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Flumazenil-precipitated withdrawal in healthy volunteers following repeated diazepam exposure

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Abstract

Rationale

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.

Objective

This study was designed to assess the effect of duration of benzodiazepine exposure on the intensity of flumazenil-precipitated withdrawal in healthy volunteers.

Method

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.

Results

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.

Conclusions

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.

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References

  • Bernik MA, Gorenstein C, Gentil V (1991) Flumazenil-precipitated withdrawal symptoms in chronic users of therapeutic doses of diazepam. J Psychopharmacol 5:215–219

    Google Scholar 

  • Bernik MA, Gorenstein C, Vieira Filho AH (1998) Stressful reactions and panic attacks induced by flumazenil in chronic benzodiazepine users. J Psychopharmacol 12:146–150

    CAS  PubMed  Google Scholar 

  • Brogden RN, Goa KL (1991) Flumazenil. A reappraisal of its pharmacodynamic properties and therapeutic efficacy as a benzodiazepine antagonist. Drugs 42:1061–1089

    CAS  PubMed  Google Scholar 

  • Bruce SE, Vasile RG, Goisman RM, Salzman C, Spencer M, Machan JT, Keller MB (2003) Are benzodiazepines still the medication of choice for patients with panic disorder with or without agoraphobia? Am J Psychiatry 160:1432–1438

    Article  PubMed  Google Scholar 

  • Busto UE, Sykora K, Sellers, EM (1989) A clinical scale to assess benzodiazepine withdrawal. J Clin Psychopharmacol 9:412–416

    CAS  PubMed  Google 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, DC

  • Gallager DW, Heninger K, Heninger G (1986) Periodic benzodiazepine antagonist administration prevents benzodiazepine withdrawal symptoms in primates. Eur J Pharmacol 132:31–38

    Article  CAS  PubMed  Google 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 54:580–587

    Google Scholar 

  • Gerra G, Giucasto G, Zaimovic A, Fertonani G, Chittolini B, Avanzini P, Caccavari R, Delsignore R (1996) Intravenous flumazenil following prolonged exposure to lormetazepam in humans: lack of precipitated withdrawal. Int Clin Psychopharmacol 11:81–88

    CAS  PubMed  Google 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 1:35–40

    Google Scholar 

  • Griffiths RR, Weerts EM (1997) Benzodiazepine self-administration in humans and laboratory animals-implications for problems of long-term use and abuse. Psychopharmacology (Berl) 134:1–37

    Article  CAS  Google Scholar 

  • Griffiths RR, Evans SM, Guarino JJ, Roache JD, Furman WR, Liebson I, Schwam EM (1993) Intravenous flumazenil following acute and repeated exposure to lorazepam in healthy volunteers: antagonism and precipitated withdrawal. J Pharmacol Exp Ther 265:1163–1174

    CAS  PubMed  Google 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 10:89–97

    CAS  Google Scholar 

  • IMS Health (2003) Available from http://www.imshealth.com/ims/portal/front/articleC/O,2777,6599_42720951_43989693,00.html, accessed 2003

  • Kaminski BJ, Sannerud CA, Weerts EM, Lamb RJ, Griffiths RR (2003) Physical dependence in baboons chronically treated with low and high doses of diazepam. Behav Pharmacol 14:331–342

    CAS  PubMed  Google Scholar 

  • Kaufman DW, Kelly JP, Rosenberg L, Anderson TE, Mitchell AA (2002) Recent patterns of medication use in the ambulatory adult population of the United States: the Slone survey. JAMA 287:337–344

    Article  PubMed  Google Scholar 

  • Keppel G (1991) Design and analysis: a researcher’s handbook, 3rd edn. Prentice Hall, Englewood Cliffs

    Google Scholar 

  • Lader MH, Morton SV (1992) A pilot study of the effects of flumazenil on symptoms persisting after benzodiazepine withdrawal. J Psychopharmacol 6:357–363

    Google Scholar 

  • Lamb RJ, Griffiths RR (1985) Effects of repeated Ro 15-1788 administration in benzodiazepine-dependent baboons. Eur J Pharmacol 110:257–261

    Article  CAS  PubMed  Google Scholar 

  • Lamb RJ, Griffiths RR (1987) Effects of Ro 15-1788 and CGS 8216 in diazepam-dependent baboons. Eur J Pharmacol 143:205–212

    Article  CAS  PubMed  Google Scholar 

  • Lukas SE, Griffiths RR (1982) Precipitated withdrawal by a benzodiazepine receptor antagonist (Ro 15-1788) after 7 days of diazepam. Science 217:1161–1163

    CAS  PubMed  Google Scholar 

  • Lukas SE, Griffiths RR (1984) Precipitated diazepam withdrawal in baboons: effects of dose and duration of exposure. Eur J Pharmacol 100:163–171

    Article  CAS  PubMed  Google Scholar 

  • Martin WR, Sloan JW, Wala E (1990) Precipitated abstinence in orally dosed benzodiazepine-dependent dogs. J Pharmacol Exp Ther 255:744–755

    CAS  PubMed  Google Scholar 

  • McNicholas LF, Martin WR (1982) The effect of a benzodiazepine antagonist, RO15-1788, in diazepam dependent rats. Life Sci 31:731–737

    Article  CAS  PubMed  Google Scholar 

  • McNicholas LF, Martin WR, Sloan JW, Wala E (1988) Precipitation of abstinence in nordiazepam- and diazepam-dependent dogs. J Pharmacol Exp Ther 245:221–224

    CAS  PubMed  Google Scholar 

  • Mintzer MZ, Stoller KB, Griffiths RR (1999) A controlled study of flumazenil-precipitated withdrawal in chronic low-dose benzodiazepine users. Psychopharmacology 147:200–209

    Article  CAS  PubMed  Google Scholar 

  • Nutt DJ (1990) Pharmacological mechanisms of benzodiazepine withdrawal. J Psychiatr Res 24(Suppl 2):105–110

    Article  PubMed  Google Scholar 

  • Nutt DJ, Glue P, Lawson C, Wilson S (1990) Flumazenil provocation of panic attacks. Arch Gen Psychiatry 47:917–925

    CAS  PubMed  Google Scholar 

  • Petursson H, Lader M (1984) Dependence on tranquilizers, Maudsley monographs 28. Oxford University Press, Oxford

    Google Scholar 

  • Physicians’ Desk Reference (2003) 57th edn. Medical Economics, Montvale

  • Rosenberg HC, Chiu TH (1985) Time course for development of benzodiazepine tolerance and physical dependence. Neurosci Biobehav Rev 9:123–131

    Article  CAS  PubMed  Google Scholar 

  • Sannerud CA, Cook JM, Griffiths RR (1989) Behavioral differentiation of benzodiazepine ligands after repeated administration in baboons. Eur J Pharmacol 167:333–343

    Article  CAS  PubMed  Google Scholar 

  • Sannerud CA, Allen M, Cook JM, Griffiths RR (1991) Behavioral effects of benzodiazepine ligands in non-dependent, diazepam-dependent and diazepam-withdrawn baboons. Eur J Pharmacol 202:159–169

    Article  CAS  PubMed  Google Scholar 

  • Savic I, Widen L, Stone-Elander S (1991) Feasibility of reversing benzodiazepine tolerance with flumazenil. Lancet 337:133–137

    Article  CAS  PubMed  Google Scholar 

  • Saxon L, Hjemdahl P, Hiltunen AJ, Borg S (1997) Effects of flumazenil in the treatment of benzodiazepine withdrawal—a double-blind pilot study. Psychopharmacology (Berl) 131:153–160

    Article  CAS  Google Scholar 

  • Scherkl R, Frey HH (1986) Physical dependence on clonazepam in dogs. Pharmacology 32:18–24

    CAS  PubMed  Google 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:A703

    Google Scholar 

  • Sloan JW, Martin WR, Wala E, Dickey KM (1991b) Chronic administration of and dependence on halazepam, diazepam, and nordiazepam in the dog. Drug Alcohol Depend 28:249–264

    Article  CAS  PubMed  Google Scholar 

  • Sloan JW, Martin WR, Wala E (1993) Effect of the chronic dose of diazepam on the intensity and characteristics of the precipitated abstinence syndrome in the dog. J Pharmacol Exp Ther 265:1152–1162

    CAS  PubMed  Google Scholar 

  • Spielberger CD, Gorsuch RL, Lushene RE (1970) STAI manual for the state-trait anxiety inventory (“Self-Evaluation Questionnaire”). Consulting Psychologists, Palo Alto

    Google Scholar 

  • Wilson MA, Gallager DW (1988) Ro 15-1788-induced seizures in rats continually exposed to diazepam for prolonged periods. Epilepsy Res 2:14–19

    Article  CAS  PubMed  Google Scholar 

  • Woods JH, Katz JL, Winger G (1987) Abuse liability of benzodiazepines. Pharmacol Rev 39:251–419

    CAS  PubMed  Google Scholar 

  • Woods JH, Katz JL, Winger G (1992) Benzodiazepines: use, abuse, and consequences. Pharmacol Rev 44:151–347

    CAS  PubMed  Google Scholar 

  • Zharkovskii AM, Zharkovskaia TA (1987) Characteristics of the abstinence syndrome induced by the administration of the benzodiazepine antagonist CGS 8216 to rats following chronic treatment with diazepam. Biull Eksp Biol Med 104:318–321

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This project was supported by National Institute on Drug Abuse Research Grant DA-03889. The authors thank Ryan Vandrey for technical assistance, Tim Mudric and Paul Nuzzo for statistical consultation, John Yingling for programming and technical support, and David Ginn, M.D. for medical coverage.

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Authors and Affiliations

  1. Johns Hopkins University School of Medicine, 5510 Nathan Shock Drive, Baltimore, MD 21224, USA

    Miriam Z. Mintzer & Roland R. Griffiths

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  1. Miriam Z. Mintzer
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  2. Roland R. Griffiths
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Correspondence to Miriam Z. Mintzer.

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Mintzer, M.Z., Griffiths, R.R. Flumazenil-precipitated withdrawal in healthy volunteers following repeated diazepam exposure. Psychopharmacology 178, 259–267 (2005). https://doi.org/10.1007/s00213-004-2009-1

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