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Benzodiazepines

A Risk-Benefit Profile

CNS Drugs volume 1, pages 377–387 (1994)Cite this article

Summary

The benefits and risks of the benzodiazepines when used to treat generalised anxiety disorder, panic disorder and insomnia are important considerations. In discussing these parameters a distinction must be drawn between short term (of up to 28 days) and long term use.

Benzodiazepine anxiolytics and hypnotics have undoubted efficacy, although it can be difficult to distinguish between a substantial nonspecific (placebo) effect and true pharmacodynamic drug effects. Response to benzodiazepines is prompt. However, in the long term, efficacy wanes and becomes difficult to disentangle from the suppression of rebound or withdrawal.

The risks of benzodiazepines are well known, and comprise those associated with drug use and those that occur following discontinuation. Benzodiazepines have effects on psychological function, such as cognition and memory, and psychomotor performance. This translates into some interference with real-life functioning. Tolerance occurs to many but not all of these effects. Benzodiazepines have few effects on physical function, few drug interactions and are fairly safe in overdose.

On discontinuation after short term use, some rebound of the disorder for which the agents were prescribed may occur. After long term use, up to a third of patients will show a characteristic and clinically troublesome withdrawal syndrome.

Anxiety, panic and insomnia are unpleasant conditions that, especially in their severest forms, are associated with appreciable mortality. Alternative treatments to benzodiazepines are being developed, but are most efficacious in milder conditions. Therefore, the use of benzodiazepines can be justified in the short term management of anxiety, panic disorder and insomnia. However, in the long term, the risks of these agents probably outweigh their benefits.

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References

  1. Maczaj M. Pharmacological treatment of insomnia. Drugs 1993; 45: 44–55

    PubMed  CAS  Google Scholar 

  2. Rosenbaum JF. The drug treatment of anxiety. New Engl J Med 1982; 306: 401–4

    PubMed  CAS  Google Scholar 

  3. Quality Assurance Project. Treatment outlines for the management of anxiety states. Aust NZ J Psychiatry 1985; 19: 138–51

    Google Scholar 

  4. Nicholson AN. Hypnotics. Their place in therapeutics. Drugs 1986; 31: 164–76

    PubMed  CAS  Google Scholar 

  5. Task Force Report of the American Psychiatric Association. Benzodiazepine dependence, toxicity and abuse. Washington DC: American Psychiatric Association, 1990

    Google Scholar 

  6. Cowley DS, Dunner DL. Benzodiazepines in anxiety and depression. In: Roy-Byrne PP, Cowley DS, editors. Benzodiazepines in clinical practice: risks and benefits. Washington DC: American Psychiatric Press, 1991: 35–56

    Google Scholar 

  7. Rickels K, Case G, Downing RW, et al. Long-term diazepam therapy and clinical outcome. JAMA 1983; 250: 767–71

    PubMed  CAS  Google Scholar 

  8. Rickels K, Schweizer S, Casanalosi I, et al. Long-term treatment of anxiety and risk of withdrawal. Arch Gen Psychiatry 1988; 45: 444–50

    PubMed  CAS  Google Scholar 

  9. Tyrer P, Murphy S, Kingdon D, et al. The Nottingham study of neurotic disorder: comparison of drug and psychological treatments. Lancet 1988; 2: 235–40

    PubMed  CAS  Google Scholar 

  10. Ballenger JC, Burrows GD, DuPont RL, et al. Alprazolam in panic disorder and agoraphobia: results from a multicenter trial. Arch Gen Psychiatry 1988; 45: 413–22

    PubMed  CAS  Google Scholar 

  11. Dunner DL, Ishiki D, Avery DH, et al. Effect of alprazolam and diazepam on anxiety and panic attacks in panic disorder: a controlled study. J Clin Psychiatry 1986; 47: 458–60

    PubMed  CAS  Google Scholar 

  12. Liebowitz MR, Fyer AJ, Gorman JM. Alprazolam in the treatment of panic disorders. J Clin Psychopharmacol 1986; 6: 13–20

    PubMed  CAS  Google Scholar 

  13. Pecknold JC, Swinson RP, Kuch K, et al. Alprazolam in panic disorder and agoraphobia: results from a multicenter trial. Arch Gen Psychiatry 1988; 45: 429–35

    PubMed  CAS  Google Scholar 

  14. Noyes R, Anderson DJ, Clancy J, et al. Diazepam and propranolol in panic disorder and agoraphobia. Arch Gen Psychiatry 1984; 41: 287–92

    PubMed  Google Scholar 

  15. Noyes RJ Jr, Dupont RL, Pecknold JC, et al. Alprazolam in panic disorder and agoraphobia: results from a multicenter trial. Arch Gen Psychiatry 1988; 45: 423–8

    PubMed  Google Scholar 

  16. Cross-national collaborative panic study, second phase investigators. Drug treatment of panic disorder. Comparative efficacy of alprazolam, imipramine, and placebo. Br J Psychiatry 1992; 160: 191–202

    Google Scholar 

  17. Kales A, Kales J. Sleep laboratory studies of hypnotic drugs: efficacy and withdrawal effects. J Clin Psychopharmacol 1983; 3: 140–50

    PubMed  CAS  Google Scholar 

  18. Schneider-Helmert D. Why low-dose benzodiazepine-dependent insomniacs can’t escape their sleeping pills. Acta Psychiatr Scand 1988; 78: 706–11

    PubMed  CAS  Google Scholar 

  19. Salzman C. Behavioural side effects of benzodiazepines. In: Kane JM, Lieberman JA, editors. Adverse effects of psychotropic drugs. New York: Guildford Press, 1992: 139–52

    Google Scholar 

  20. Aranko K, Mattola MJ, Bordignon D. Psychomotor effects of alprazolam and diazepam during acute and subacute treatment, and during the follow-up phase. Acta Pharmacol Toxicol 1985; 56: 364–72

    CAS  Google Scholar 

  21. Nikaido AM, Ellinwood EH, Heatherly D, et al. Differential CNS effects of diazepam in elderly adults. Pharmacol Biochem Behav 1987; 27: 273–81

    PubMed  CAS  Google Scholar 

  22. Greenblatt DJ, Harmatz JS, Shader RL Clinical pharmacokinetics of anxiolytics and hypnotics in the elderly. Therapeutic considerations (part I). Clin Pharmacokinet 1991; 21: 165–77

    PubMed  CAS  Google Scholar 

  23. Wilkinson CJ. Effects of diazepam (Valium) and trait anxiety on human physical aggression and emotional state. J Behav Med 1985; 8: 101–13

    PubMed  CAS  Google Scholar 

  24. Hall RCW, Disook S. Paradoxical reactions to benzodiazepines. Br J Clin Pharmacol 1981; 11 Suppl. 1: 99S–104S

    PubMed  Google Scholar 

  25. Gardner DL, Cowdry RW. Alprazolam-induced dyscontrol in borderline personality disorder. Am J Psychiatry 1988; 142: 98–100

    Google Scholar 

  26. Dietch JT, Jennings RK. Aggressive dyscontrol in patients treated with benzodiazepines. J Clin Psychiatry 1988; 49: 184–7

    PubMed  CAS  Google Scholar 

  27. Goodman WK, Charney DS. A case of alprazolam, but not lorazepam inducing manic symptoms. J Clin Psychiatry 1987; 48: 117–8

    PubMed  CAS  Google Scholar 

  28. Koelega HS. Benzodiazepines and vigilance performance: a review. Psychopharmacology 1989; 98: 145–56

    PubMed  CAS  Google Scholar 

  29. Ellinwood EH, Nikaido AM. Perceptual-neuromotor pharmacodynamics of psychotropic drugs. In: Meltzer HY, editor. Psychopharmacology. The third generation of progress. New York: Raven Press, 1987: 1457–66

    Google Scholar 

  30. Johnson LC, Chernik DA. Sedative-hypnotics and human performance. Psychopharmacology 1982; 76: 101–13

    PubMed  CAS  Google Scholar 

  31. Bond AJ, Lader MH. Residual effects of hypnotics. Psychopharmacol 1972; 25: 117–32

    CAS  Google Scholar 

  32. Bond AJ, Lader MH. The residual effects of flurazepam. Psychopharmacol 1973; 32: 223–35

    CAS  Google Scholar 

  33. Bond AJ, James DC, Lader M. Physiological and psychological measures in anxious patients. Psychol Med 1974; 43: 364–73

    Google Scholar 

  34. Kleinknecht RA, Donaldson D. A review of the effects of diazepam on cognitive and psychomotor performance. J Nerv Ment Dis 1975; 161: 399–411

    PubMed  CAS  Google Scholar 

  35. Linnoila M, Erwin CW, Brendle A, et al. Psychomotor effects of diazepam in anxious patients and healthy volunteers. J Clin Psychopharmacol 1983; 3: 88–96

    PubMed  CAS  Google Scholar 

  36. Moskowitz H, Smiley A. Effects of chronically administered buspirone and diazepam on driving-related skill performance. J Clin Psychiatry 1982; 43 Dec section 2: 45–55

    PubMed  CAS  Google Scholar 

  37. Kruse WH-H. Problems and pitfalls in the use of benzodiazepines in the elderly. Drug Safety 1990; 5: 328–44

    PubMed  CAS  Google Scholar 

  38. Lucki I, Rickels K, Geller KM. Chronic use of benzodiazepines and psychomotor and cognitive test performance. Psychopharmacology 1986; 88: 426–33

    PubMed  CAS  Google Scholar 

  39. Petursson H, Gudjonsson GH, Lader MH. Psychometric performance during withdrawal from long-term benzodiazepine treatment. Psychopharmacology 1983; 81: 345–9

    PubMed  CAS  Google Scholar 

  40. Golombok S, Moodley P, Lader M. Cognitive impairment in long-term benzodiazepine users. Psychol Med 1988; 18: 365–74

    PubMed  CAS  Google Scholar 

  41. Zimmermann-Tansella C, Tansella M, Lader M. A comparison of the clinical and psychological effects of diazepam and amylobarbitone in anxious patients. Br J Clin Pharmacol 1979; 7: 605–11

    Google Scholar 

  42. Curran HV. Benzodiazepines, memory and mood: a review. Psychopharmacology 1991; 105: 1–8

    PubMed  CAS  Google Scholar 

  43. Ghoneim MM, Mewaldt SP. Benzodiazepines and human memory: a review. Anesthesiology 1990; 72: 926–38

    PubMed  CAS  Google Scholar 

  44. Hendler N, Cimini C, Terence MA, et al. A comparison of cognitive impairment due to benzodiazepines and to narcotics. Am J Psychiatry 1980; 137: 828–30

    PubMed  CAS  Google Scholar 

  45. Shader RI, Dreyfuss D, Gerrein JR, et al. Sedative effects and impaired learning and recall following single oral doses of lorazepam. Clin Pharmacol Ther 1986; 39: 526–9

    PubMed  CAS  Google Scholar 

  46. Spinweber CL, Johnson LC. Effects of triazolam (0.5mg) on sleep, performance memory and arousal threshold. Psychopharmacology 1982; 76: 5–12

    PubMed  CAS  Google Scholar 

  47. Curran HV, Schiwy W, Lader M. Differential amnesic properties of benzodiazepines: a dose-response comparison of two drugs with similar elimination half-lives. Psychopharmacology 1987; 92: 358–64

    PubMed  CAS  Google Scholar 

  48. Morton S, Lader M. Alpidem and lorazepam in the treatment of patients with anxiety disorders: comparison of efficacy and rebound. Human Psychopharmacol 1992; 7: 239–48

    Google Scholar 

  49. Cook PJ. Benzodiazepine hypnotics in the elderly. Acta Psychiatr Scand 1986; 74 Suppl. 332: 149–58

    Google Scholar 

  50. Foy A, Drinkwater V, March S, et al. Confusion after admission to hospital in elderly patients using benzodiazepines. BMJ 1986; 293: 1072

    PubMed  CAS  Google Scholar 

  51. Ancill RJ, Embury GD, MacEwan GW, et al. Lorazepam in the elderly - a retrospective study of the side-effects in 20 patients. J Psychopharmacol 1987; 2: 126–7

    Google Scholar 

  52. Betts TA, Birtle J. Effect of two hypnotic drugs on actual driving performance next morning. BMJ 1982; 285: 852

    PubMed  CAS  Google Scholar 

  53. Linnoila M, Hakkinen S. Effects of diazepam and codeine, alone and in combination with alcohol, on simulated driving. Clin Pharmacol Ther 1974; 15: 368–73

    PubMed  CAS  Google Scholar 

  54. O’Hanlon JD, Haak TW, Blaauw GJ, et al. Diazepam impairs lateral position control in highway driving. Science 1982; 217: 79–81

    PubMed  Google Scholar 

  55. van Laar MW, Volkerts ER, von Willigenburg APP. Therapeutic effects and effects on actual driving performance of chronically administered buspirone and diazepam in anxious outpatients. J Clin Psychopharmacol 1992; 12: 86–95

    PubMed  Google Scholar 

  56. Barnas C, Miller CH, Sperner G, et al. The effects of alcohol and benzodiazepines on the severity of ski accidents. Acta Psychiatr Scand 1992; 86: 296–300

    PubMed  CAS  Google Scholar 

  57. Ray WA, Fought RL, Decker MD. Psychoactive drugs and the risk of injurious motor vehicle crashes in elderly drivers. Am J Epidemiol 1992; 136: 873–83

    PubMed  CAS  Google Scholar 

  58. Caplan RD, Andrews FM, Conway TL, et al. Social effects of diazepam use: a longitudinal field study. Soc Sci Med 1985; 21: 887–98

    PubMed  CAS  Google Scholar 

  59. Oster G, Russell MW, Huse DM, et al. Accident- and injury-related health-care utilization among benzodiazepine users and non-users. J Clin Psychiatry 1987; 48 Suppl. 12: 17–21

    PubMed  Google Scholar 

  60. Evans JG, Jarvis EH. Nitrazepam and the elderly [letter]. BMJ 1972; 4: 487

    PubMed  CAS  Google Scholar 

  61. MacDonald JB. The role of drugs in falls in the elderly. Clin Geriatr Med 1985; 1: 621–32

    PubMed  CAS  Google Scholar 

  62. Sorock GS, Shimkin EE. Benzodiazepine sedatives and the risk of falling in a community-dwelling elderly cohort. Ann Int Med 1988; 148: 2441–4

    CAS  Google Scholar 

  63. Lader MH, Ron M, Petursson H. Computed axial brain tomography in long-term benzodiazepine users. Psychol Med 1984; 14: 203–20

    PubMed  CAS  Google Scholar 

  64. Moodley P, Golombok S, Shine P, et al. Computed axial brain tomograms in long-term benzodiazepine users. Psychiatry Res 1993; 48: 135–44

    PubMed  CAS  Google Scholar 

  65. Schmauss C, Kreig JC. Enlargement of cerebrospinal fluid spaces in long-term benzodiazepine users. Psychol Med 1987; 17: 869–73

    PubMed  CAS  Google Scholar 

  66. Uhde TW, Kellner CH. Cerebral ventricular size in panic disorder. J Affect Disord 1987; 12: 175–8

    PubMed  CAS  Google Scholar 

  67. Perera KMH, Powell T, Jenner FA. Computerized axial tomographic studies following long-term use of benzodiazepines. Psychol Med 1987; 17: 775–7

    PubMed  CAS  Google Scholar 

  68. Poser W, Poser S, Roscher D, et al. Do benzodiazepines cause cerebral atrophy? Lancet 1983; 1: 715

    PubMed  CAS  Google Scholar 

  69. Rickels K. Clinical management of benzodiazepine dependence [letter]. BMJ 1985; 291: 1649

    PubMed  CAS  Google Scholar 

  70. Laegreid L, Olegard R, Wahlstrom J, et al. Abnormalities in children exposed to benzodiazepines in utero. Lancet 1987; 1: 108–9

    PubMed  CAS  Google Scholar 

  71. Cohen LS, Heller VL, Rosenbaum JE Treatment guidelines for psychotropic drug use in pregnancy. Psychosomatics 1989; 30: 25–33

    PubMed  CAS  Google Scholar 

  72. Remonteria JL, Bhatt K. Withdrawal symptoms in neonates from intrauterine exposure to diazepam. J Pediatr 1977; 90: 123–6

    Google Scholar 

  73. Kanto JH. Use of benzodiazepines during pregnancy, labour and lactation, with particular reference to pharmacokinetic considerations. Drugs 1982; 23: 354–80

    PubMed  CAS  Google Scholar 

  74. Wilson D. Experience with drugs and driving in Queensland, Australia. Med Sci Law 1985; 25: 2–10

    PubMed  CAS  Google Scholar 

  75. Linnoila M, Stapleton JM, Lister R, et al. Effects of single doses of alprazolam and diazepam, alone and in combination with ethanol, on psychomotor and cognitive performance and on autonomic nervous system reactivity in healthy volunteers. Eur J Clin Pharmacol 1990; 39: 21–8

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  77. Serfaty M, Masterton G. Fatal poisonings attributed to benzodiazepines in Britain during the 1980’s. Br J Psychiatry 1993; 163: 386–93

    PubMed  CAS  Google Scholar 

  78. Hallström C, editor. Benzodiazepine dependence. Oxford: Oxford University Press, 1993

    Google Scholar 

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

    PubMed  CAS  Google Scholar 

  80. Woods JH, Katz JL, Winger G. Benzodiazepines: Use, abuse, and consequences. Pharmacol Rev 1992; 44: 151–347

    PubMed  CAS  Google Scholar 

  81. Lader M. Rebound insomnia and newer hypnotics. Psychopharmacology 1992; 108: 248–55

    PubMed  CAS  Google Scholar 

  82. Scharf MB, Sachais BA, Mayleben DW A polysomnographic comparison of temazepam 15 and 30 mg with triazolam 0.125 and 0.25 mg in chronic insomnia. Curr Ther Res 1990; 18: 555–67

    Google Scholar 

  83. Merlotti L, Roehrs T, Zorick F, et al. Rebound insomnia: duration of use and individual differences. J Clin Psychopharmacol 1991; 11: 368–73

    PubMed  CAS  Google Scholar 

  84. Busto U, Sellers EM, Naranjo CA, et al. Withdrawal reaction after long-term therapeutic use of benzodiazepines. New Engl J Med 1986; 315: 854–9

    PubMed  CAS  Google Scholar 

  85. Petursson H, Lader M. Dependence on tranquillisers. Maudsley Monograph No. 28. Oxford: Oxford University Press, 1984

    Google Scholar 

  86. Higgitt A, Fonagy P. Benzodiazepine dependence syndromes and syndromes of withdrawal. In: Hallström C, editor. Benzodiazepine dependence. Oxford: Oxford University Press, 1993: 58–70

    Google Scholar 

  87. Tyrer P, Rutherford D, Huggett T. Benzodiazepine withdrawal symptoms and propranolol. Lancet 1981; 1: 520–2

    PubMed  CAS  Google Scholar 

  88. Laux G, König W. Long-term use of benzodiazepines in psychiatric patients. Acta Psychiatr Scand 1987; 76: 64–70

    PubMed  CAS  Google Scholar 

  89. Brown JL, Hauge KJ. A review of alprazolam withdrawal. Drug Intelligence Clin Pharm 1986; 20: 837–41

    Google Scholar 

  90. Golombok S, Higgitt A, Fonagy P, et al. A follow-up study of patients treated for benzodiazepine dependence. Br J Med Psychol 1987; 60: 141–9

    PubMed  Google Scholar 

  91. Rickels K, Case WG, Schweizer E, et al. Long-term benzodiazepine users 3 years after participation in a discontinuation program. Am J Psychiatry 1991; 148: 757–61

    PubMed  CAS  Google Scholar 

  92. Olajide D, Lader M. Depression following withdrawal from long-term benzodiazepine use: a report of four cases. Psychol Med 1984; 14: 937–40

    PubMed  CAS  Google Scholar 

  93. Busto U, Sellers EM, Naranjo CA, et al. Patterns of benzodiazepine abuse and dependence. Br J Addict 1986; 81: 87–94

    PubMed  CAS  Google Scholar 

  94. Strang J, Seivewright N, Farrell M. Intravenous and other novel abuses of benzodiazepines: the opening of Pandora’s box? Br J Addict 1992; 87: 1373–5

    PubMed  CAS  Google Scholar 

  95. Bond A, Seijas D, Dawling S, et al. Systematic absorption and abuse liability of snorted flunitrazepam. Addiction. In press

  96. Allgulander C, Lavori PW. Excess mortality among 3302 patients with ‘pure’ anxiety neurosis. Arch Gen Psychiatry 1991; 48: 599–602

    PubMed  CAS  Google Scholar 

  97. Angst J, Vollrath M. The natural history of anxiety disorders. Acta Psychiatr Scand 1991; 84: 446–52

    PubMed  CAS  Google Scholar 

  98. Dement WC. The proper use of sleeping pills in the primary care setting. J Clin Psychiatry 1992; 53 Suppl. 12: 50–6

    PubMed  Google Scholar 

  99. Uhlenhuth EH, De Wit H, Balter MB, et al. Risks and benefits of long-term benzodiazepine use. J Clin Psychopharmacol 1988; 8: 161–7

    PubMed  CAS  Google Scholar 

  100. Da Roza Davis J, Gelder M. Long-term management of anxiety states. Int Rev Psychiatry 1991; 3: 5–17

    Google Scholar 

  101. Durham RC, Allan T. Psychological treatment of generalised anxiety disorder. A review of the clinical significance of results in outcome studies since 1980. Br J Psychiatry 1993; 163: 19–26

    PubMed  CAS  Google Scholar 

  102. Hackmann A. Psychological alternatives to taking benzodiazepines. In: Hallström C, editor. Benzodiazepine dependence. Oxford: Oxford University Press, 1993: 282–95

    Google Scholar 

  103. Sloan EP, Hauri P, Bootzin R, et al. The nuts and bolts of behavioral therapy for insomnia. J Psychosom Res 1993; 37 Suppl. 1: 19–38

    PubMed  Google Scholar 

  104. Lader M. The medical management of insomnia in general practice, Round Table Series No. 28, Royal Society of Medicine, London, 1992

  105. Lader M. Guidelines for the management of patients with generalised anxiety. Psychiatr Bull 1992; 16: 560–5

    Google Scholar 

  106. Donnan P, Hutchinson A, Paxton R, et al. Self-help materials for anxiety: a randomized controlled trial in general practice. Br J Gen Pract 1990; 40: 498–501

    PubMed  CAS  Google Scholar 

  107. Deakin JFW. A review of clinical efficacy of 5-HT1A agonists in anxiety and depression. J Psychopharmacol 1993; 7: 283–9

    PubMed  CAS  Google Scholar 

  108. Mendelson WB, Roehrs TA, Roth T. Replacement of benzodiazepines with ‘old-fashioned’ hypnotics. A cause for concern? Drug Safety 1993; 9: 149–50

    PubMed  CAS  Google Scholar 

  109. Morgan K. Hypnotics in the elderly. What cause for concern? Drugs 1990; 40: 688–96

    PubMed  CAS  Google Scholar 

  110. Balter MB, Ban TA, Uhlenhuth EH. International study of expert judgment on therapeutic use of benzodiazepines and other psychotherapeutic medications I. Current concerns. Hum Psychopharmacol 1993; 8: 253–61

    Google Scholar 

  111. Lyons JS, Larson DB, Hromco J. Clinical and economic evaluation of benzodiazepines. A value analysis. Pharmaco-Economics 1992; 2: 397–407

    CAS  Google Scholar 

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    Malcolm Lader

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Lader, M. Benzodiazepines. CNS Drugs 1, 377–387 (1994). https://doi.org/10.2165/00023210-199401050-00008

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Keywords

  • Adis International Limited
  • Panic Disorder
  • Buspirone
  • Alprazolam
  • Triazolam