Skip to main content

Benzodiazepine Dependence

A Review of the Evidence

Summary

Classical pharmacological dependence accompanied by euphoria, clinical evidence of tolerance and escalation of dosage are very rare with the benzodiazepines. However, there is now abundant evidence that prolonged administration of doses within the therapeutic range leads to true dependence in a significant minority of patients. This dependence is characterised by withdrawal symptoms on stopping treatment; these include perceptual disturbances, epileptic seizures, weight loss, insomnia and autonomic symptoms. As some of the symptoms are qualitatively different from those of anxiety neurosis, and as the withdrawal syndrome commonly lasts between 5 and 15 days, the possibility that the symptoms represent a return of pre-existing anxiety can be discounted.

The withdrawal syndrome is more likely if: (a) the benzodiazepine has been taken in regular dosage for more than 4 months; (b) higher dosages have been used; (c) the drug is stopped suddenly; and (d) a short acting benzodiazepine has been taken. The withdrawal syndrome is most likely to occur when there is a rapid fall in blood benzodiazepine concentrations; this may be associated with altered sensitivity of benzodiazepine receptors. The syndrome can best be avoided by gradual reduction of dosage. The temporary prescription of other drugs, particularly β-adrenoceptor blocking drugs, may attenuate withdrawal symptoms, but antipsychotic drugs in low dosage are of no benefit.

This is a preview of subscription content, access via your institution.

References

  • Allgulander, C. and Borg, S.: A case report: A delirious abstinence syndrome associated with clorazepate (Tranxilene). British Journal of Addiction 73: 175–177 (1978).

    Article  CAS  Google Scholar 

  • Athinarayanan, P.; Pierog, S.H.; Nigram, S.K. and Glass, L.: Chlordiazepoxide withdrawal in the neonate. American Journal of Obstetrics and Gynecology 124: 212–213 (1976).

    PubMed  CAS  Google Scholar 

  • Ayd Jr, F.J.: Benzodiazepines: Dependence and withdrawal. Journal of the American Medical Association 242: 1401–1402 (1979).

    PubMed  Article  Google Scholar 

  • Bant, W.: Diazepam withdrawal symptoms. British Medical Journal 4: 285 (1975).

    PubMed  Article  CAS  Google Scholar 

  • Bismuth, C.; Le Bellec, M.; Dalby, S. and Lagier, G.: Dépendence physique aux benzodiazépines. Nouvelle Press Médicale 9: 1941–1945 (1980).

    CAS  Google Scholar 

  • Blackwell, B.: Psychotropic drugs in use today: The role of diazepam in medical practice. Journal of the American Medical Association 225: 1637–1641 (1973).

    PubMed  Article  CAS  Google Scholar 

  • Bowes, H.A.: The role of diazepam (Valium) in emotional illness. Psychosomatics 6: 336–340 (1965).

    PubMed  CAS  Google Scholar 

  • Braestrup, C.; Nielsen, M. and Squires, R.F.: No changes in rat benzodiazepine receptors after withdrawal from continuous treatment with lorazepam and diazepam. Life Sciences 24: 347–350 (1979).

    PubMed  Article  CAS  Google Scholar 

  • Braestrup, C. and Nielsen, M.: Multiple benzodiazepine receptors. Trends in Neurosciences 3: 301–304 (1980).

    CAS  Google Scholar 

  • Castleden, CM.; George, CF.; Marcer, P. and Hallett, C.: Increased sensitivity to nitrazepam in old age. British Medical Journal 1: 10–12 (1977).

    PubMed  Article  CAS  Google Scholar 

  • Conney, A.H.: Pharmacological implications of microsomal enzyme induction. Pharmacological Reviews 19: 317–366 (1967).

    PubMed  CAS  Google Scholar 

  • Costa, E.: Mechanism of Action of Benzodiazepines, pp.113–151 (Raven Press, New York, 1975).

    Google Scholar 

  • Covi, L.; Lipman, R.S.; Pattison, J.A.; Deragatis, L.R. and Uhlenhuth, E.H.: Length of treatment with anxiolytic sedatives and response to their sudden withdrawal. Acta Psychiatrica Scandinavica 49: 51–64 (1973).

    PubMed  Article  CAS  Google Scholar 

  • De Bard, M.L.: Diazepam withdrawal syndrome: A case of psychosis, seizure and coma. American Journal of Psychiatry 136: 105–106 (1979).

    Google Scholar 

  • Dysken, M.W. and Chan, C.H.: Diazepam withdrawal psychosis: A case report. American Journal of Psychiatry 134: 573 (1977).

    PubMed  CAS  Google Scholar 

  • Einarson, T.R.: Lorazepam withdrawal seizures. Lancet 1: 151 (1980).

    PubMed  Article  CAS  Google Scholar 

  • Goldberg, H.L. and Finnerty, R.J.: Comparative efficacy of tofisopam and placebo. American Journal of Psychiatry 136: 196–199 (1979).

    PubMed  CAS  Google Scholar 

  • Gordon, E.B.: Addiction to diazepam (Valium). British Medical Journal 1: 112 (1967).

    Article  Google Scholar 

  • Gray, J.A.; Holt, L. and McNaughton, N.: Clinical implications of the experimental pharmacology of the benzodiazepines; in Costa (Ed.) The Benzodiazepines, From Molecular Biology to Clinical Practice (Raven Press, New York 1983).

    Google Scholar 

  • Greenblatt, D.J.; Langhren, T.P.; Thomas, P.; Allen, M.D.; Hermatz J.S. and Shader, R.I.: Plasma diazepam and desmethyldiazepam concentrations during long-term diazepam therapy. British Journal of Clinical Pharmacology 11: 35–40 (1981).

    PubMed  Article  CAS  Google Scholar 

  • Greenblatt, D.J. and Shader, R.I.: Benzodiazepines in Clinical Practice (Raven Press, New York 1974).

    Google Scholar 

  • Greenblatt, D.J.; Woo, E.; Allen, M.D.; Orvulak, P.J. and Shader, R.I.: Rapid recovery from massive diazepam overdose. Journal of the American Medical Association 240: 1872–1874 (1978).

    PubMed  Article  CAS  Google Scholar 

  • Griffiths, R.R.; Lucas, S.; Bradford, L.D.; Brady, J. and Snell, J.D.: Self-injection of barbiturates and benzodiazepines in baboons. Psychpharmacologica 75: 101–109 (1981).

    Article  CAS  Google Scholar 

  • Guile, L.A.: Rapid habituation to chlordiazepoxide (Librium). Medical Journal of Australia 50: 56–57 (1963).

    Google Scholar 

  • Hanks, G.W.; Lader, M.H. and Lawson, D.H. (Eds): Proceedings of a symposium on clobazam. British Journal of Clinical Pharmacology 7:Suppl. 1 (1979).

    Google Scholar 

  • Harris, T.H.: Methaminodiazepoxide. Journal of the American Medical Association 172: 1162 (1960).

    PubMed  Article  CAS  Google Scholar 

  • Hollister, L.E.; Motzembecker, F.P. and Degan, R.O.: Withdrawal reactions from chlordiazepoxide (Librium). Psychopharmacologia 2: 63–68 (1961).

    PubMed  Article  CAS  Google Scholar 

  • Hollister, L.E.: Withdrawal from benzodiazepine therapy. Journal of the American Medical Association 237: 1432 (1977).

    PubMed  Article  CAS  Google Scholar 

  • Howe, J.G.: Lorazepam withdrawal seizures. British Medical Journal 280: 1163–1164 (1980).

    PubMed  Article  CAS  Google Scholar 

  • Hume-Kendall, P.: Use of intravenous diazepam in acute skeletal muscle spasm. Annals of Physical Medicine (Suppl.) 14–15 (1964).

    Google Scholar 

  • Isbell, H.; Altschul, S.; Kornetsky, C.H.; Eisenman, A.J.; Flanary, H.G. and Fraser, H.F.: Chronic barbiturate intoxication. Archives of Neurology and Psychiatry 64: 1–16 (1950).

    PubMed  CAS  Google Scholar 

  • Kalant, H.; Leblanc, A.E. and Gibbins, R.J.: Tolerance to and dependence on some non-opiate psychtropic drugs. Pharmacological Reviews 23: 123–191 (1971).

    Google Scholar 

  • Kales, A.; Scharf, M.B.; Kales, J.D. and Soldatos, C.R.: Rebound insomnia: A potential hazard following withdrawal of certain benzodiazepines. Journal of the American Medical Association 241: 1692–1695 (1979).

    PubMed  Article  CAS  Google Scholar 

  • Kanto, J.; Liselo, E.; Lehtinen, V. and Salminen, J.: The concentration of diazepam and its metabolites in the plasma after an acute and chronic administration. Psychopharmacologia 36: 123–131 (1974).

    PubMed  Article  CAS  Google Scholar 

  • Lapierre, Y.D.: Benzodiazepine withdrawal. Canadian Journal of Psychiatry 26: 93–95 (1980).

    Google Scholar 

  • Maletzky, B.M. and Klotter, J.: Addiction to diazepam. International Journal of Addictions 11: 95–115 (1976).

    CAS  Google Scholar 

  • Marks, J.: The benzodiazepines: Use, overuse, misuse, abuse. (MTP Press, Lancaster 1978).

    Google Scholar 

  • Marks, J.: The benzodiazepines: Use and abuse. Arzneimittel-Forschung/Drug Research 30: 398–390 (1980).

    Google Scholar 

  • Mazzi, E.: Possible neonatal diazepam withdrawal: A case report. American Journal of Obstetrics and Gynecology 129: 586–587 (1977).

    PubMed  CAS  Google Scholar 

  • Miller, F. and Nielsen, J.: Diazepam (Valium) detoxification. Journal of Nervous and Mental Diseases 167: 637–638 (1979).

    Article  CAS  Google Scholar 

  • Möhler, H. and Okada, T.: Benzodiazepine receptors demonstrated in the central nervous system. Science 198: 849–851 (1977).

    PubMed  Article  Google Scholar 

  • Morgan, K. and Oswald, I.: Anxiety caused by a short-life hypnotic. British Medical Journal 284: 942 (1982).

    PubMed  Article  CAS  Google Scholar 

  • Murray, J.: Long-term psychotropic drug taking and the process of withdrawal. Psychological Medicine 11: 853–858 (1981).

    PubMed  Article  CAS  Google Scholar 

  • Murray, J.; Dunn, G.; Williams, P. and Tarnopolsky, A.: Factors affecting the consumption of psychotropic drugs. Psychological Medicine 11: 551–560 (1981).

    PubMed  Article  CAS  Google Scholar 

  • Nicholson, A.N.; Stone, B.M. and Spencer, M.B.: Anxiety caused by a short-life hypnotic. (Correspondence). British Medical Journal 284: 1785 (1982).

    Article  Google Scholar 

  • Parsonage, M.J. and Noms, J.W.: Use of diazepam in treatment of severe convulsive status epilepticus. British Medical Journal 3: 85–88 (1967).

    PubMed  Article  CAS  Google Scholar 

  • Peet, M. and Moonie, L.: Abuse of benzodiazepines. British Medical Journal 1: 714 (1977).

    PubMed  Article  CAS  Google Scholar 

  • Petursson, H.: Clinical and laboratory studies of withdrawal from long-term benzodiazepine treatment Ph. D. thesis, University of London.

  • Petursson, H. and Lader, M.H.: Withdrawal from long-term benzodiazepine treatment. British Medical Journal 283: 643–645 (1981).

    PubMed  Article  CAS  Google Scholar 

  • Petursson, H.; Shur, E.; Checkley, S.; Slade, A. and Lader, M.H.: A neuroendocrine approach to benzodiazepine tolerance and dependence. British Journal of Clinical Pharmacology 11: 526–528 (1981).

    PubMed  Article  CAS  Google Scholar 

  • Pevnick, J.S.; Jasinski, D.R. and Haertzen, C.A.: Abrupt withdrawal from therapeutically administered diazepam. Archives of General Psychiatry 35: 995–998 (1978).

    PubMed  Article  CAS  Google Scholar 

  • Preskorn, H. and Denner, J.: Benzodiazepines and withdrawal psychosis: Report of three cases. Journal of the American Medical Association 237: 36–38 (1977).

    PubMed  Article  CAS  Google Scholar 

  • Randall, L.O.; Schalleck, W.; Heise, G.A.; Keith, E.F. and Bagdon, R.E.: The psychosedative properties of methaminodiazepoxide. Journal of Pharmacology and Experimental Therapeutics 129: 163 (1960).

    PubMed  CAS  Google Scholar 

  • Randall, L.O.; Heise, G.A.; Schalleck, W.; Bagdon, R.E.; Banziger, R.F.; Boris, A.; Moe, R.A. and Abrams, W.B.: Pharmacological and clinical studies on Valium, a new psychotherapeutic agent of the benzodiazepine class. Current Therapeutic Research 3: 465–469 (1961).

    Google Scholar 

  • Rifkin, A.; Quitkin, F. and Klein, D.F.: Withdrawal reaction to diazepam. Journal of the American Medical Association 236: 2172–2173 (1976).

    PubMed  Article  CAS  Google Scholar 

  • Rutherford, D.M.; Okoko, A. and Tyrer, P.J.: Plasma concentrations of diazepam and desmethyldiazepam during chronic diazepam therapy. British Journal of Clinical Pharmacology 6: 69–73 (1978).

    PubMed  Article  CAS  Google Scholar 

  • Sackett, D.L. and Haynes, B.: Compliance with therapeutic regimens. (Johns Hopkins University Press, Baltimore 1976).

    Google Scholar 

  • Schapira, K.; Roth, M; Kerr, T.A. and Gurney, C.: The prognosis of affective disorders: The differentiation of anxiety states from depressive illness. British Journal of Psychiatry 121: 175–181 (1972).

    PubMed  Article  CAS  Google Scholar 

  • Scharf, M.B.; Bixler, E.O.; Kales, A. and Soldatos, C.R.: Long term sleep laboratory evaluation of flunitrazepam. Pharmacology (Switzerland). 19: 173–181 (1979).

    CAS  Google Scholar 

  • Shader, R.I. and Greenblatt, D.J.: Benzodiazepines: Some aspects of their clinical pharmacology; in Porter et al. (Eds) Drug Concentrations in Neuropsychiatry, CIBA Foundation Symposium No. 74, pp. 141–155 (Elsevier, North Holland 1980).

    Google Scholar 

  • Skegg, D.C.G.; Doll, R. and Perry, J.: Use of medicines in general practice. British Medical Journal 1: 1561–1563 (1977).

    PubMed  Article  CAS  Google Scholar 

  • Slater, J.: Suspected dependence on chlordiazepoxide hydrochloride (Librium). Canadian Medical Association Journal 95: 416 (1966).

    PubMed  CAS  Google Scholar 

  • Snyder, S.H.; Enna, S.J. and Young, A.B.: Brain mechanisms associated with therapeutic actions of benzodiazepines: Focus on neurotransmitters. American Journal of Psychiatry 134: 662–666 (1977).

    PubMed  CAS  Google Scholar 

  • Stein, L.; Belluzi, J.D. and Wise, CD.: Benzodiazepines: Behavioural and neurochemical mechanisms. American Journal of Psychiatry 134: 665–669 (1977).

    PubMed  CAS  Google Scholar 

  • Sternbach, L.H. and Reeder, E.J.: Quinazolines and 1,4-benzo-diazepines. IV. Transformations of 7-chloro-2-methylamino-5-phenyl-3H-l,4-benzodiazepines. Journal of Organic Chemistry 26: 4936–4938 (1961).

    Article  CAS  Google Scholar 

  • Stewart, R.B.; Salem, R.B. and Springer, P.K.: A case report of lorazepam withdrawal. American Journal of Psychiatry 137: 1113–1114 (1980).

    PubMed  CAS  Google Scholar 

  • Stolerman, I.P.; Kumar, R. and Steinberg, C.: Development of morphine dependence in rats: Lack of effect of previous ingestion of other drugs. Psychopharmacologia 20: 321–336 (1971).

    PubMed  Article  CAS  Google Scholar 

  • Svenson, S.F. and Hamilton, R.G.: A critique of overemphasis of side effects with the psychotropic drugs: An analysis of 18,000 chlordiazepoxide treated cases. Current Therapeutic Research 8: 455–464 (1966).

    PubMed  CAS  Google Scholar 

  • Syvälahti, E.K.G. and Kanto, J.H.: Serum growth hormone, serum immunoreactive insulin and blood glucose response to oral and intravenous diazepam. International Journal of Clinical Pharmacology 12: 74–82 (1975).

    Google Scholar 

  • Tobin, J.M. and Lewis, N.D.C.: New psychotherapeutic agent, chlordiazepoxide: Use in treatment of anxiety states and related symptoms. Journal of the American Medical Association 174: 1242 (1960).

    PubMed  Article  CAS  Google Scholar 

  • Trethowan, W.: Pills for personal problems. British Medical Journal 3: 749–751 (1975).

    PubMed  Article  CAS  Google Scholar 

  • Tyrer, P.: The benzodiazepine bonanza. Lancet 2: 709–710 (1974).

    PubMed  Article  CAS  Google Scholar 

  • Tyrer, P.: Drug treatment of psychiatric patients in general practice. British Medical Journal 2: 1008–1010 (1978).

    PubMed  Article  CAS  Google Scholar 

  • Tyrer, P.; Owen, R. and Dawling, S.: Gradual withdrawal of diazepam after chronic treatment (submitted for publication).

  • Tyrer, P.; Rutherford, D. and Huggett, T.: Benzodiazepine withdrawal symptoms and propranolol. Lancet 1: 520–522 (1981).

    PubMed  Article  CAS  Google Scholar 

  • Uhlenhuth, E.H.; Balter, M.B. and Lipman, R.S.: Minor tranquillisers: Clinical correlates of use in an urban population. Archives of General Psychiatry 35: 650–655 (1978).

    PubMed  Article  CAS  Google Scholar 

  • Vellucci, S.V. and File, S.E.: Chlordiazepoxide loses its anxiolytic action with long term treatment. Psychopharmacologia 62: 61–65 (1979).

    Article  CAS  Google Scholar 

  • Vyas, I. and Carney, M.W.P.: Diazepam withdrawal fits. British Medical Journal 4: 44 (1975).

    PubMed  Article  CAS  Google Scholar 

  • Walters, L. and Nel, P.: Die afhanklikheidspotensiaal van die benzodiazepine. South Afrikan Medical Journal 54: 115–116 (1981).

    Google Scholar 

  • Winokur, A.; Rickels, K.; Greenblatt, D.J.; Snyder, P.J. and Schatz, N.J.: Withdrawal reaction from long term low dosage administration of diazepam. Archives of General Psychiatry 37: 101–105 (1980).

    PubMed  Article  CAS  Google Scholar 

  • Winstead, D.K.; Anderson, A.; Eilers, M.K.; Blackwell, B. and Zaremba, A.L.: Diazepam on demand: Drug seeking behaviour in psychiatric inpatients. Archives of General Psychiatry 30: 349–351 (1974).

    PubMed  Article  CAS  Google Scholar 

  • Woody, G.E.; O’Brien, C.P. and Greenstein, R.: Misuse and abuse of diazepam; an increasingly common medical problem. International Journal of Addiction 10: 843–848 (1975).

    CAS  Google Scholar 

  • World Health Organization: Expert Committee on Drug Dependence, 20th Report. WHO Report Series, No. 551 (World Health Organization, Geneva 1974).

    Google Scholar 

  • Yanagita, T.: Dependence producing effects of anxiolytics; in Hoffmeister and Stille (Eds) Psychotropic Agents, part 2, pp. 395–406 (Springer-Verlag, Berlin 1982).

    Google Scholar 

  • Yanagita, T. and Takahashi, S.: Dependence liability of several sedative agents evaluated in monkeys. Journal of Pharmacology and Experimental Therapeutics 185: 307–316 (1973).

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Owen, R.T., Tyrer, P. Benzodiazepine Dependence. Drugs 25, 385–398 (1983). https://doi.org/10.2165/00003495-198325040-00003

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00003495-198325040-00003

Keywords

  • Diazepam
  • British Medical Journal
  • Withdrawal Symptom
  • Withdrawal Syndrome
  • Abstinence Syndrome