Skip to main content
SpringerLink
Log in

Management of Benzodiazepine Overdose

  • Practical Therapeutics
  • Published:
CNS Drugs Aims and scope Submit manuscript

Summary

Today, benzodiazepines are the drugs most commonly involved in cases of self-poisoning. Fortunately, compared with several other drugs they are relatively safe in overdose, and symptoms of severe poisoning are rarely observed in young adults with pure benzodiazepine overdosage. However, respiratory depression, hypotension and prolonged coma are often seen in other patient groups with benzodiazepine overdosage, such as the elderly, children and patients with chronic pulmonary disease.

Flumazenil, a specific benzodiazepine antagonist, is a valuable and safe diagnostic and therapeutic tool in the short term management of drug poisoning with involvement of benzodiazepines. Its use should therefore be considered in all unconscious patients admitted because of benzodiazepine overdosage.

In self-poisoning, the drugs ingested are frequently a mixture of several compounds and their identity is often unknown. Flumazenil can also be used diagnostically in cases of unclear multiple drug poisoning or coma of unknown aetiology.

During use of flumazenil, consideration should be paid to a few contraindications, including patients with epilepsy who are receiving long term benzodiazepine medication. Moreover, some precautions should be taken during administration, such as individual titration of the dosage to minimise the risk of inducing benzodiazepine withdrawal syndrome or unmasking toxic effects of other concurrently ingested drugs. A normal electrocardiogram recording before the antidote is given will imply a minimal risk of any adverse reactions in cases of combined intake of benzodiazepine and antidepressants. Further, the short half-life of flumazenil necessitates a period of careful supervision after its administration.

Supportive care in a patient with benzodiazepine overdose includes close monitoring, preferably in the drainage position. If hypotension or prolonged eNS depression occurs, intravenous fluids should be administered. Occasionally, gastric lavage and administration of activated charcoal is indicated, but only if the patient is awake and potentially sensitive to benzodiazepines and if a large dose has been ingested within the last 1 to 2 hours.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Sternbach LH. The discovery of CNS active 1,4-benzodiazepines. In: Costa E, editor. The benzodiazepines: from molecular biology to clinical practice. New York: Raven Press, 1983: 1–6

    Google Scholar 

  2. Greenblatt DJ, Allen MD, Noel BJ, et al. Acute overdosage with benzodiazepine derivatives. Clin Pharmacol Ther 1977; 21: 497–514

    PubMed  CAS  Google Scholar 

  3. Matthew H, Roscoe P, Wright N. Acute poisoning. A comparison of hypnotic drugs. Practitioner 1972; 208: 254–8

    PubMed  CAS  Google Scholar 

  4. Divoll M, Greenblatt DJ, Lacasse Y, et al. Benzodiazepine overdosage: plasma concentrations and clinical outcome. Psychopharmacology 1981; 73: 381–3

    Article  PubMed  CAS  Google Scholar 

  5. Kop P, Cosic V, Simic B, et al. Analysis of the clinical experience in 100 cases of acute intoxication with Apaurin (diazepam). Bull Med Leg Toxicol 1972; 15: 243–51

    Google Scholar 

  6. Chapallez S. Intoxications aigues par le nitrazepam (Mogadon). Schweiz Apotheker Ztg 1973; 111: 95–9

    Google Scholar 

  7. Castleden CM, George CF, Marcer D, et al. Increased sensitivity to nitrazepam in old age. BMJ 1977; 1: 10–2

    Article  PubMed  CAS  Google Scholar 

  8. Greenblatt DJ, Allen MD, Shader RI. Toxicity of high dose flurazepam in the elderly. Clin Pharmacol Ther 1977; 21: 355–61

    PubMed  CAS  Google Scholar 

  9. Berger R, Green B, Melnick A. Cardiac arrest caused by oral diazepam intoxication. Clin Pediatr 1975; 14: 842–4

    Article  CAS  Google Scholar 

  10. Jager U, Hruby K, Haubenstock A, et al. Comparative clinical toxicology of 5 benzodiazepine derivatives. Nervenarzt 1984; 55: 150–3

    PubMed  CAS  Google Scholar 

  11. Clark TJH, Collins JV, Tong D. Respiratory depression caused by nitrazepam in patients with respiratory failure. Lancet 1971; 2: 737–8

    Article  PubMed  CAS  Google Scholar 

  12. Model DG. Effects of chlordiazepoxide in respiratory failure due to chronic bronchitis. Lancet 1974; 2: 869–70

    Article  PubMed  CAS  Google Scholar 

  13. Finkle BS, McCloskey KL, Goodman LS. Diazepam and drug-associated deaths. A survey in the United States and Canada. JAMA 1979; 242: 429–34

    Article  PubMed  CAS  Google Scholar 

  14. Martin CD, Chan SC. Distribution of temazepam in body fluids and tissues in lethal overdose. J Anal Toxicol 1986; 10: 77–8

    PubMed  CAS  Google Scholar 

  15. Dinovo EC, Gottschalk LA, McGuire FL, et al. Analysis of results of toxicological examinations performed by coroners or medical examiners’ laboratories in 2000 drug-involved deaths in nine major US cities. Clin Chem 1979; 22: 847–50

    Google Scholar 

  16. Höjer J, Baehrendtz S, Gustafsson LL. Benzodiazepine poisoning: experience of 702 admissions to an intensive care unit during a 14-year period. J Intern Med 1989; 226: 117–22

    Article  PubMed  Google Scholar 

  17. Heyndrickx B. Fatal intoxication due to flunitrazepam [letter]. J Anal Toxicol 1987; 11: 278

    PubMed  CAS  Google Scholar 

  18. Mignee C, Garnier R, Conso F, et al. Acute overdosage with flunitrazepam. Therapie 1988; 35: 581–9

    Google Scholar 

  19. Sunter JP, Bal TS, Cowan WK. Three cases of fatal triazolam poisoning. BMJ 1988; 297: 719

    Article  PubMed  CAS  Google Scholar 

  20. Olson KR, Yin L, Osterloh J, et al. Coma caused by trivial triazolam overdose. Am J Emerg Med 1985; 3: 210–1

    Article  PubMed  CAS  Google Scholar 

  21. Reidenberg MM, Levy M, Warner H, et al. Relationship between diazepam dose, plasma level, age, and central nervous depression. Clin Pharmacol Ther 1978; 23: 371–4

    PubMed  CAS  Google Scholar 

  22. Hardwicke C, Holt L, James R, et al. Trends in self-poisoning with drugs in Newcastle, New South Wales, 1980-1982. Med J Aust 1986; 144: 453–5

    PubMed  CAS  Google Scholar 

  23. Leykin Y, Halpern P, Silbiger A, et al. Acute poisoning treated in the intensive care unit: a case series. Isr J Med Sci 1989; 25: 98–102

    PubMed  CAS  Google Scholar 

  24. Proudfoot AT, Par J. Changing pattern of drugs used for self-poisoning. BMJ 1978; 1: 90–3

    Article  PubMed  CAS  Google Scholar 

  25. Willox DGA. Self-poisoning. A review of patients seen in the Victoria Infirmary, Glasgow. Scott Med J 1985; 30: 220–4

    PubMed  CAS  Google Scholar 

  26. Haefely W, Kulcsar A, Mohler H, et al. Possible involvement of GABA in the central actions of benzodiazepines. In: Costa E, Greengard P, editors. Mechanism of action of benzodiazepines. New York: Raven Press, 1975: 131–51

    Google Scholar 

  27. Möhler H, Okada T. Benzodiazepine receptor: demonstration in the central nervous system. Science 1977; 198: 849–51

    Article  PubMed  Google Scholar 

  28. Hunkeler W, Mohler H, Pieri L, et al. Selective antagonists of benzodiazepines. Nature 1981; 290: 514–6

    Article  PubMed  CAS  Google Scholar 

  29. Haefely W. Structure and function of the benzodiazepine receptor. CHIMIA 1987; 41: 389–96

    CAS  Google Scholar 

  30. Caldwell CB, Gross JB. Physostigmine reversal of midazolam induced sedation. Anesthesiology 1982; 57: 125–7

    Article  PubMed  CAS  Google Scholar 

  31. Meyer BH, Weis OF, Muller FO. Antagonism of diazepam by aminophylline in healthy volunteers. Anesth Analg 1984; 63: 900–2

    Article  PubMed  CAS  Google Scholar 

  32. Jordan C, Lehane JR, Jones JG. Respiratory depression following diazepam: reversal with high dose naloxone. Anesthesiology 1980; 53: 293–8

    Article  PubMed  CAS  Google Scholar 

  33. Garber JG, Ominsky AJ, Orkin FK, et al. Physostigmine atropine solution fails to reverse diazepam sedation. Anesth Analg 1980; 54: 58–60

    Google Scholar 

  34. Christensen KN, Huttel M. Naloxone does not antagonize diazepam-induced sedation [letter]. Anesthesiology 1979; 51: 187

    Article  PubMed  CAS  Google Scholar 

  35. Brogden RN, Goa KL. Flumazenil: a reappraisal of its pharmacological properties and therapeutic efficacy as a benzodiazepine antagonist. Drugs 1991; 42: 1061–89

    Article  PubMed  CAS  Google Scholar 

  36. Darragh A, Lambe R, Kenny M, et al. Tolerance of healthy volunteers to intravenous administration of the benzodiazepine antagonist Ro 15-1788. Eur J Clin Pharmacol 1983; 24: 569–70

    Article  PubMed  CAS  Google Scholar 

  37. Darragh A, Lambe R, Scully M, et al. Investigation in man of the efficacy of a benzodiazepine antagonist, Ro 15-1788. Lancet 1981; 2: 8–10

    Article  PubMed  CAS  Google Scholar 

  38. Darragh A, Lambe R, O’Boyle C, et al. Absence of central effects in man of the benzodiazepine antagonist Ro 15-1788. Psychopharmacology 1983; 80: 192–5

    Article  PubMed  CAS  Google Scholar 

  39. Scollo-Lavizzari G. The anticonvulsant effect of the benzodiazepine antagonist, Ro 15-1788: an EEG study in 4 cases. Eur Neurol 1984; 23: 1–6

    Article  PubMed  CAS  Google Scholar 

  40. Klotz U, Ziegler G, Reimann IW. Pharmacokinetics of the selective benzodiazepine antagonist Ro 15-1788 in man. Eur J Clin Pharmacol 1984; 27: 115–7

    PubMed  CAS  Google Scholar 

  41. Lauven PM, Schwilden H, Stoeckel H, et al. The effects of a benzodiazepine antagonist Ro 15-1788 in the presence of stable concentrations of midazolam. Anesthesiology 1983; 63: 61–4

    Article  Google Scholar 

  42. Scollo-Lavizzari G. First clinical investigation of the benzodiazepine antagonist Ro 15-1788 in comatose patients. Eur Neurol 1983; 22: 7–11

    Article  PubMed  CAS  Google Scholar 

  43. Geller E, Niv D, Rudick V, et al. The use of Ro 15-1788: a benzodiazepine antagonist in the diagnosis and treatment of benzodiazepine overdose [abstract]. Anesthesiology 1984; 61: A135

    Article  Google Scholar 

  44. Hofer P, Scollo-Lavizzari G. Benzodiazepine antagonist Ro 15-1788 in self-poisoning. Diagnostic and therapeutic use. Arch Intern Med 1985; 145: 663–4

    Article  PubMed  CAS  Google Scholar 

  45. Höjer J, Baehrendtz S, Matell G, et al. Diagnostic utility of flumazenil in coma with suspected poisoning: a double blind, randomised controlled study. BMJ 1990; 301: 1308–11

    Article  PubMed  Google Scholar 

  46. Höjer J, Baehrendtz S. The effect of flumazenil (Ro 15-1788) in the management of self-induced benzodiazepine poisoning. Acta Med Scand 1988; 224: 357–65

    Article  PubMed  Google Scholar 

  47. O’Sullivan GF, Wade DN. Flumazenil in the management of acute drug overdosage with benzodiazepines and other agents. Clin Pharmacol Ther 1987; 42: 254–9

    Article  PubMed  Google Scholar 

  48. Ritz R, Zuber M, Elsasser S, et al. Use of flumazenil in intoxicated patients with coma. A double-blind placebo-controlled study in ICU. Intensive Care Med 1990; 16: 242–7

    Article  PubMed  CAS  Google Scholar 

  49. Amrein R, Leishman B, Bentzinger C, et al. Flumazenil in benzodiazepine antagonism: actions and clinical use in intoxications and anaesthesiology. Med Toxicol 1987; 2: 411–29

    CAS  Google Scholar 

  50. Naef MM, Forster A, Nahory A, et al. Flumazenil antagonizes the sedative action of Zolpidem. A new imidazopyridine hypnotic [abstract]. Anesthesiology 1989; 71: A298

    Article  Google Scholar 

  51. Lheureux P, Debailleul G, De Witte O, et al. Zolpidem intoxication mimicking narcotic overdose: response to flumazenil. Hum Exp Toxicol 1990; 9: 105–7

    Article  PubMed  CAS  Google Scholar 

  52. Lheureux P, Vranckx M, Askenasi R. Use and misuse of flumazenil in clinical toxicology. In: Vincent JL, editor. Update in intensive care and emergency medicine. Berlin Heidelberg: Springer Verlag, 1991: 482–90

    Google Scholar 

  53. Klotz U, Zielger G, Rosenkranz B, et al. Does the benzodiazepine antagonist Ro 15-1788 antagonize the action of ethanol? Br J Clin Pharmacol 1986; 22: 513–20

    Article  PubMed  CAS  Google Scholar 

  54. Scollo-Lavizzari G, Matthis H. Benzodiazepine antagonist (Ro 15-1788) in ethanol intoxication: a pilot study. Eur Neurol 1985; 24: 352–4

    Article  PubMed  CAS  Google Scholar 

  55. Ziegler WH, Fliickiger A, Meier PJ, et al. Effects of the benzodiazepine-antagonist flumazenil (Anexate) in acute ethanol intoxication. Therapie 1988; 43: 143–63

    Google Scholar 

  56. Clausen TG, Wolff J, Carl P, et al. The effect of the benzodiazepine antagonist, flumazenil, on psychometric performance in acute ethanol intoxication in man. Eur J Clin Pharmacol 1990; 38: 233–6

    Article  PubMed  CAS  Google Scholar 

  57. Bodenham A, Brownlie G, Dixon JS, et al. Reversal of sedation by prolonged infusion of flumazenil (Anexate, Ro 15-1788). Anaesthesia 1988; 43: 376–8

    Article  PubMed  CAS  Google Scholar 

  58. Pollard BJ, Masters AP, Bunting P. The use of flumazenil (Anexate, Ro 15-1788) in the management of drug overdose. Anaesthesia 1989; 44: 137–8

    Article  PubMed  CAS  Google Scholar 

  59. Roald OK, Dahl V. Flunitrazepam intoxication in a child successfully treated with the benzodiazepine antagonist flumazenil. Crit Care Med 1989; 17: 1355–6

    PubMed  CAS  Google Scholar 

  60. Geller E, Niv D, Weinbrum A, et al. The use of flumazenil in the treatment of 34 intoxicated patients. Resuscitation 1988; Suppl. 16: 57–62

    Article  Google Scholar 

  61. Höjer J, Baehrendtz S, Magnusson A, et al. A placebo-controlled trial of flumazenil given by continuous infusion in severe benzodiazepine overdosage. Acta Anaesthesiol Scand 1991; 35: 584–90

    Article  PubMed  Google Scholar 

  62. Winkler E, Almog S, Kriger D, et al. Use of flumazenil in the diagnosis and treatment of patients with coma of unknown etiology. Crit Care Med 1993; 21: 538–42

    Article  PubMed  CAS  Google Scholar 

  63. Skeie B, Emhjellen S, Wickstrom E, et al. Antagonism of flunitrazepam-induced sedative effects by flumazenil in patients after surgery under general anaesthesia. A double-blind placebo-controlled investigation of efficacy and safety. Acta Anaesthesiol Scand 1988; 32: 290–4

    CAS  Google Scholar 

  64. Burr W, Sandham P, Judd A. Death after flumazenil [letter]. BMJ 1989; 298: 1713

    Article  PubMed  CAS  Google Scholar 

  65. Bodenham AR. Death after flumazenil [letter]. BMJ 1989; 299: 457

    Article  PubMed  CAS  Google Scholar 

  66. Savic I, Widén L, Stone-Elander S. Feasibility of reversing benzodiazepine tolerance with flumazenil. Lancet 1991; 337: 133–7

    Article  PubMed  CAS  Google Scholar 

  67. Short TG, Maling T, Galletly DC. Ventricular arrhythmia precipitated by flumazenil. BMJ 1988; 296: 1070–1

    Article  PubMed  CAS  Google Scholar 

  68. Marchant B, Wray R, Leach A, et al. Flumazenil causing convulsions and ventricular tachycardia [letter]. BMJ 1989; 299: 860

    Article  PubMed  CAS  Google Scholar 

  69. Aarseth HP, Bredesen JE, Grynne B, et al. Benzodiazepine-receptor antagonist, a clinical double blind study. J Toxicol Clin Toxicol 1988; 26: 283–92

    PubMed  CAS  Google Scholar 

  70. Knudsen L, Lonka L, Sorensen BH, et al. Benzodiazepine intoxication treated with flumazenil (Anexate, Ro 15-1788). Anaesthesia 1988; 43: 274–6

    Article  PubMed  CAS  Google Scholar 

  71. Levy DE, Bates D, Caronna JJ, et al. Prognosis in nontraumatic coma. Ann Int Med 1981; 94: 293–301

    PubMed  CAS  Google Scholar 

  72. Plum F, Posner JB, editors. Approach to the unconscious patient. In: The diagnosis of stupor and coma. Philadelphia: FA Davis Co, 1980: 345–64

  73. Rubenstein E. Intoxication by centrally acting agents. In: Rubenstein E, Federman DD, editors. Scientific American medicine. New York: Scientific American 1989; 8(I): 2–13

    Google Scholar 

  74. Mora CT, Torjman M, White PF. Effects of diazepam and flumazenil on sedation and hypoxic ventilatory response. Anesth Analg 1989; 68: 473–8

    Article  PubMed  CAS  Google Scholar 

  75. Sioufi A, Dubois JP. Review: chromatography of benzodiazepines. J Chromatogr 1990; 531: 459–80

    Article  PubMed  CAS  Google Scholar 

  76. Lillsunde P, Seppälä T. Simultaneous screening and quantitative analysis of benzodiazepines by dual-channel gas chromatography using electron-capture and nitrogen-phosphorus detection. J Chromatogr 1990; 533: 97–110

    Article  PubMed  CAS  Google Scholar 

  77. Riou B, Barriot P, Rimailhoa A, et al. Treatment of severe chloroquine poisoning. N Engl J Med 1988; 318: 1–6

    Article  PubMed  CAS  Google Scholar 

  78. Boehnert MT, Lovejoy Jr FH. Value of the QRS duration versus the serum drug level in predicting seizures and ventricular arrhythmias after an acute overdose of tricyclic antidepressants. N Engl J Med 1985; 313: 474–9

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Internal Medicine, Southern Hospital, Karolinska Institute, Stockholm, Sweden

    Jonas Höjer

Authors
  1. Jonas Höjer
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Höjer, J. Management of Benzodiazepine Overdose. CNS Drugs 2, 7–17 (1994). https://doi.org/10.2165/00023210-199402010-00002

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00023210-199402010-00002

Keywords

Search

Navigation