, Volume 120, Issue 2, pp 220–226 | Cite as

Differential effects of flumazenil in alcoholic and nonalcoholic cirrhotic patients

  • Flávio Kapczinski
  • David Sherman
  • Roger Williams
  • Malcolm Lader
  • Valerie Curran
Original Investigation


Ligands to the benzodiazepine receptor (BZR) accumulate in hepatic encephalopathy; the benzodiazepine antagonist flumazenil can reverse some manifestations of this condition. This study was designed to explore the effects of flumazenil on cognitive function and anxiety levels in cirrhotic patients without hepatic encephalopathy. Twenty such patients — ten alcoholic, ten nonalcoholics — and ten normal volunteers matched for age and sex were randomly allocated to treatment order (flumazenil or placebo first) in a double-blind cross-over trial. Cognitive function was evaluated with a battery of psychological tests shown previously to be sensitive to the impairment induced by liver disease. Cirrhotic patients performed worse than controls on several tests: digit cancellation, digit symbol substitution, key tapping and Reitan's trail B test. Flumazenil did not reverse these cognitive impairments but it did induce anxiety in nonalcoholic cirrhotics. On one index of memory — delayed word recall — alcoholics performed worse than nonalcoholic cirrhotics. Flumazenil reversed this memory impairment in the alcoholic cirrhotic group. These results suggest that alcohol consumption induces changes at the BZR that are different from changes induced solely by liver impairment.

Key words

Cirrhosis Flumazenil Anxiety Memory Endogenous benzodiazepines 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Arria AM, Tarter RE, Kabene MA, Laird SB, Moss H, Van Thiel DH (1991a) The role of cirrhosis in memory functioning of alcoholics. Alcohol Clin Exp Res 15:932–937Google Scholar
  2. Arria AM, Tarter RE, Starzl TE, Van Thiel DH (1991b) Improvement in cognitive functioning of alcoholics following orthotopic liver transplantation. Alcohol Clin Exp Res 15:956–962Google Scholar
  3. Ball DM, Wilson S, Glue P, Lawson C, Nutt DJ (1992) Alterations in benzodiazepine receptor function underlying panic disorder. In: Burrows GD, Roth M, Noyes R (eds) Handbook of anxiety, vol. 5. Elsevier, Amsterdam, pp 421–435Google Scholar
  4. Bansky G, Meier PJ, Riederer E, Walser H, Ziegler WH, Schmid M (1989) Effects of the benzodiazepine receptor antagonist flumazenil in hepatic encephalopathy in humans. Gastroenterology 97:744–750Google Scholar
  5. Basile AS, Harrison PM, Hughes RD, Gu ZQ, Pannell L, McKinney A, Jones EA, Williams R (1994) Relationship between plasma benzodiazepine receptor ligand concentrations and severity of hepatic encephalopathy. Hepatology 19:112–121Google Scholar
  6. Bond A, Lader M (1974) The use of analogue scales in rating subjective feelings Br J Med Psychol 47:211–218Google Scholar
  7. Curran HV (1991) Benzodiazepines, memory and mood: a review. Psychopharmacology 105:1–8Google Scholar
  8. Curran HV, Schiwy W, Lader M (1987) Differential amnesic properties of benzodiazepines: a dose response comparison of two drugs with similar elimination half-lives. Psychopharmacology 92:358–364Google Scholar
  9. Curran HV, Gardiner JM, Java RI, Allen D (1993) Effects of lorazepam upon recollective experience in recognition memory. Psychopharmacology 110:374–378Google Scholar
  10. Dollery C (1991) Flumazenil. In: Dollery C (ed) Therapeutic durgs vol. 1. Churchill Livingstone, London, pp F 50-F 54Google Scholar
  11. File SE, Hitchcott PK (1990) A theory of benzodiazepine dependence that can explain whether flumazenil will enhance or reverse the phenomena. Psychopharmacology 101:525–532Google Scholar
  12. File SE, Lister RG, Nutt DJ (1982) The anxiogenic action of benzodiazepine antagonits. Neuropharmacology 21:1033–1037Google Scholar
  13. Frith CD (1967) The effects of nicotine on tapping. Life Sci 6:321–326Google Scholar
  14. Grimm G, Ferenci P, Katzenschlager R, Madl C, Schneeweiss B, Laggner AN, Lenz K, Gangl A (1988) Improvement of hepatic encephalopathy treated with flumazenil. Lancet 2:1392–1394Google Scholar
  15. Guimaraes FS, Zuardi AW, Graeff FG (1987) Effect of chlorimipramine and maprotiline on experimental anxiety in humans. J Psychopharmacol 3:184–192Google Scholar
  16. Higgitt A, Lader M, Fonagy P (1986) The effects of the benzodiazepine antagonists RO-151788 on psychophysiological performance and subjective measures in normal subjects. Psychopharmacology 89:395–403Google Scholar
  17. Hills M, Armitage P (1979) The two-period cross-over clinical trial. Br J Clin Pharmacol 8:7–20Google Scholar
  18. Irwin M, Smith TL, Butters N, Brown S, Baird S, Grant I, Schuckit MA (1989) Graded neuropsychological impairment and elevated gamma-glutamyl transferase in chronic alcoholic men. Alcohol Clin Exp Res 13:99–103Google Scholar
  19. Litton JE, Neiman J, Pauli S, Farde L, Hindmarsh T, Halldin C, Sedvall G (1993) PET analysis of [11C] flumazenil binding to benzodiazepine receptors in chronic alcohol-dependent men and healthy controls. Psychiatry Res 50:1–13Google Scholar
  20. Mhatre MC, Ticku MK (1992) Chronic ethanol administration alters gamma-aminobutyric acidA receptor gene expression. Mol Pharmacol 42:415–422Google Scholar
  21. Mhatre MC, Pena G, Sieghart W, Ticku MK (1993) Antibodies specific for GABAA receptor alpha subunits reveal that chronic alcohol treatment down-regulates alpha-subunit expression in rat brain regions. J Neurochem 61:1620–1625Google Scholar
  22. Nelson H (1982) The national adult reading test. NFER-Nelson, WindsorGoogle Scholar
  23. Nutt DJ, Glue P, Lawson C, Wilson S (1990) Flumazenil provocation of panic attacks. Evidence for altered benzodiazepine receptor sensitivity in panic disorder. Arch Gen Psychiatry 47:917–925Google Scholar
  24. Ohmann C, Stoltzing H, Wins L, Busch E, Thon K (1990) Prognostic scores in oesophageal or gastric variceal bleeding. Scand J Gastroenterol 25:501–512Google Scholar
  25. Olasmaa M, Guidotti A, Costa E, Rothstein JD, Goldman ME, Weber RJ, Paul SM (1989) Edogenous benzodiazepines in hepatic encephalopathy. Lancet 1:491–492Google Scholar
  26. Pomier Layrargues G, Giguere JF, Lavoie J, Perney P, Gagnon S, D'Amour M, Wells J, Butterworth RF (1994) Flumazenil in cirrhotic patients in hepatic coma: a randomized double-blind placebo-controlled crossover trial. Hepatology 19:32–37Google Scholar
  27. Reitan RM, Wolfson D (1985) The Halstead-Reitan neuropsychological test battery. Neuropsychology Press, TucsonGoogle Scholar
  28. Ritson EB, Chick JD, Strang F (1993) Dependence on alcohol and other drugs. In: Kendell RE, Zealley AK (eds) Companion to psychiatric studies, 5th edn. Churchill Livingstone, London, p 369Google Scholar
  29. Scollo-Lavizzari G, Steinman E (1985) Reversal of hepatic coma by benzodiazepine antagonist (RO 15-1788). Lancet 1:1324Google Scholar
  30. Spielberger CD, Gorsuch RL, Lushene RE (1970) Manual for the state-trait anxiety inventory. Consulting Psychologist Press, Palo AltoGoogle Scholar
  31. Tarter RE, Hegedus AM, Van Thiel DH, Gavaler JS, Schade RR (1986) Hepatic dysfunction and neuropsychological test performance in alcoholics with cirrhosis. J Stud Alcohol 47:74–77Google Scholar
  32. Tarter RE, Van-Thiel DH, Arria AM, Carra J, Moss H (1988) Impact of cirrhosis on the neuropsychological test performance of alcoholics. Alcohol Clin Exp Res 12:619–621Google Scholar
  33. Tarter RE, Moss H, Arria A, Van Thiel D (1990a) Hepatic, nutritional, and genetic influences on cognitive process in alcoholics. In: Spencer JW, Boren JJ (eds) Residual effects of abused drugs on behavior — NIDA research monograph 101. National Institute on Drug Abuse, Rockville, pp 124–135Google Scholar
  34. Tarter RE, Switala JA, Arria A, Plail J, Van Thiel DH (1990b) Subclinical hepatic encephalopathy. Comparison before and after orthotopic liver transplantation. Transplantation 50:632–637Google Scholar
  35. Ticku MK, Mhatre M, Mehta AK (1992) Modulation of GABAergic transmission by ethanol. Adv Biochem Psychopharmacol 47:255–268Google Scholar
  36. Tyrer P (1976) The role of body feelings in anxiety — Maudsley Monograph 23. Oxford University Press, LondonGoogle Scholar
  37. Wechsler D (1981) WAIS-R manual. Psychological Corporation, New YorkGoogle Scholar
  38. Wilson B, Cockburn J, Baddeley A (1985) The Rivermead behavioural memory test. Thames Valley Test Company, ReadingGoogle Scholar
  39. World Health Organization (1992) The ICD-10 classification of mental nad behavioural disorders. World Health Organization, GenevaGoogle Scholar

Copyright information

© Springer-Verlag 1995

Authors and Affiliations

  • Flávio Kapczinski
    • 1
  • David Sherman
    • 2
  • Roger Williams
    • 2
  • Malcolm Lader
    • 1
  • Valerie Curran
    • 1
  1. 1.Clinical Psychopharmacology Team, MRCInstitute of PsychiatryLondonUK
  2. 2.Institute of Liver StudiesKing's College HospitalLondonUK

Personalised recommendations