Flumazenil-precipitated withdrawal in healthy volunteers following repeated diazepam exposure
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Parametric preclinical studies of the benzodiazepine antagonist flumazenil have contributed to the understanding of the physical dependence associated with chronic benzodiazepine use. However, few parametric studies have been conducted in human participants.
This study was designed to assess the effect of duration of benzodiazepine exposure on the intensity of flumazenil-precipitated withdrawal in healthy volunteers.
Participants were randomly assigned to receive either oral diazepam (15 mg/70 kg; n=10) or placebo (n=8) capsules nightly for 28 days. Effects of flumazenil (1 mg/70 kg, intravenously administered) were assessed in challenge sessions conducted before capsule ingestion, and after 1, 7, 14, and 28 days of capsule ingestion.
Flumazenil produced a profile of participant-rated effects consistent with benzodiazepine withdrawal that peaked immediately after completion of the 5-min flumazenil injection and rapidly dissipated thereafter. The magnitude of these effects was comparable after 7, 14, and 28 days of diazepam. Flumazenil also produced modest elevations in blood pressure and decreases in skin temperature in the diazepam group, both of which were sustained throughout the approximate 60-min session.
These findings support previous human research studies indicating that flumazenil precipitates withdrawal after short chronic exposure to benzodiazepines and suggests that duration of exposure does not influence the intensity of withdrawal beyond the first week of exposure.
- Bernik MA, Gorenstein C, Gentil V (1991) Flumazenil-precipitated withdrawal symptoms in chronic users of therapeutic doses of diazepam. J Psychopharmacol 5:215–219Google Scholar
- Frey JM, Rush CR, Griffiths RR (1996) Physiological, behavioral and subjective effects of flumazenil-precipitated withdrawal in benzodiazepine-dependent methadone clients. Poster presented at the annual meeting of the Society for Neuroscience, Washington, DCGoogle Scholar
- Gerra G, Marcato A, Caccavari R, Fertonani-Affini G, Fontanesi B, Zaimovic A, Avanzini P, Delsignore R (1993) Effectiveness of flumazenil (RO 15-1788) in the treatment of benzodiazepine withdrawal. Curr Ther Res Clin Exp 54:580–587Google Scholar
- Greenblatt DJ, Laughren TP, Allen MD, Harmatz JS, Shader RI (1981) Plasma diazepam and desmethyldiazepam concentrations during long-term diazepam therapy. Br J Clin Pharmacol 1:35–40Google Scholar
- Harrison-Read PE, Tyrer P, Lawson C, Lack S, Fernandes C, File SE (1996) Flumazenil-precipitated panic and dysphoria in patients dependent on benzodiazepines: a possible aid to abstinence. J Psychopharmacol 10:89–97Google Scholar
- IMS Health (2003) Available from http://www.imshealth.com/ims/portal/front/articleC/O,2777,6599_42720951_43989693,00.html, accessed 2003
- Keppel G (1991) Design and analysis: a researcher’s handbook, 3rd edn. Prentice Hall, Englewood CliffsGoogle Scholar
- Lader MH, Morton SV (1992) A pilot study of the effects of flumazenil on symptoms persisting after benzodiazepine withdrawal. J Psychopharmacol 6:357–363Google Scholar
- Petursson H, Lader M (1984) Dependence on tranquilizers, Maudsley monographs 28. Oxford University Press, OxfordGoogle Scholar
- Physicians’ Desk Reference (2003) 57th edn. Medical Economics, MontvaleGoogle Scholar
- Sloan JW, Martin WR, Wala E (1991a) Duration of diazepam (DZ) treatment and the intensity of flumazenil precipitated abstinence (FPA) in dogs. FASEB J 5:A703Google Scholar
- Spielberger CD, Gorsuch RL, Lushene RE (1970) STAI manual for the state-trait anxiety inventory (“Self-Evaluation Questionnaire”). Consulting Psychologists, Palo AltoGoogle Scholar