A prototype benzodiazepine (BDZ) antagonist, flumazenil (1 mg, i.v.) or placebo was administered to eight chronic users (5-15 years) of therapeutic doses of diazepam (10-25 mg/d), in a double-blind, placebo-controlled design in order to evaluate the presence of physiological dependence. The three patients receiving flumazenil developed anxiety reactions, with significant increases in bodily and psychological symptoms, as measured by rating scales. In two these amounted to a panic attack. Subjects on placebo tended to show decreases in measures of anxiety. The severity of precipitated reactions was not related to the total cumulative exposure to diazepam, but to a history of panic attacks. Previous panic may increase the vulnerability to severe reactions to flumazenil.
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References
1.
American Psychiatry Association (1987) Diagnostic and statistical manual of mental disorders, 3rd edn, revised. APA Press, Washington DC
2.
Ballenger J.C., Burrows G.D., DuPont R.L. Jr, Lesser I.M., Noyes R., Pecknold J.C., Rifkin A., Swinson R.P. (1988) Alprazolam in panic disorder and agoraphobia: results from a multicenter trialI. Efficacy in short-term treatment. Arch Gen Psychiatr45: 413-422
3.
Beck A., Ward C., Mendelson M., Mock J., Erbaugh J. (1961) An inventory for measuring depressionArch Gen Psychiatr4: 561-571
4.
Bernik M.A., Gorenstein C., Tavares S M A, Gentil Filho V. (1989) Tolerância e dependência a benzodiazepínicos: a respeito de um casoRev Ass Med Bras35: 207-210
5.
Biaggio A M B, Natalício L. (1979) Manual para o inventário de ansiedade traco-estado (IDATE). Centro Editor de Psicologia Aplicada (CEPA), Rio de Janeiro
6.
Boisse N.R., Okamoto M. (1978) Physical dependence to barbital compared to pentobarbital IV. Influence of elimination kinetics J Pharmacol Exp Ther204: 526-540
7.
De la Fuente J.R. (1989) Long term treatment of panic and agoraphobia with benzodiazepines VIII World Congress of Psychiatry, Athens
8.
Dixon W.J., Massey F.J. (1957) Introduction to statistical analysis, 2nd edn. McGraw-Hill, New York.
9.
Duka T., Ackenheil M., Noderer J., Doernicke A., Dorow R. (1986) Changes in noradrenaline plasma levels and behavioral responses induced by benzodiazepine agonists with the benzodiazepine antagonist Ro 15-1788Psychopharmacology90: 351-357
10.
File S.E., Lister R.G., Nutt D.J. (1982) The anxiogenic action of benzodiazepine antagonistsNeuropharmacology21 : 1033-1037
11.
Gentil V., Tavares S., Gorenstein C., Bello C., Mathias L., Gronich G., Singer J. (1990) Acute reversal of flunitrazepam effects by Ro 15-1788 and Ro 15-3505: inverse agonism, tolerance, and reboundPsychopharmacology100: 54-59
12.
Gentil Filho V (1985) Ansiedade induzida por antagonistas de receptores de benzodiazepínicos In Gentil Filho, V. (ed.), Anais.Fontoura Wyeth, São Paulo
13.
Golombok S., Higgitt A., Fonagy P., Dodds S., Saper J., Lader M. (1987) A follow-up study of patients treated for benzodiazepine dependenceBr J Med Psychol60: 141-149
14.
Guelfi J.D., Bobon D. (1989) Echelles d'evaluation en psychiatrie. Encyclopédie Médico-Chirurgicale, Psychiatrie 37200 A 10.10
15.
Haefely W. (1985) Pharmacology of benzodiazepine antagonistsPharmacopsychiatry18: 163-166
16.
Haefely W. (1986) Biological basis of drug induced tolerance, rebound and dependence: contribution of recent research on benzodiazepinesPharmacopsychiatry19: 353-361
17.
Hamilton M. (1959) The assessment of anxiety states by ratingBr J Med Psychol32: 50-55
18.
Hamilton M. (1967) Development of a rating scale for primary depressive illnessBr J Soc Clin Psychol6: 278-296
19.
Higgitt A., Lader M., Fonagy P. (1986) The effects of the benzodiazepine antagonist Ro 15-1788 on psychophysiological performance and subjective measures in normal subjectsPsychopharmacology89: 395-403
20.
Khan A., Hornblom A.R., Walshe J W B (1981) Benzodiazepine dependence: a general practice surveyN Z Med J94: 19-21
21.
Krauth J. (1988) Distribution-free statistics: an application-oriented approachElsevier, Amsterdam
22.
Lader M. (1983) Dependence on benzodiazepinesJ Clin Psychiatr44: 121-127
23.
Lader M. (1989) Benzodiazepine dependenceInt Rev Psychiatr1: 149-156
24.
Lamb R.J., Griffiths R.R. (1984) Precipitated and spontaneous withdrawal in baboons after chronic dosing with lorazepam and CGS 9896Drug Alcohol Depend14: 11-17
Lukas S.E., Griffiths R.R. (1982) Precipitated withdrawal by a benzodiazepine receptor antagonist (Ro 15-1788) after 7 days of diazepamScience217: 1161-1163
27.
Nutt D.J., Glue P., Lawson C., Wilson S. (1990) Flumazenil provocation of panic attacksArch Gen Psychiatr47: 917-925
28.
Owen R.T., Tyrer P. (1983) Benzodiazepine dependence: a review of the evidenceDrugs25: 385-398
29.
Pecknold J.C., Swinson R.P., Kuch K., Lewis C.P. (1988) Alprazolam in panic disorder and agoraphobia: results from a multicenter trialIII. Discontinuation effects. Arch Gen Psychiatr45: 429-436
Petursson H., Lader M. (1984) Dependence on tranquilizers. Maudsley Monogr 28 , Oxford University Press, Oxford.
32.
Rickels K., Case W.G., Schweizer E.E., Swenson C., Fridman R.B. (1986) Low dose dependence in chronic benzodiazepine users: a preliminary report on 119 patientsPsychopharmacol Bull22: 407-415
33.
Rouiller M., Forster A., Gemperle M. (1987) Evaluation de l'efficacité et de la tolérance d'un antagoniste des benzodiazépines (Ro 15-1788)Ann Fr Anesth Réanim6: 1-6
34.
Sheehan D.V. (1987) Benzodiazepines in panic disorder and agoraphobiaJ Affect Disord13: 169-181
35.
Sougey E.B. (1987) As escalas de avaliacão nos ensaios clinicos com benzodiazepínicos. A propósito da escala de ansiedade de HamiltonJ Bras Psiquiatr36: 49-53
36.
Spielberger C.D., Gorsuch R.L., Lushene R.E. (1970) Manual for the State-Trait anxiety inventoryConsulting Psychologists Press, Palo Alto
37.
Tyrer P., Owen R., Dawling S. (1983) Gradual withdrawal of diazepam after long term therapyLancet i: 1402-1406
38.
Woods J.H., Kats J.L., Winger G. (1987) Abuse liability of benzodiazepinesPharmacol Rev39: 251-413
