Drug Alcohol Depend. 2001;63(1):1–22.

    Article  CAS  PubMed  Google Scholar 

  16. Treskov VG, Krashkina II, Tsirenina ML, et al. Effect of sodium hydroxybutyrate on catecholamine and serotonin levels and monoamine oxidase activity in alcoholics. Bull Exp Biol Med. 1989;108:976–8.

    Article  Google Scholar 

  17. Caputo F, Vignoli T, Maremmani I, et al. Gamma hydroxybutyric acid (GHB) for the treatment of alcohol dependence: a review. Int J Environ Res Public Health. 2009;6(6):1917–29.

    Article  CAS  PubMed  Google Scholar 

  18. Carai MAM, Lobina C, Maccioni P, et al. γ-Aminobutyric acidB (GABAB)-receptor mediation of different in vivo effects of γ-butyrolactone. J Pharmacol Sci. 2008;106(2):199–207.

    Article  CAS  PubMed  Google Scholar 

  19. Carai MA, Colombo G, Reali R, et al. Central effects of 1,4-butanediol are mediated by GABAB receptors via its conversion into γ-hydroxybutyric acid. Eur J Pharmacol. 2002;441(3):157–63.

    Article  CAS  PubMed  Google Scholar 

  20. Absalom N, Eghorn LF, Villumsen IS, et al. α4βδ GABAA receptors are high-affinity targets for γ-hydroxybutyric acid (GHB). Proc Natl Acad Sci USA. 2012;109(33):13404–9.

    Article  CAS  PubMed  Google Scholar 

  21. Gessa GL, Agabio R, Carai MAM, et al. Mechanism of the antialcohol effect of gamma-hydroxybutyric acid. Alcohol. 2000;20(3):271–6.

    Article  CAS  PubMed  Google Scholar 

  22. Biggio G, Cibin M, Diana M, et al. Suppression of voluntary alcohol intake in rats and alcoholics by gamma-hydroxybutyric acid: a non-GABAergic mechanism. Adv Biochem Psychopharmacol. 1992;47:281–8.

    CAS  PubMed  Google Scholar 

  23. Colombo G, Gessa GL. Gamma-hydroxybutyric acid in alcohol preference, dependence and withdrawal. Addict Biol. 2000;5(4):389–403.

    Article  CAS  PubMed  Google Scholar 

  24. Fadda F, Colombo G, Mosca E, et al. Suppression by gamma-hydroxybutyric acid of ethanol withdrawal syndrome in rats. Alcohol Alcohol. 1989;24(5):447–51.

    CAS  PubMed  Google Scholar 

  25. Colombo G, Agabio R, Lobina C, et al. Cross-tolerance to ethanol and γ-hydroxybutyric acid. Eur J Pharmacol. 1995;273(3):235–8.

    Article  CAS  PubMed  Google Scholar 

  26. Agabio R, Colombo G, Loche A, et al. γ-Hydroxybutyric acid reducing effect on ethanol intake: evidence in favour of a substitution mechanism. Alcohol Alcohol. 1998;33(5):465–74.

    Article  CAS  PubMed  Google Scholar 

  27. Maccioni P, Pes D, Fantini N, et al. γ-Hydroxybutyric acid (GHB) suppresses alcohol’s motivational properties in alcohol-preferring rats. Alcohol. 2008;42(2):107–13.

    Article  CAS  PubMed  Google Scholar 

  28. Caputo F, Addolorato G, Trevisani F, et al. γ-Hydroxybutyrate as a treatment for alcoholism. Lancet. 2005;366(9490):981–2.

    Article  PubMed  Google Scholar 

  29. Leone MA, Vigna-Taglianti F, Avanzi G, et al. Gamma-hydroxybutyrate (GHB) for treatment of alcohol withdrawal and prevention of relapses. Cochrane Database Syst Rev. 2010.(2):CD006266.

  30. Xyrem® (sodium oxybate) oral solution CIII: US prescribing Information. 2012. http://www.xyrem.com/images/XYREM_PI.pdf. Accessed 14 Oct 2013.

  31. European Medicines Agency. Xyrem (sodium oxybate): EU summary of product characteristics. 2011. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000593/WC500057103.pdf. Accessed 14 Oct 2013.

  32. Wang YG, Swick TJ, Carter LP, et al. Safety overview of postmarketing and clinical experience of sodium oxybate (Xyrem): abuse, misuse, dependence, and diversion. J Clin Sleep Med. 2009;5(4):365–71.

    CAS  PubMed  Google Scholar 

  33. Drasbek KR, Christensen J, Jensen K. Gamma-hydroxybutyrate: a drug of abuse. Acta Neurol Scand. 2006;114(3):145–56.

    Article  CAS  PubMed  Google Scholar 

  34. Addolorato G, Caputo F, Capristo E, et al. Gamma-hydroxybutyric acid: efficacy, potential abuse, and dependence in the treatment of alcohol addiction. Alcohol. 2000;20(3):217–22.

    Article  CAS  PubMed  Google Scholar 

  35. Dyer JE. γ-Hydroxybutyrate: a health-food product producing coma and seizurelike activity. Am J Emerg Med. 1991;9(4):321–4.

    Article  CAS  PubMed  Google Scholar 

  36. McDonough M, Kennedy N, Glasper A, et al. Clinical features and management of gamma-hydroxybutyrate (GHB) withdrawal: a review. Drug Alcohol Depend. 2004;75(1):3–9.

    Article  CAS  PubMed  Google Scholar 

  37. Beghè F, Carpanini MT. Safety and tolerability of gamma-hydroxybutyric acid in the treatment of alcohol-dependent patients. Alcohol. 2000;20(3):223–5.

    Article  PubMed  Google Scholar 

  38. Thai D, Dyer JE, Benowitz NL, et al. GHB and ethanol effects and interactions in humans. J Clin Psychopharmacol. 2006;26(5):524–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Van Cauter E, Plat L, Scharf MB, et al. Simultaneous stimulation of slow-wave sleep and growth hormone secretion by gamma-hydroxybutyrate in normal young men. J Clin Invest. 1997;100(3):745–53.

    Article  PubMed Central  PubMed  Google Scholar 

  40. Addolorato G, Capristo E, Gessa GL, et al. Long-term administration of GHB does not affect muscular mass in alcoholics. Life Sci. 1999;65(14):PL191–6.

    Google Scholar 

  41. Ferrara SD, Giorgetti R, Zancaner S, et al. Effects of single dose of gamma-hydroxybutyric acid and lorazepam on psychomotor performance and subjective feelings in healthy volunteers. Eur J Clin Pharmacol. 1999;54(11):821–7.

    Article  CAS  PubMed  Google Scholar 

  42. Carter LP, Griffiths RR, Mintzer MZ. Cognitive, psychomotor, and subjective effects of sodium oxybate and triazolam in healthy volunteers. Psychopharmacology (Berl). 2009;206(1):141–54.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  43. Nava F, Premi S, Manzato E, et al. Gamma-hydroxybutyrate reduces both withdrawal syndrome and hypercortisolism in severe abstinent alcoholics: an open study vs. diazepam. Am J Drug Alcohol Abuse. 2007;33(3):379–92.

    Article  PubMed  Google Scholar 

  44. Franchi S, Sacerdote P, Moretti S, et al. The effects of alcoholism pharmacotherapy on immune responses in alcohol-dependent patients. Int J Immunopathol Pharmacol. 2010;23(3):847–55.

    CAS  PubMed  Google Scholar 

  45. Ferrara SD, Zotti S, Tedeschi L, et al. Pharmacokinetics of γ-hydroxybutyric acid in alcohol dependent patients after single and repeated oral doses. Br J Clin Pharmacol. 1992;34(3):231–5.

    Article  CAS  PubMed  Google Scholar 

  46. Vivet P, Pross N, Denot C, et al. Pharmacodynamic interactions of a solid formulation of sodium oxybate and alcohol in healthy volunteers [abstract no. SAT2.3]. Alcohol Alcohol. 2013;48(Suppl 1):i34.

    Article  Google Scholar 

  47. Data on file, D&A Pharma, 2013.

  48. American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 3rd ed. revised. Washington, DC: American Psychiatric Association; 1987.

  49. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994.

    Google Scholar 

  50. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed. (text revision). Washington, DC: American Psychiatric Association; 2000.

  51. World Health Organization. International classification of diseases, 10th revision. Geneva: World Health Organization; 1992.

    Google Scholar 

  52. Gallimberti L, Canton G, Gentile N, et al. Gamma-hydroxybutyric acid for treatment of alcohol withdrawal syndrome. Lancet. 1989;2(8666):787–9.

    Article  CAS  PubMed  Google Scholar 

  53. Nimmerrichter AA, Walter H, Gutierrez-Lobos KE, et al. Double-blind controlled trial of γ-hydroxybutyrate and clomethiazole in the treatment of alcohol withdrawal. Alcohol Alcohol. 2002;37(1):67–73.

    Article  CAS  PubMed  Google Scholar 

  54. Addolorato G, Balducci G, Capristo E, et al. Gamma-hydroxybutyric acid (GHB) in the treatment of alcohol withdrawal syndrome: a randomized comparative study versus benzodiazepine. Alcohol Clin Exp Res. 1999;23(10):1596–604.

    CAS  PubMed  Google Scholar 

  55. Korninger C, Roller RE, Lesch OM. Gamma-hydroxybutyric acid in the treatment of alcohol withdrawal syndrome in patients admitted to hospital. Acta Med Austriaca. 2003;30(3):83–6.

    CAS  PubMed  Google Scholar 

  56. Moncini M, Masini E, Gambassi F, et al. Gamma-hydroxybutyric acid and alcohol-related syndromes. Alcohol. 2000;20(3):285–91.

    Article  CAS  PubMed  Google Scholar 

  57. Elsing C, Stremmel W, Grenda U, et al. Gamma-hydroxybutyric acid versus clomethiazole for the treatment of alcohol withdrawal syndrome in a medical intensive care unit: an open, single-center randomized study. Am J Drug Alcohol Abuse. 2009;35(3):189–92.

    Article  PubMed  Google Scholar 

  58. Gallimberti L, Ferri M, Ferrara SD, et al. Gamma-hydroxybutyric acid in the treatment of alcohol dependence: a double-blind study. Alcohol Clin Exp Res. 1992;16(4):673–6.

    Article  CAS  PubMed  Google Scholar 

  59. Cacciaglia R, Lesch OM, Vivet P. GATE 2 study: sodium oxybate in the maintenance of alcohol abstinence and prevention of alcohol relapse [abstract no. P30]. Alcohol Alcohol. 2013;48 Suppl 1:i47–8 plus poster presented at the 14th Congress of the European Society for Biomedical Research on Alcoholism; 8–11 Sep 2013; Warsaw.

  60. Nava F, Premi S, Manzato E, et al. Comparing treatments of alcoholism on craving and biochemical measures of alcohol consumptions. J Psychoactive Drugs. 2006;38(3):211–7.

    Article  PubMed  Google Scholar 

  61. Caputo F, Addolorato G, Lorenzini F, et al. Gamma-hydroxybutyric acid versus naltrexone in maintaining alcohol abstinence: an open randomized comparative study. Drug Alcohol Depend. 2003;70(1):85–91.

    Article  CAS  PubMed  Google Scholar 

  62. Stella L, Addolorato G, Rinaldi B, 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 

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

    Article  CAS  PubMed  Google Scholar 

  64. Addolorato G, Castelli E, Stefanini GF, et al. An open multicentric study evaluating 4-hydroxybutyric acid sodium salt in the medium-term treatment of 179 alcohol dependent subjects. Alcohol Alcohol. 1996;31(4):341–5.

    Article  CAS  PubMed  Google Scholar 

  65. Addolorato G, Cibin M, Caputo F, et al. γ-Hydroxybutyric acid in the treatment of alcoholism: dosage fractioning utility in non-responder alcoholic patients. Drug Alcohol Depend. 1998;53(1):7–10.

    Article  CAS  PubMed  Google Scholar 

  66. Maremmani I, Lamanna F, Tagliamonte A. Long-term therapy using GHB (sodium gamma hydroxybutyrate) for treatment-resistant chronic alcoholics. J Psychoactive Drugs. 2001;33(2):135–42.

    Article  CAS  PubMed  Google Scholar 

  67. Maremmani AGI, Pani PP, Rovai L, et al. Long-term γ-hydroxybutyric acid (GHB) and disulfiram combination therapy in GHB treatment-resistant chronic alcoholics. Int J Environ Res Public Health. 2011;8(7):2816–27.

    Article  CAS  PubMed  Google Scholar 

  68. Caputo F, Francini S, Brambilla R, et al. Sodium oxybate in maintaining alcohol abstinence in alcoholic patients with and without psychiatric comorbidity. Eur Neuropsychopharmacol. 2011;21(6):450–6.

    Article  CAS  PubMed  Google Scholar 

  69. Caputo F, Del Re A, Brambilla R, et al. Sodium oxybate in maintaining alcohol abstinence in alcoholic patients according to Lesch typologies: a pilot study. J Psychopharmacol (Oxf). 2013. doi:10.1177/0269881113504015.

    Google Scholar 

  70. Caputo F, Francini S, Stoppo M, et al. Incidence of craving for and abuse of gamma-hydroxybutyric acid (GHB) in different populations of treated alcoholics: an open comparative study. J Psychopharmacol (Oxf). 2009;23(8):883–90.

    Article  CAS  Google Scholar 

  71. Lesch O, Skala K, Addolorato G, et al. Sodium oxybate in alcohol withdrawal: results from the GATE 1 study [abstract no. SAT2.1]. Alcohol Alcohol. 2013;48(Suppl 1):i33–4.

    Article  Google Scholar 

  72. European Medicines Agency. Guideline on the development of medicinal products for the treatment of alcohol dependence. 2010. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/03/WC500074898.pdf. Accessed 10 Sep 2013.

  73. AOP Orphan Pharmaceuticals AG. Ethylex (naltrexone) film-coated tablets: Irish summary of product characteristics. 2011. http://www.imb.ie/images/uploaded/swedocuments/LicenseSPC_PA0934-002-001_05072012085042.pdf. Accessed 10 Oct 2013.

  74. Actavis UK Ltd. Antabuse tablets (disulfiram): UK summary of product characteristics. 2012. http://beta.medicines.org.uk/emc/medicine/519. Accessed 10 Oct 2013.

  75. Merck Serono. Campral EC (acamprosate): UK summary of product characteristics. 2012. http://beta.medicines.org.uk/emc/medicine/1042. Accessed 10 Oct 2013.

  76. Keating GM. Nalmefene: a review of its use in the treatment of alcohol dependence. CNS Drugs. 2013;27(9):761–72.

    Article  CAS  PubMed  Google Scholar 

  77. Németh Z, Kun B, Demetrovics Z. The involvement of gamma-hydroxybutyrate in reported sexual assaults: a systematic review. J Psychopharmacol (Oxf). 2010;24(9):1281–7.

    Article  Google Scholar 

  78. Nava F, Bravin S, Borroni G, et al. A retrospective study on the use of sodium oxybate in northern Italy [abstract no. SAT2.4]. Alcohol Alcohol. 2013;48(Suppl 1):i34.

    Article  Google Scholar 

Download references

Disclosure

The preparation of this review was not supported by any external funding. During the peer review process, the manufacturer of the agent under review was offered an opportunity to comment on this article. Changes resulting from comments received were made by the author on the basis of scientific and editorial merit.

Author information

Authors and Affiliations

  1. Adis, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, North Shore, 0754, Auckland, New Zealand

    Gillian M. Keating

Authors
  1. Gillian M. Keating
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gillian M. Keating.

Additional information

The manuscript was reviewed by: G. Addolorato, Department of Internal Medicine, Catholic University of Rome, Rome, Italy; F. Caputo, Department of Internal Medicine, SS Annunziata Hospital, Cento, Ferrara, Italy; O. M. Lesch, Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria; F. Vigna-Taglianti, Department of Clinical and Biological Sciences, University of Torino, Torino, Italy.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Keating, G.M. Sodium Oxybate: A Review of Its Use in Alcohol Withdrawal Syndrome and in the Maintenance of Abstinence in Alcohol Dependence. Clin Drug Investig 34, 63–80 (2014). https://doi.org/10.1007/s40261-013-0158-x

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40261-013-0158-x

Keywords

Search

Navigation