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.
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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).
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).
Ayd Jr, F.J.: Benzodiazepines: Dependence and withdrawal. Journal of the American Medical Association 242: 1401–1402 (1979).
Bant, W.: Diazepam withdrawal symptoms. British Medical Journal 4: 285 (1975).
Bismuth, C.; Le Bellec, M.; Dalby, S. and Lagier, G.: Dépendence physique aux benzodiazépines. Nouvelle Press Médicale 9: 1941–1945 (1980).
Blackwell, B.: Psychotropic drugs in use today: The role of diazepam in medical practice. Journal of the American Medical Association 225: 1637–1641 (1973).
Bowes, H.A.: The role of diazepam (Valium) in emotional illness. Psychosomatics 6: 336–340 (1965).
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).
Braestrup, C. and Nielsen, M.: Multiple benzodiazepine receptors. Trends in Neurosciences 3: 301–304 (1980).
Castleden, CM.; George, CF.; Marcer, P. and Hallett, C.: Increased sensitivity to nitrazepam in old age. British Medical Journal 1: 10–12 (1977).
Conney, A.H.: Pharmacological implications of microsomal enzyme induction. Pharmacological Reviews 19: 317–366 (1967).
Costa, E.: Mechanism of Action of Benzodiazepines, pp.113–151 (Raven Press, New York, 1975).
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).
De Bard, M.L.: Diazepam withdrawal syndrome: A case of psychosis, seizure and coma. American Journal of Psychiatry 136: 105–106 (1979).
Dysken, M.W. and Chan, C.H.: Diazepam withdrawal psychosis: A case report. American Journal of Psychiatry 134: 573 (1977).
Einarson, T.R.: Lorazepam withdrawal seizures. Lancet 1: 151 (1980).
Goldberg, H.L. and Finnerty, R.J.: Comparative efficacy of tofisopam and placebo. American Journal of Psychiatry 136: 196–199 (1979).
Gordon, E.B.: Addiction to diazepam (Valium). British Medical Journal 1: 112 (1967).
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).
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).
Greenblatt, D.J. and Shader, R.I.: Benzodiazepines in Clinical Practice (Raven Press, New York 1974).
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).
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).
Guile, L.A.: Rapid habituation to chlordiazepoxide (Librium). Medical Journal of Australia 50: 56–57 (1963).
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).
Harris, T.H.: Methaminodiazepoxide. Journal of the American Medical Association 172: 1162 (1960).
Hollister, L.E.; Motzembecker, F.P. and Degan, R.O.: Withdrawal reactions from chlordiazepoxide (Librium). Psychopharmacologia 2: 63–68 (1961).
Hollister, L.E.: Withdrawal from benzodiazepine therapy. Journal of the American Medical Association 237: 1432 (1977).
Howe, J.G.: Lorazepam withdrawal seizures. British Medical Journal 280: 1163–1164 (1980).
Hume-Kendall, P.: Use of intravenous diazepam in acute skeletal muscle spasm. Annals of Physical Medicine (Suppl.) 14–15 (1964).
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).
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).
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).
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).
Lapierre, Y.D.: Benzodiazepine withdrawal. Canadian Journal of Psychiatry 26: 93–95 (1980).
Maletzky, B.M. and Klotter, J.: Addiction to diazepam. International Journal of Addictions 11: 95–115 (1976).
Marks, J.: The benzodiazepines: Use, overuse, misuse, abuse. (MTP Press, Lancaster 1978).
Marks, J.: The benzodiazepines: Use and abuse. Arzneimittel-Forschung/Drug Research 30: 398–390 (1980).
Mazzi, E.: Possible neonatal diazepam withdrawal: A case report. American Journal of Obstetrics and Gynecology 129: 586–587 (1977).
Miller, F. and Nielsen, J.: Diazepam (Valium) detoxification. Journal of Nervous and Mental Diseases 167: 637–638 (1979).
Möhler, H. and Okada, T.: Benzodiazepine receptors demonstrated in the central nervous system. Science 198: 849–851 (1977).
Morgan, K. and Oswald, I.: Anxiety caused by a short-life hypnotic. British Medical Journal 284: 942 (1982).
Murray, J.: Long-term psychotropic drug taking and the process of withdrawal. Psychological Medicine 11: 853–858 (1981).
Murray, J.; Dunn, G.; Williams, P. and Tarnopolsky, A.: Factors affecting the consumption of psychotropic drugs. Psychological Medicine 11: 551–560 (1981).
Nicholson, A.N.; Stone, B.M. and Spencer, M.B.: Anxiety caused by a short-life hypnotic. (Correspondence). British Medical Journal 284: 1785 (1982).
Parsonage, M.J. and Noms, J.W.: Use of diazepam in treatment of severe convulsive status epilepticus. British Medical Journal 3: 85–88 (1967).
Peet, M. and Moonie, L.: Abuse of benzodiazepines. British Medical Journal 1: 714 (1977).
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).
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).
Pevnick, J.S.; Jasinski, D.R. and Haertzen, C.A.: Abrupt withdrawal from therapeutically administered diazepam. Archives of General Psychiatry 35: 995–998 (1978).
Preskorn, H. and Denner, J.: Benzodiazepines and withdrawal psychosis: Report of three cases. Journal of the American Medical Association 237: 36–38 (1977).
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).
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).
Rifkin, A.; Quitkin, F. and Klein, D.F.: Withdrawal reaction to diazepam. Journal of the American Medical Association 236: 2172–2173 (1976).
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).
Sackett, D.L. and Haynes, B.: Compliance with therapeutic regimens. (Johns Hopkins University Press, Baltimore 1976).
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).
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).
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).
Skegg, D.C.G.; Doll, R. and Perry, J.: Use of medicines in general practice. British Medical Journal 1: 1561–1563 (1977).
Slater, J.: Suspected dependence on chlordiazepoxide hydrochloride (Librium). Canadian Medical Association Journal 95: 416 (1966).
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).
Stein, L.; Belluzi, J.D. and Wise, CD.: Benzodiazepines: Behavioural and neurochemical mechanisms. American Journal of Psychiatry 134: 665–669 (1977).
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).
Stewart, R.B.; Salem, R.B. and Springer, P.K.: A case report of lorazepam withdrawal. American Journal of Psychiatry 137: 1113–1114 (1980).
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).
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).
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).
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).
Trethowan, W.: Pills for personal problems. British Medical Journal 3: 749–751 (1975).
Tyrer, P.: The benzodiazepine bonanza. Lancet 2: 709–710 (1974).
Tyrer, P.: Drug treatment of psychiatric patients in general practice. British Medical Journal 2: 1008–1010 (1978).
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).
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).
Vellucci, S.V. and File, S.E.: Chlordiazepoxide loses its anxiolytic action with long term treatment. Psychopharmacologia 62: 61–65 (1979).
Vyas, I. and Carney, M.W.P.: Diazepam withdrawal fits. British Medical Journal 4: 44 (1975).
Walters, L. and Nel, P.: Die afhanklikheidspotensiaal van die benzodiazepine. South Afrikan Medical Journal 54: 115–116 (1981).
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).
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).
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).
World Health Organization: Expert Committee on Drug Dependence, 20th Report. WHO Report Series, No. 551 (World Health Organization, Geneva 1974).
Yanagita, T.: Dependence producing effects of anxiolytics; in Hoffmeister and Stille (Eds) Psychotropic Agents, part 2, pp. 395–406 (Springer-Verlag, Berlin 1982).
Yanagita, T. and Takahashi, S.: Dependence liability of several sedative agents evaluated in monkeys. Journal of Pharmacology and Experimental Therapeutics 185: 307–316 (1973).
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Owen, R.T., Tyrer, P. Benzodiazepine Dependence. Drugs 25, 385–398 (1983). https://doi.org/10.2165/00003495-198325040-00003
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DOI: https://doi.org/10.2165/00003495-198325040-00003