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Paradoxical Reactions &
Long-Term Side-Effects

It is now a well-known fact that benzodiazepine sedatives and antianxiety drugs can lead to dependence, even at therapeutic doses, after only a brief period of use (1, 2, 3, 4). However, this knowledge is relatively new. At the end of the 1970s, such low-dose dependence was still the subject of controversy, and an acknowledged expert in the field, Dr. David Greenblatt, made the following statement at a round-table conference held by ROCHE:

"I have never seen a case of diazepam dependence ... it is unusual enough to be a medical curiosity worthy of a medical case report or of being picked up by the press" (5).

This categorical and deeply ignorant remark was made by a leading expert as late as 1976. Today, massive medical documentation clearly shows that dependence is a common and almost anticipated complication in the use of benzodiazepines.

But experts still disagree about the mental side-effects occurring in dependence and in long-term use of benzodiazepine drugs. Some doctors and scientists still maintain that the only adverse effect of chronic benzodiazepine consumption is dependence and possible withdrawal symptoms when the drugs are discontinued (6). Others have found a clear correlation between the poor mental health of long-term users and the chronic consumption of sedatives (7,8). The adverse effects usually reported in this context are chronic depression (9, 10), OCD, phobias (11) and personality changes (12).

Benzodiazepines dependence can also cause patients to deteriorate socially, with job loss and early retirement as a result (13, 14). All told, the medical literature documents a number of adverse effects in long-term usage. But despite this, many patients are still afflicted by benzodiazepine dependence lasting for years, and even decades in some instances, without the intervention of public health and a critical review of the reasons for such prolonged pharmacological treatment.

'Paradoxical' reactions are other serious complications occurring in conjunction with the use of sedatives (15, 16). Some European pharmacopoeias have put the incidence of paradoxical reactions at less than one per mill, but the actual figure remains unknown. Malcolm Lader at the Institute of Psychiatry in London estimates the incidence of these adverse reactions at about 5%, even in short-term use of the drugs (17). The 'paradoxical' reactions consist of depression (18), with or without suicidal tendencies (19), phobias (20), aggressiveness (21, 22), violent behaviour (23, 24, 25) and symptoms misdiagnosed as psychosis in some instances (26, 27).

In the U.S., manufacturers feel compelled to report these adverse reactions and note that e.g. depression can occur. In most European countries, however, drug manufacturers do not even mention this adverse reaction, even though depression is a long-term effect which has been well-documented in the medical literature (7, 8, 9, 10, 13, 28). Since these reactions are often interpreted as symptoms of worsening health, many patients become ensnared by dependence merely because they respond with serious adverse reactions, thereby tragically obscuring the link to benzodiazepines for both patients and prescribing physicians. It is high time for the WHO and national regulatory authorities to force ROCHE and other benzodiazepine manufacturers to supply complete and accurate information on these adverse reactions.


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  2. Khan A, Joyce P et al. Benzodiazepine Withdrawal Syndromes. New Zealand Medical Journal 1980; 92: 94-96.

  3. Lennane KJ. Treatment of Benzodiazepine Dependence. Medical Journal of Australia 1986; 144: 593-596.

  4. Trickett S. Withdrawal from Benzodiazepines. Journal of the Royal College of General Practitioners 1983; 33: 608.

  5. Hollister LE. Valium: A Discussion of Current Issues. Psychosomatics 1977; 18: 44-58.

  6. Romach M, Busto U et al. Clinical Aspects of Chronic Use of Alprazolam and Lorazepam. Am J Psychiatry 1995; 152: 1161-1167.

  7. Haskell D, Cole OJ et al. A Survey of Diazepam Patients. Psychopharmacology Bulletin 1986; 22: 434-438.

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  10. Patten SB, Williams JVA et al. Self-Reported Depressive Symptoms Following Treatment with Corticosteroids and Sedative-Hypnotics. Int J Psych Med 1996; 26: 15-24.

  11. Cohen SI. Phobic Disorders and Benzodiazepines in the Elderly. British Journal of Psychiatry 1992; 160: 135.

  12. Murray N. Covert Effects of Chlordiazepoxide Therapy. J Neuropsychiatry 1962; 3: 168-179.

  13. Binder W, Kornhuber HH et al. Benzodiazepin-Sucht - unsere iatrogene Seuche. Öffentliches Gesundheitswesen 1984; 46: 80-86.

  14. Blennow G, Romelsjö A et al. Sedatives and Hypnotics in Stockholm: Social Factors and Kinds of Use. American Journal of Public Health 1994; 84: 242-246.

  15. Hall RCW, Zisook S. Paradoxical Reactions to Benzodiazepines. Br J Clin Pharmacol 1981; 11: 99S-104S.

  16. van der Bijl P, Roelofse JA. Disinhibitory Reactions to Benzodiazepines. J Oral Maxillofac Surg 1991; 49; 519-523.

  17. Lader M, Morton S. Benzodiazepine Problems. British Journal of Addiction 1991; 86: 823-828.

  18. Hall RCW, Joffe JR. Aberrant Response to Diazepam: A New Syndrome. American Journal of Psychiatry 1972; 129: 738-742.

  19. Ryan HF, Merrill B et al. Increase in Suicidal Thoughts and Tendencies. Association with Diazepam Therapy. JAMA 1968; 203: 1137-1139.

  20. Cohen SI. Alcohol and Benzodiazepines Generate Anxiety, Panic and Phobias. Journal of Royal Society of Medicine 1995; 88: 73-77.

  21. Dimascio A, Shader RI. Psychotropic Drugs and Induced Hostility. Psychosomatics 1969; 10: 46-47.

  22. Editorial. Tranquillizers Causing Aggression. BMJ 1975; 1: 113-114.

  23. Zisook S, DeVaul RA. Adverse Behavioral Effects of Benzodiazepines. Journal of Family Practice 1977; 6: 963-966.

  24. French AP. Dangerously Aggressive Behavior as a Side Effect of Alprazolam. Am J Psychiatry 1989; 146: 276.

  25. Karch FE. Rage Reaction Associated with Clorazepate Dipotassium. Annals of Internal Medicine 1979; 91: 61-62.

  26. Hansson O, Tonnby B. [Serious Psychological Symptoms Caused by Clonazepam.] Läkartidningen 1976; 73: 1210-1211.

  27. Teo SH, Chee KT et al. Psychiatric Complications of Rohypnol Abuse. Singapore Medical Journal 1979; 20: 270-273.

  28. Michelini S, Cassano GB et al. Long-Term Use of Benzodiazepines: Tolerance, Dependence and Clinical Problems in Anxiety and Mood Disorders. Pharmacopsychiatry 1996; 29: 127-134.

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