Download PDF
Pharmacopsychiatry 2004; 37(5): 228-235
DOI: 10.1055/s-2004-832597
Original Paper
© Georg Thieme Verlag KG Stuttgart · New York

Polysomnography During Withdrawal with Clomethiazole or Placebo in Alcohol Dependent Patients - A Double-Blind and Randomized Study

H. Gann1 , B. Feige1 , O. Cloot1 , H. van Wasen1 , D. Zinzgraf1 , F. Hohagen2 , D. Riemann1
  • 1Dept. of Psychiatry & Psychotherapy, University of Freiburg, Germany
  • 2Dept. of Psychiatry & Psychotherapy, Medical University of Lübeck, Germany
Further Information

Publication History

Received: 12.2.2003 Revised: 9./11.5.2003

Accepted: 6.10.2003

Publication Date:
10 September 2004 (online)

Also available at
    Permissions and Reprints

Introduction: The present study was designed to assess if the routine application of clomethiazole to ameliorate withdrawal symptoms in chronic alcohol dependent patients perpetuates sleep disturbances. Methods: Twenty inpatients with alcohol dependence according to DSM-IV criteria received clomethiazole or placebo in a double-blind, randomized design upon admission. 11 patients were randomized to the clomethiazole group and 9 patients to the placebo group. During the first 5 days of treatment the patients received either clomethiazole (1st day: 3 × 384 mg, 2nd day: 4 × 384 mg, 3rd day: 3 × 384 mg, 4th day: 2 × 384 mg and 5th day: 1 × 384 mg) or placebo capsules at constant intervals. The patients spent two consecutive nights in the sleep laboratory at each of three assessment times: the first time at the beginning of abstinence (night 1 and 2, T0), the second time 6 days later (i. e. after 5 days of treatment and one day of discontinuation of clomethiazole or placebo: nights 6 and 7, T1) and the third time after 13 days (nights 13 and 14, T2). The first night at each of the three assessment times was an adaptation night. Results: During the first two weeks of abstinence, the analysis of variance demonstrated a significant variation of Rapid Eye Movement (REM) sleep variables in the clomethiazole group. The placebo group showed no such variation. Clomethiazole evidently had a pronounced REM sleep suppressing effect, whereas the discontinuation of clomethiazole led to a REM sleep rebound. Furthermore, analysis of sleep continuity and sleep architecture variables showed that the clomethiazole group had significantly disturbed sleep at T1 in comparison to the placebo group. Simultaneous statistical testing with alcohol intake as covariate reduced the test power so that contrasts between the groups became nonsignificant. Conclusions: The REM sleep results are in line with earlier findings that REM sleep disinhibition in primary alcohol dependency is partly due to a REM sleep rebound after withdrawal from medication. Differences in the polysomnographic variables of sleep continuitiy and sleep architecture at T0 and T1 found between the clomethiazole and the placebo patients correspond to rebound insomnia following discontinuation of clomethiazole. Our findings indicate that drugs enforcing GABAergic neurotransmission may perpetuate the neuroadaptative effects caused by chronic alcohol consumption.

References

  • 1 Aldrich M S, Brower K J, Hall J M. Sleep-disordered breathing in alcoholics.  Alcohol Alcohol Clin Exp Res. 1999;  23 134-140
    PubMedGoogle Scholar
  • 2 Allen R P, Wagman A MI, Funderburk F R. Slow wave sleep changes. Alcohol tolerance and treatment implications.  Adv Exp Med Biol. 1977;  85A 629-640
    PubMedGoogle Scholar
  • 3 Athen D, Hippius H, Meyendorf R, Riemer C H, Steiner C H. A comparison of the efficacy of neuroleptic agents and chlormethiazole in the treatment of alcoholic delirium.  Nervenarzt. 1977;  48 528-532
    PubMedGoogle Scholar
  • 4 Becker H C. Alcohol withdrawal: Neuroadaptation and sensitization.  CNS Spectrums. 1999;  4 38-40
    PubMedGoogle Scholar
  • 5 Benuzzi P, Muller C. Three methods of treating delirium tremens-comparative study.  Schweiz Med Wochenschr. 1967;  97 1283-1289
    PubMedGoogle Scholar
  • 6 Brower K J, Aldrich M S, Hall J M. Polysomnographic and subjective sleep predictors of alcoholic relapse.  Alcohol Clin Exp Res. 1998;  22 1864-1871
    PubMedGoogle Scholar
  • 7 Brower K J. Alcohol’s effects on sleep in alcoholics.  Alcohol Res Health. 2001;  25 110-125
    PubMedGoogle Scholar
  • 8 Buysse D J, Reynolds C F, Monte T H, Berman S R, Kupfer D J. The Pittsburgh Sleep Quality Index: A new instrument for psychiatric practice and research.  Psychiatry Res. 1989;  28 193-213
    Google Scholar
  • 9 Calanca A, Jalonetsky S, Muller C. Further assessment of Heminevrin in the treatment of delirium tremens.  L’Encephale. 1977;  3 63-69
    PubMedGoogle Scholar
  • 10 Clark C P, Gillin J C, Goshan S. et al . Increased REM sleep density at admission predicts relapse by three months in primary alcoholics with a lifetime diagnosis of secondary depression.  Biol Psychiatry. 1998;  43 601-607
    CrossrefPubMedGoogle Scholar
  • 11 Drummond S PA, Gillin J C, Smith T L, Demodena A. The sleep of abstinent pure primary alcoholic patients: Natural course and relationship to relapse.  Alcohol Clin Exp Res. 1998;  22 1796-1802
    PubMedGoogle Scholar
  • 12 Foster J H, Peters T J. Impaired sleep in alcohol misusers and dependent alcoholics and the impact upon outcome.  Alcohol Clin Exp Res. 1999;  23 1044-1051
    PubMedGoogle Scholar
  • 13 Funderburk F R, Allen R P, Wagman A MI. Residual effects of ethanol and chlordiazepoxode treatments for alcohol withdrawal.  J Nerv Ment Dis. 1978;  166 195-203
    PubMedGoogle Scholar
  • 14 Gann H, Kiemen A, Klein T, Ebert D, Backhaus J, Hornyak M, Voderholzer U, Hohagen F, Berger M, Riemann D. Schlaf und cholinerger REM-Schlaf-Induktionstest bei Patienten mit primärer Alkoholabhängigkeit.  Somnologie. 1997;  1 119-125
    PubMedGoogle Scholar
  • 15 Gann H, Faulmann A, Kiemen A, Klein T, Ebert D, Backhaus J, Hornyak M, Voderholzer U, Hohagen F, Berger M, Riemann D. Sleep and the cholinergic REM sleep induction test in patients with primary alcoholism.  Sleep Res Online. 1998;  1 92-95
    PubMedGoogle Scholar
  • 16 Gann H, Gardziella S, Backhaus J, Hohagen F, Riemann D. Der Schlaf und seine cholinerge Beeinflussbarkeit bei Patienten mit primärer Alkoholabhängigkeit im subakuten Entzug.  Sucht. 1999;  45 89-99
    PubMedGoogle Scholar
  • 17 Gann H, Feige B, Hohagen F, van Calker D, Geiss D, Riemann D. Sleep and the cholinergic rapid eye movement sleep induction test in patients with primary alcohol dependence.  Biol Psychiatry. 2001;  50 383-390
    CrossrefPubMedGoogle Scholar
  • 18 Gillin J C, Smith T L, Irwin M, Buttos N, Demodena A, Schuckit M. Increased pressure for rapid eye movement sleep at time of hospital admission predicts relapse in non-depressed patients with primary alcoholism at 3-month follow-up.  Arch Gen Psychiatry. 1994;  51 189-197
    PubMedGoogle Scholar
  • 19 Glatt M M, George H R, Frisch E P. Controlled trial of chlormethiazole in treatment of the alcoholic withdrawal phase.  Br J Med. 1965;  2 401-404
    PubMedGoogle Scholar
  • 20 Görtelmeyer R. Schlaffragebogen SF-A and SF-B. In Collegium Internationale Psychiatriae Scolarum (CIPS), Herausgeber Internationale Skalen für Psychiatrie. Weinheim; Beltz 1981
    Google Scholar
  • 21 Green A R. Clomethiazole (Zendra) in acute ischemic stroke: basic pharmacology and biochemistry and clinical efficacy.  Pharmacol Ther. 1998;  80 123-147
    CrossrefPubMedGoogle Scholar
  • 22 Hollister L E, Prusmack J J, Lipscomp W. Treatment of acute alcohol withdrawal with chlormethiazole (Herminevrin).  Dis Nerv Syst. 1972;  33 247-250
    PubMedGoogle Scholar
  • 23 Koob G F, Roberts A J. Brain reward circuits in alcoholism.  CNS Spectrums. 1999;  4 23-37
    PubMedGoogle Scholar
  • 24 Landolt H P, Gillin J C. Sleep abnormalities during abstinence in alcohol-dependent patients.  CNS Drugs. 2001;  15 413-425
    PubMedGoogle Scholar
  • 25 Littleton J. Neurochemical mechanisms underlying alcohol withdrawal.  Alcohol Health Res World. 1998;  22 13-24
    PubMedGoogle Scholar
  • 26 Maxion H, Schneider E. Der Einfluss von Chlormethiazol (Distraneurin) auf das Schlaf-Elektroenzephalogramm nach Alkoholdelir.  Pharmakopsychiatry. 1970;  4 233-238
    PubMedGoogle Scholar
  • 27 Mc Lellan A T, Luborksy L, Woody G, O’Brien C P. An improved diagnostic evaluation instrument for substance abuse patients - The Addiction Severity Index (ASI).  J Nerv Ment Dis. 1980;  168 26-33
    PubMedGoogle Scholar
  • 28 McGrath S D. A controlled trial of chlormethiazole and chlordiazeproxide in the treatment of acute withdrawal phase of alcoholism.  Br J Addict. 1975;  70 (Suppl. 1) 81-90
    PubMedGoogle Scholar
  • 29 Rechtschaffen A, Kales A. A manual of standardized terminology techniques and scoring system for sleep stages of human subjects. Washington DC; Washington U.S. Government Printing Office (Public Health Service) 1968
    Google Scholar
  • 30 Riemann D, Backhaus J. Behandlung von Schlafstörungen - Ein psychologisches Gruppenprogramm. Weinheim; Beltz 1996
    Google Scholar
  • 31 Riemann D, Voderholzer U, Cohrs S. Rodenbeck A, Hajak G, Rüther E, et al. Trimipramne in primary insomnia: Results of a polysomnographic double-blind placebo and reference substance (Lormetazepam)-controlled study.  Pharmacopsychiatry. 2002;  35 165-174
    Google Scholar
  • 32 Stuppacek C H, Barnas C, Falk M, Guenther V, Hummer M, Oberbauer H. et al . Assessment of the alcohol withdrawal syndrome - validity and reliability of the translated and modified Clinical Institute Withdrawal Assessment for Alcohol scale (CIWA-A).  Addiction. 1994;  89 1287-1992
    PubMedGoogle Scholar
  • 33 Wittchen H U, Wunderlich U, Gruschwitz S, Zaudig M. Strukturiertes Klinisches Interview für DSM-IV, Achse I (SKID). Göttingen; Hogrefe 1997
    Google Scholar

PD Dr. H. Gann

Department of Psychiatry and Psychotherapy

University of Freiburg

Hauptstrasse 5

79104 Freiburg

Germany

Phone: +49 761 270 6969

Fax: +49 761 270 6667

Email: Horst_Gann@psyallg.ukl.uni-freiburg.de