Alcohol Withdrawal Syndrome and Delirium –  from its Pathophysiology to Treatment

Authors: T. Kašpárek;  M. Dreisig;  R. Barteček
Authors‘ workplace: Psychiatrická klinika LF MU a FN Brno
Published in: Cesk Slov Neurol N 2014; 77/110(2): 153-157
Category: Review Article


Alcohol dependence leads to adaptations of the nervous system that leads to withdrawal syndrome manifestation when regular alcohol consumption is abruptly discontinued. Withdrawal syndrome is characterized mainly by excessive excitatory and diminished inhibitory mechanisms, mediated by glutamatergic and gaba-ergic systems. This imbalance leads to anxiety, restlessness, tremor and decreased seizure threshold. Furthermore, changes to dopaminergic, serotoninergic, noradrenergic, opioid system, or corticotropin releasing hormone-related activation of stress reaction contribute to the clinical picture that includes vegetative hyperactivity, affective changes, dysphoria, hypohedonia, etc. Delirium – a complication of severe withdrawal – is a significant clinical syndrome that complicates health care management and may lead to fatal outcomes. Treatment of alcohol withdrawal and delirium is based on gradual establishment of a new balance of excitatory and inhibitory systems without the presence of external inhibitory substance – alcohol. In clinical practice the pathophysiology is reflected in the administration of gaba-ergic compounds (benzodiazepines, clomethiazole) with gradual dose tapering. Complex effect of alcohol with a number of related somatic complications requires additional systematic somatic care.

Key words:
alcohol – withdrawal syndrome – delirium – neurotoxicity

The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.

The Editorial Board declares that the manu­script met the ICMJE “uniform requirements” for biomedical papers.


1. de Wit M, Jones DG, Sessler CN, Zilberberg MD, Weaver MF. Alcohol‑ use disorders in the critically ill patient. Chest 2010; 138(4): 994– 1003.

2. O‘Regan NA, Fitzgerald J, Timmons S, O‘Connell H, Meagher D. Delirium: a key challenge for perioperative care. Int J Surg 2013; 11(2): 136– 144.

3. Csemy L, Nespor K, Brozova J. Delirium tremens v České republice: strmý vzestup. Casopis lekaru ceskych 2007; 146(1): 82– 83.

4. Wrase J, Schlagenhauf F, Kienast T, Wustenberg T, Bermpohl F, Kahnt T et al. Dysfunction of reward processing correlates with alcohol craving in detoxified alcoholics. Neuroimage 2007; 35(2): 787– 794.

5. de Greck M, Supady A, Thiemann R, Tempelmann C,Bogerts B, Forschner L et al. Decreased neural activity in reward circuitry during personal reference in abstinent alcoholics –  a fMRI study. Hum Brain Mapp 2009; 30(5): 1691– 1704.

6. Heinz A, Beck A, Grüsser SM, Grace AA, Wrase J. Identifying the neural circuitry of alcohol craving and relapse vulnerability. Addict Biol 2009; 14(1): 108– 118.

7. Grant KA, Lovinger DM. Cellular and behavioral neurobio­logy of alcohol: receptor‑ mediated neuronal processes. Clin Neurosci 1995; 3(3): 155– 164.

8. Snell LD, Nunley KR, Lickteig RL, Browning MD, Tabakoff B, Hoffman PL. Regional and subunit specific changes in NMDA receptor mRNA and immunoreactivity in mouse brain following chronic ethanol ingestion. Brain Res Mol Brain Res 1996; 40(1): 71– 78.

9. Gulya K, Grant KA, Valverius P, Hoffman PL, Tabakoff B. Brain regional specificity and time‑ course of changes in the NMDA receptor‑ ionophore complex during ethanol withdrawal. Brain Res 1991; 547(1): 129– 134.

10. Tsai G, Gastfriend DR, Coyle JT. The glutamatergic basis of human alcoholism. Am J Psychiatry 1995; 152(3): 332– 340.

11. Bleich S, Degner D, Sperling W, Bonsch D, Thurauf N, Kornhuber J. Homocysteine as a neurotoxin in chronic alcoholism. Prog Neuropsychopharmacol Biol Psychiatry 2004; 28(3): 453– 464.

12. Brown ME, Anton RF, Malcolm R, Ballenger JC. Alcohol detoxification and withdrawal seizures: clinical support for a kindling hypothesis. Biol Psychiatry 1988; 23(5): 507– 514.

13. Snell LD, Szabo G, Tabakoff B, Hoffman PL. Gangliosides reduce the development of ethanol dependence without affecting ethanol tolerance. J Pharmacol Exp Ther 1996; 279(1): 128– 136.

14. Zeise ML, Kasparov S, Capogna M, Zieglgansberger W. Acamprosate (calciumacetylhomotaurinate) decreases postsynaptic potentials in the rat neocortex: possible involvement of excitatory amino acid receptors. Eur J Pharmacol 1993; 231(1): 47– 52.

15. Montpied P, Morrow AL, Karanian JW, Ginns EI, Martin BM, Paul SM. Prolonged ethanol inhalation decreases gamma‑ aminobutyric acidA receptor alpha subunit mRNAs in the rat cerebral cortex. Mol Pharmacol 1991; 39(2): 157– 163.

16. Allan AM, Harris RA. Acute and chronic ethanol treatments alter GABA receptor‑ operated chloride channels. Pharmacol Biochem Behav 1987; 27(4): 665– 670.

17. Hemmingsen R, Braestrup C, Nielsen M, Barry DI. The benzodiazepine/ GABA receptor complex during severe ethanol intoxication and withdrawal in the rat. Acta Psychiatr Scand 1982; 65(2): 120– 126.

18. Brodie MS, Shefner SA, Dunwiddie TV. Ethanol increases the firing rate of dopamine neurons of the rat ventral tegmental area in vitro. Brain Res 1990; 508(1): 65– 69.

19. Imperato A, Di Chiara G. Preferential stimulation of dopamine release in the nucleus accumbens of freely moving rats by ethanol. J Pharmacol Exp Ther 1986; 239(1): 219– 228.

20. Weiss F, Parsons LH, Schulteis G, Hyytia P, Lorang MT,Bloom FE et al. Ethanol self‑ administration restores withdrawal‑associated deficiencies in accumbal dopamine and 5- hydroxytryptamine release in dependent rats. J Neurosci 1996; 16(10): 3474– 3485.

21. Nutt D, Glue P, Molyneux S, Clark E. Alpha‑ 2‑adrenoceptor function in alcohol withdrawal: a pilot study of the effects of iv. clonidine in alcoholics and normals. Alcohol Clin Exp Res 1988; 12(1): 14– 18.

22. Tabakoff B, Hoffman PL. Alcohol interactions with brain opiate receptors. Life Sci 1983; 32(3): 197– 204.

23. Tabakoff B, Urwyler S, Hoffman PL. Ethanol alters kinetic characteristics and function of striatal morphine receptors. J Neurochem 1981; 37(2): 518– 521.

24. O‘Malley SS, Jaffe AJ, Chang G, Rode S, Schottenfeld R, Meyer RE et al. Six‑ month follow‑up of naltrexone and psychotherapy for alcohol dependence. Arch Gen Psychiatry 1996; 53(3): 217– 224.

25. 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– 713.

26. Johnson BA, Roache JD, Javors MA, DiClemente CC,Cloninger CR, Prihoda TJ et al. Ondansetron for reduction of drinking among bio­logically predisposed alcoholic patients: A randomized controlled trial. JAMA 2000; 284(8): 963– 971.

27. Merlo Pich E, Lorang M, Yeganeh M, Rodriguez de Fonseca F, Raber J, Koob GF et al. Increase of extracellular corticotropin‑releasing factor‑like immunoreactivity levels in the amygdala of awake rats during restraint stress and ethanol withdrawal as measured by microdialysis. J Neurosci 1995; 15(8): 5439– 5447.

28. Schuckit MA, Smith TL, Tipp JE. The Self‑ Rating of the Effects of alcohol (SRE) form as a retrospective measure of the risk for alcoholism. Addiction 1997; 92(8): 979– 988.

29. Schuckit MA, Smith TL, Kalmijn J. The search for genes contributing to the low level of response to alcohol: patterns of findings across studies. Alcohol Clin Exp Res 2004; 28(10): 1449– 1458.

30. Li TK, Bosron WF. Genetic variability of enzymes of alcohol metabolism in human beings. Ann Emerg Med 1986; 15(9): 997– 1004.

31. Evren C, Durkaya M, Evren B, Dalbudak E, Cetin R.Relationship of relapse with impulsivity, novelty seeking and craving in male alcohol‑ dependent inpatients. Drug Alcohol Rev 2012; 31(1): 81– 90.

32. Tomassini A, Struglia F, Spaziani D, Pacifico R, Stratta P, Rossi A. Decision making, impulsivity, and personality traits in alcohol‑ dependent subjects. Am J Addict 2012; 21(3): 263– 267.

33. Metten P, Belknap JK, Crabbe JC. Drug withdrawal convulsions and susceptibility to convulsants after short‑term selective breeding for acute ethanol withdrawal. Behav Brain Res 1998; 95(1): 113– 122.

34. Metten P, Phillips TJ, Crabbe JC, Tarantino LM, McClearn GE, Plomin R et al. High genetic susceptibility to ethanol withdrawal predicts low ethanol consumption. Mamm Genome 1998; 9(12): 983– 990.

35. Khan A, Levy P, DeHorn S, Miller W, Compton S. Predictors of mortality in patients with delirium tremens. Acad Emerg Med 2008; 15(8): 788– 790.

36. Monte R, Rabunal R, Casariego E, López‑ Agreda H, Mateos A, Pértega S. Analysis of the factors determining survival of alcoholic withdrawal syndrome patients in a general hospital. Alcohol Alcohol 2010; 45(2): 151– 158.

37. Foy A, Kay J, Taylor A. The course of alcohol withdrawal in a general hospital. QJM 1997; 90(4): 253– 261.

38. Simioni N, Cottencin O, Guardia D, Rolland B. Early relapse in alcohol dependence may result from late withdrawal symptoms. Med Hypotheses 2012; 79(6): 894– 895.

39. De Soto CB, O‘Donnell WE, Allred LJ, Lopes CE. Symptomatology in alcoholics at various stages of abstinence. Alcohol Clin Exp Res 1985; 9(6): 505– 512.

40. Mayo‑ Smith MF, Beecher LH, Fischer TL, Gorelick DA,Guillaume JL, Hill A et al. Management of alcohol withdrawal delirium. An evidence‑based practice guideline. Arch Intern Med 2004; 164(13): 1405– 1412.

41. Nimmerrichter AA, Walter H, Gutierrez‑ Lobos KE,Lesch OM. Double‑blind controlled trial of gamma‑ hydroxybutyrate and clomethiazole in the treatment of alcohol withdrawal. Alcohol Alcohol 2002; 37(1): 67– 73.

42. de Millas W, Ganzer F, Kuhn S, Haasen C. Oxazepam versus clomethiazol in alcohol withdrawal treatment. Eur Addict Res 2010; 16(4): 179– 184.

43. Rosenson J, Clements C, Simon B, Vieaux J, Graffman S, Vahidnia F et al. Phenobarbital for acute alcohol withdrawal: a prospective randomized double‑blind placebo‑ controlled study. J Emerg Med 2013; 44(3): 592– 598.

44. 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– 1329.

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

46. Barrons R, Roberts N. The role of carbamazepine and oxcarbazepine in alcohol withdrawal syndrome. J Clin Pharm Ther 2010; 35(2): 153– 167.

47. Carlson RW, Kumar NN, Wong‑Mckinstry E, Ayyagari S, Puri N, Jackson FK et al. Alcohol withdrawal syndrome. Crit Care Clin 2012; 28(4): 549– 585.

48. Dreisig M, Kašpárek T. Komplikace odvykacího stavu při závislosti na alkoholu –  dia­gnostika a léčba. Psychiatrie pro praxi 2013; 14(1): 18– 20.

49. Nespor K. Antipsychotika u deliria tremens znamenají nepřiměřené riziko. Česká a slovenská psychiatrie 2005; 101(4): 230– 231.

50. Cadete‑ Leite A, Alves MC, Paula‑ Barbosa MM, Uylings HB, Tavares MA. Quantitative analysis of basal dendrites of prefrontal pyramidal cells after chronic alcohol consumption and withdrawal in the adult rat. Alcohol Alcohol 1990; 25(5): 467– 475.

51. Harper C. The neuropathology of alcohol‑ specific brain damage, or does alcohol damage the brain? J Neuropathol Exp Neurol 1998; 57(2): 101– 110.

52. Kril JJ, Halliday GM, Svoboda MD, Cartwright H. The cerebral cortex is damaged in chronic alcoholics. Neuroscience 1997; 79(4): 983– 998.

53. Jernigan TL, Butters N, DiTraglia G, Schafer K, Smith T, Irwin M et al. Reduced cerebral grey matter observed in alcoholics using magnetic resonance imaging. Alcohol Clin Exp Res 1991; 15(3): 418– 427.

54. Pfefferbaum A, Sullivan EV, Mathalon DH, Lim KO.Frontal lobe volume loss observed with magnetic resonance imaging in older chronic alcoholics. Alcohol Clin Exp Res 1997; 21(3): 521– 529.

55. Pfefferbaum A, Sullivan EV, Rosenbloom MJ, Mathalon DH, Lim KO. A controlled study of cortical gray matter and ventricular changes in alcoholic men over a 5‑year interval. Arch Gen Psychiatry 1998; 55(10): 905– 912.

56. Barthauer L, Tarter R, Hirsch W, Van Thiel D. Brain morphologic characteristics of cirrhotic alcoholics and cirrhotic nonalcoholics: an MRI study. Alcohol Clin Exp Res 1992; 16(5): 982– 985.

57. Sullivan EV, Marsh L, Mathalon DH, Lim KO, Pfefferbaum A. Relationship between alcohol withdrawal seizures and temporal lobe white matter volume deficits. Alcohol Clin Exp Res 1996; 20(2): 348– 354.

58. Pfefferbaum A, Sullivan EV, Mathalon DH, Shear PK,Rosenbloom MJ, Lim KO. Longitudinal changes in magnetic resonance imaging brain volumes in abstinent and relapsed alcoholics. Alcohol Clin Exp Res 1995; 19(5): 1177– 1191.

59. Gazdzinski S, Durazzo TC, Meyerhoff DJ. Temporal dynamics and determinants of whole brain tissue volume changes during recovery from alcohol dependence. Drug Alcohol Depend 2005; 78(3): 263– 273.

60. Duka T, Townshend JM, Collier K, Stephens DN. Impairment in cognitive functions after multiple detoxifications in alcoholic inpatients. Alcohol Clin Exp Res 2003; 27(10): 1563– 1572.

61. Jenkins RL, Parsons OA. Recovery of cognitive abilities in male alcoholics. Curr Alcohol 1979; 7: 229– 237.

62. Smith DM, Atkinson RM. Alcoholism and dementia. Int J Addict 1995; 30(13– 14): 1843– 1869.

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