suicide, teratogenic effects, tinnitus, tolerance, traffic, withdrawal, withdrawal psychosis

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Nathan RG, Robinson D, Cherek DR, Davison S, Sebastian S, Hack M.
Long-Term Benzodiazepine Use and Depression.
American Journal of Psychiatry 1985; 142: 144-145.
" A 1979 household survey found that 1,6 % of the adults in the United States (approximately 2.5 million people) had used antianxiaety agents daily for 1 year or more. Withdrawal symptoms following discontinuation of these agents have been studied, but little is known about the effects of long-term use." [p. 144]

" Our findings strongly support the need for increased epidemiological research with long-term users of benzodiazepines. Continuing medical education has emphasized the importance of the differential diagnosis of depression and anxiety disorders. Our findings suggest that patients using the drug for more than 1 year should be reassessed for depressive disorders. " [p. 145]
[Key words; addiction, dependence, abuse, depression, long-term effects]

Nerenz K.
[ A Case of Grand-Mal Seizures Following Withdrawal of Valium.] German
Nervenarzt 1974; 45: 384-386.
" Eine erhöhte Wachsamkeit in Klinik und Praxis und genauere Analysen der Fälle von Valiummissbrauch und -sucht sind erforderlich; dazu möchten wir mit diesem Beitrag anregen. Soviel lässt sich aber schon jetzt mit Sicherheit feststellen: die Zunahme von Valium-Missbrauch und Valiumsucht und die Schwere des Entzugssyndroms zeigen, dass vor einer bedenkenlosen Langzeitverordnung dieses Medikamentes dringend zu warnen ist. " [p. 386]

[Key words; Valium, diazepam, addiction, abuse, dependence, withdrawal, detoxification]

Noyes R, Clancy J, Coryell WH, Crowe RR, Chaudhry DR, Domingo DV.
A Withdrawl Syndrome after Abrupt Discontinuation of Alprazolam.
American Journal of Psychiatry 1985; 142: 114-116.
A patient who received therapeutic doses of alprazolam for 8 weeks experienced a withdrawal syndrome beginning 18 hours after its abrupt discontinuation. Short-acting and minimally sedating benzodiazepines may have increased poten tial for withdrawal reactions. [\~ABSTRACT p. 114]
[Key words; Xanax, alprazolam, addiction, dependence, withdrawal]

O'Brian CP, McLellan AT.
Myths about the Treatment of Addiction.
Lancet 1996; 347: 237-240.
"... addictions are similar to other chronic disorders such as arthritis, hypertension, asthma and diabetes. Addicting drugs produce changes in brain pathways that endure long after the person stops taking them. Further, the associated medical, social, and occupational difficulties that usually develop during the course of addiction do not disappear when the patient is detoxified. These protracted brain changes and the associated personal and social difficulties put the former addict at great risk of relapse. Treatment for addiction, therefore, should be regarderd as being long term... " [p. 237]

O'Dowd JJ, Spragg PP, Routledge PA.
Fatal Triazolam Poisoning.
BMJ 1988; 297: 1048.
" A 5 8 year old women was being treated for depression and taking 0,25 mg triazolam at night... on the day of her death she ran into a neighbour s house and stated that she had taken 70 tablets. She collapsed, became unconscious, and died shortly after reaching the accident and emergency department. "

" It is often stated that benzodiazepine poisoning is comparatively safe, but we would agree with Dr Sunter and others that patients who have taken an overdose of triazolam should be carefully monitored and that death can result from an overdose of this drug. " [p. 1084]
[Key words; Halcion, triazolam, poisoning, suicide]

Olajide D, Lader M.
Depression Following Withdrawal from Long-Term Benzodiazepine Use: A Report of Four Cases.
Psychological Medicine 1984; 14: 937-940.
Depression following withdrawal from long- or short-term use of benzodiazepines is not uncommon, yet it is underreported in the benzodiazepine withdrawal literature. Four cases of depressive illness supervening during benzodiazepine wit hdrawal are reported. Depression may, it is suggested, be an integral part of the benzodiazepine withdrawal syndrome. [SUMMARY p. 937]
[Key words; withdrawal, depression]

Olson KR, Yin L, Osterloh J, Tani A.
Coma Caused by Trivial Triazolam Overdose.
American Journal of Emergency Medicine 1985; 3: 210-211.
Physicians should be aware that unlike older, longer-acting benzodiazepines, the new hypnotic triazolam may cause serious central nervous system depression following relatively small overdosage. Patients receiving triazolam should be carefully instructed not to exceed ususal recommended doses. [ SUMMARY p. 211]
[Key words; Halcion, triazolam, poisoning]

Oster G, Huse DM, Adams SF, Imbimbo J, Russell MW.
Benzodiazepine Tranquilizers and the Risk of Accidental Injury.
American Journal of Public Health 1990; 80: 1467-1470.
" We found accident-related care was more likely among persons who had been prescribed benzodiazepines; among these persons, the probability of an accident-related medical encounter was higher during the months in which a prescription for a benzodiazepine had recently been filled compared to other months. " [p. 1467]
[Key words; psychomotor impairment, accidents]

Oswald I.
Triazolam Syndrome 10 Years On.
Lancet 1989; i: 451-452.
" It is now 10 years since the Lancet published a letter from a Dutch psychiatrist, Dr van der Kroef, who described anxiety, derealisation, paranoid ideas, and other mental changes associated with triazolam ("Halcion"). The response was remarkable. Twelve leading investigators from across the northern hemisphere signed a coordinated letter to the Lancet expressing alarm that this report had appeared and they rejected its contents. Two medical advisors to Upjohn wrote in similar vein. " [p . 451]

" What was not being recognised was that sleeping pills are mostly taken by the middle-aged or older, often for months or years. "

" It was also not recognised that halcion had been marketed when in controlled trials (and excluding chronic schizophrenic patients), only 11 patients over the age of 40 were known to have taken 0.25 mg triazolam for more than 2 weeks. Even fewer, perhaps 3 or 4 patients over the age of 40 (one cannot tell precisely from the publication) were known to have taken 0.5 mg for over two weeks, as well as some young men. Leibowitz and Sunshine mentioned that amnesia and "restlessness and nervousness" were associated with halcion. Upjohn would claim to have additional unpublished data "on file", data that have been said to be defective, which may be why it remains unpublished. Quality of data always rests on the manner and care of collection. Upjohn's studies consistently used a breakfast-time questionnaire about the previous night's sleep, with a final question. "Did you have any side effects ?". Little wonder that grogginess emerged as the supposedly only adverse effect of triazolam. Upjohn sponsored no long-term studies in which information was collected in the evening about feelings, or events such as quarrels, during the day. " [p. 451]

" There have since been three double-blind controlled trials with adequate numbers of subjects, all aged over 40, all taking triazolam for over two weeks, and with planned evaluation of daily mood and behaviour. All three found that regular nightly triazolam causes daytime anxiety. " [p. 451]

" Upjohn-funded research has concentrated on dosing for 1-7 nights: little time for the development of tolerance. It is with regular intake of triazolam that brain function gradually changes and leads to daytime anxiety, while in the sleep laboratory the response of the brain after three weeks differs from the response after the first two doses. " [p. 452]

" van der Kroef was right, you were right to publish his letter in 1979, and the Netherlands have been right to ban triazolam since. People who complain of poor sleep are generally anxious people. If after 3 weeks they are even more anxious, doctor and patient alike easily attribute any change to the patient rather than to the drug. It is a matter of concern that halcion was marketed on the basis of deficient research. It should no longer be sold. " [p. 452]
[Key words; Halcion, triazolam, drug manufacturers]

Patch VD.
The Dangers of Diazepam, a Street Drug.
New England Journal of Medicine 1974; 290: 807.
" Diazepam (Valium) has burst on the drug scene in Massachusetts during the past year to become one of the more common drugs of abuse. Addiction-prone persons have found that in doses of 100 mg to 500 mg daily, it will produce a pleasurable state of intoxication. A 10-mg tablet has a current street-sale value of 50 c. "

" It is important that withdrawal symptoms similar in character to those noted with barbiturates and alcohol have followed abrupt discontinuance of diazepam. Characteristic symptoms of withdrawal noted in these situations may include convulsions, tremor, abdominal and muscle cramps and vomiting and sweating.

" Overdosage generally manifests itself with symptoms of somnolence, confusion, diminished reflexes and coma. Adverse paradoxical reactions have been observed, including acute hyperexcited states, anxiety, hallucinations, muscle spasticity and rage.

It is clear that physicians must exercise the same caution in prescribing diazepam as in prescribing opiates, barbiturates and amphetamines. Recent studies have demonstrated that diazepam is one of today's contenders as the leading cause of drug-abuse episodes apperaing in general-hospital emergency wards. "
[Key words; Valium, diazepam, addiction, abuse, dependence, withdrawal, hallucinations, paradoxical effects]

Patel DA, Patel AR.
Clorazepate and Congenital Malformations.
JAMA 1980; 244: 135-136.
Clorazepate has not been studied adequatelt to determine whether it is associated with an increased risk of fetal abnormalities. However, other antianxiety agents such as chlordiazepoxide hydrochloride, diazepam, and meprobamate have been known to have teratogenic potential. Demonstration of teratogenicity of a drug in clinical situations is admittedly difficult. In this case administration of chlorazepate dipotassium during early fetal development might be related to the feta l malformation. There was a striking similarity between abnormalities seen in this case and those found in thalidomide-induced abnormalities. Presently the use of clorazepate dipottasium is considered ill advised in pregnant women. Further studies are needed to clarify the teratogenicity of clorazepate dipotassium. [ABSTRACT p. 136]
[Key words; Tranxene, clorazepate, teratogenic effects]

Patten SB, Love EJ.
Neuropsychiatric Adverse Drug Reactions: Passive Reports to Health and Welfare
Canada's Adverse Drug Reaction Database (1965-Present). International Journal of Psychiatry in Medicine 1994; 24: 45-62.
" Chlordiazepoxide, clorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam, and triazolam were included in the database search. The number of reports which named one of these benzodiazepines as a suspected cause of adverse reactions were: seventy-four for chlordiazepoxide, three for clorazepate, 165 for diazepam, 153 for flurazepam, 143 for lorazepam, ninety-seven for oxazepam, ten for temazepam, and 446 for triazolam. However, many reports described more than one benzodiazepine as a suspected etiological agent, and many described dependence as the adverse event (n 95). Further description, therefore, involves only reports where a single benzodiazepine was a suspected etiological agent, and excludes cases of dependence.

There were 641 such reports. Surprisingly, encephalopathy was the most commonly described adverse event (n 374). Memory disturbance was reported much less often (n 56). Interestingly, while daytime disturbance is usually regarded as a clinical problem mostly for the long acting drugs, the majority of the reports of amnestic disturbance in the database involved triazolam (n 49). Twenty-six reports described disinhibition, rage, agitation, and aggression in relation to benzodiazepine use. Anxiety in the context of benzodiazepine therapy usually represents a rebound effect. Consistent with this, twelwe of the fourteen reports of anxiety were associated with the short acting drugs: triazolam, oxazepam, and lorazepam. Benzodiazepines are not usually associated with the development of hallucinations, however, these were among the most commonly reported adverse reactions to benzodiazepines in the database ( n 42). [p. 55]
[Key words; Librium, Tranxene, Valium, Dalmane, Ativan, Serax, Serenid, Serepax, Euhypnos, Normison, Halcion, chlordiazepoxide, clorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam, triazolam, dependence, rebound, tolerance, amnesia, memory impairment, encephalopathy]

Patterson JF.
Triazolam Syndrome in the Elderly.
Southern Medical Journal 1987; 80: 1425-1426.
I have described five elderly patients who had a syndrome characterized by reversible delirium, automatic movement, and anterograde amnesia after ingesting triazolam as a hypnotic. These cases raise concern about the use of short-acting, rapidly eliminated benzodiazepine hypnotics in the elderly. [ SUMMARY p. 1426]
[Key words; Halcion, triazolam, amnesia, memory impairment, hypnotics, the elderly]

Pedersen W, Lavik NJ.
Adolescents and Benzodiazepines: Prescribed Use, Self-Medication and Intoxication.
Acta Psychiatrica Scandinavica 1991; 84: 94-98.
In a longitudinal study of 1230 people aged 13-18 years from the Greater oslo Area, the past-year prevalence of anxiolytic or hypnotic use was 10%, which is higher than previously reported. The majority gave therapeutic reasons as a motive for using these drugs. However, most of the use was unprescribed. The parents, and especially the mother were the most important suppliers. A minority gave intoxication as a motive for using these drugs. In this group, the suppliers were mainly peers and the illegal market. Neither the unprescribed nor the prescribed therapeutic use show any association with use of drugs such as alcohol and cannabis. There is, however, a strong association between the unprescribed use of benzodiazepines by young people and by their parents. This suggests a pattern of learning and role modelling, which must be regarded as problematic for public health policy. Those who use the drugs to become intoxicated have particularly poor mental health and they use many other drugs as well. This group probably runs a special risk of developing more serious drug abuse. [ABSTRACT p. 94]
[Key words; addiction, abuse, dependence, adolescents]

Peet M, Moonie L.
Abuse of Benzodiazepines.
BMJ 1977; 1: 714.
" There is increasing evidence that benzodiazepines are widely abused and that withdrawal effects are much more common that was previously supposed. In a recent survey of 2500 patients seen in hospital suffering from drug-induced lethargy, drowsiness, or coma diazepam was second only to alcohol as the most common drug of abuse. In another recent study 50 of patients prescribed diazepam strong evidence was found of tolerance to the drug leading to increasing dosage and of withdrawal effects, including anxiety and insomnia. A panel of physicians, while blind to the type of drug, rated 40% of the subjects as being at least moderately addicted. However, they changed their opinion to one markedly more favourable to the drug after they learnt that is was diazepam. ( - - - )

We suggest that clinicians have become convinced that benzodiazepines do not cause dependence or withdrawal symptoms and that this has led them to overlook the available evidence. "
[Key words; addiction, abuse, dependence, withdrawal]

Peters UH, Seidel M.
[Abuse of and Addiction to Diazepam]
Drug Research 1970; 20: 876-877.
In 3 cases of exclusive diazepam (Valium) addiction, the drug had been taken in daily doses of 80 to 120 mg for several years. According to these observations, the tranquilizing effect of the drug seems to decrease with continued use, whereas the muscle relaxing effect is still enhanced with the resulting drug increase. Withdrawal caused a transient withdrawal syndrome with tremor and agitation, anxiety, feelings of weakness, and in some cases delirious manifestation. Diazepam abuse, however, is considerably more frequent, p.e. in alcoholics after withdrawal, or as an hypnotic. But in these cases, the daily dose hardly ever exceeds 30 mg. Continued use can provoke depressive manifestations which may give rise to diagnostic errors. As diazepam is a drug applied in many different fields of medicine its use is difficult to control. The risks are not yet sufficiently known. [SUMMARY p. 877]
[Key words; Valium, diazepam, addiction, abuse, dependence, withdrawal, anxiety, depression, long-term effects]

Pfefferbaum B, Butler PM, Mullins D, Copeland DR.
Two Cases of Benzodiazepine Toxicity in Children.
Journal of Clinical Psychiatry 1987; 48: 450-452.
While benzodiazepines have been widely used in adult populations, their role in the treatment of anxiety disorders in children and adolescents has not been well established. The authors report on two cases in which benzodiazepine use resulted in psychotic symptoms. The importance of eliciting a careful history as well as being familiar with drugs' side effects and withdrawal effects is stressed. [SUMMARY p. 450]

" Studies have pointed to such serious side effects from benzodiazepine treatment as psychosis and behavioral disinhibition. " [p. 451]

" Caution is essential when using medications that have not been used frequently in certain populations. The fact that specific side effcets or withdrawal effects have not been reported for a drug may simply represent a lack of experience with the medication rather than an accurate assessment of potential toxicity. " [p. 451]
[Key words; psychosis, disinhibition, paradoxical effects, children

Phelan H, O'Saughnessy G, O'Cuill D, Jenkins DM.
Night Sedation in Pregnancy - Inappropriate Prescribing.
Irish Medical Journal 1993; 86: 107.
" In summary then, we noted a high rate of prescribing of benzodiazepines to pregnant women in spite of documented evidence that this may lead to the so-called "Floppy Baby Syndrome" of neonatal drowsiness, hypotonia and withdrawal symptoms. "

" The evening prior to a planned delivery is a traumatic time in the life of any women, so it is hardly surprising that night sedation is so frequently requested. We should recommend, however, that this is a situation where psychology is a better solution than pharmacology. "
[Key words; hypnotics, pregnancy

Pomara N, Stanley B, Block R, Guido J, Stanley M, Greenblatt DJ, Newton RE, Gershon S.
Increased Sensitivity of the Elderly to the Central Depressant Effects of Diazepam.
Journal of Clinical Psychiatry 1985; 46: 185-187.
" The most striking finding in the present study is that a low diazepam dose, 2.5 mg, produced significant impairment in the elderly on the four performance tasks sensitive to diazepam effects, while our comparison group of normal young subjects showed no significant diazepam effects in these tasks. These findings support the hypothesis that elderly people may show greater adverse diazepam effects on memory and psychomotor performance. " [p.186-187]
[Key words; Valium, diazepam, amnesia, memory impairment, psychomotor impairment, the elderly]

Poser W, Poser S.
[ Abuse of and Dependence on Benzodiazepines.]
Internist 1986; 27: 738-745.
" Nicht bei allen Patienten klingt das Entzugssyndrom schnell ab, gelegentlich dauert dies Monate uber die letzte Einnahme hinaus. Die Autoren kennen einzelne Patienten, die sogar noch jahrelang uber perzeptuelle Störungen klagen, obwohl keine Angsterkrankung vor der Benzodiazepinabhängigkeit bekannt war." [p. 744]

" The withdrawal syndrome does not abate rapidly in all patients, occasionally it may be protracted for months after ingestion of the last dose. The authors know of certain patients, who are complaining of perceptual disturbances for years afterwards, although no anxiety disorder was known prior to the benzodiazepine dependence. " [ Translation of the German passage]
[Key words; addiction, dependence, withdrawal, protracted withdrawal syndrome]

Power KG, Jerrom DWA, Simpson RJ, Mitchell M.
Controlled Study of Withdrawal Symptoms and Rebound Anxiety after Six Weeks Course of Diazepam for Generalized Anxiety.
BMJ 1985; 290: 1246-1248.
" Our results suggest that withdrawal from diazepam by substitution with single blind placebo leads to an increase in both rebound and withdrawal symptoms after a short period of treatment. "

" Our finding that withdrawal symptoms can occur, albeit without graded withdrawal, after a relatively short period of treatment has important implications for management. The present trend has been the advocacy of reduced duration of treatment. The minimum length of regular treatment before dependence can occur is regarded by some as three months. Our study suggests that withdrawal symptoms occur at normal therapeutic doses and when diazepam is used for what has hitherto been regarded as a safe length of treatment. " [p. 1248]
[Key words; Valium, diazepam, dependence, withdrawal]

Prescott LF.
Safety of the Benzodiazepines
. In: Costa E, ed. The Benzodiazepines. From Molecular Biology to Clinical Practice. New York: Raven Press, 1983; 253-265.
" The most common and most important adverse effects of the benzodiazepines are those affecting the central nervous system. These effects usually represent exaggerated pharmacological actions and include drowsiness, lethargy, retardation, depression, dysarthria, ataxia, confusion, disorientation, and, in the elderly, dementia. These drugs also have subtle effects on mood, mentation, and behavior, reducing activity, drive, and initiative to the extent that patients may fail to react appropriately to adverse or dangerous situations and be unable to face and cope with their problems. In addition they may blunt discretion and precipitate the taking of an overdose.

The elderly are particularly susceptible to the central effects of benzodiazepines, and they are also least able to compensate for cerebral functional impairment. " [p. 254]

" The benzodiazepines are often prescribed as a panacea for the pressures and problems of life in people who are disappointed, unhappy, or frustrated. Al though some undoubtedly obtain benefit, there is evidence that others are made worse and have more difficulty in coping with adverse circumstances.

More worrisome is the possibility that these drugs might cause or aggravate depression and predispose to self-poisoning. Certainly, in my experience, many patients admitted to hospital with self-poisoning admit that he benzodiazepines prescribed previously for their personal problems actually made them worse, making them feel more "depressed" and less able to cope. " [p. 255]

" The adverse effects of drugs on psychomotor function may be subtle and unrecognized by the patient. The risks again are likely to be greatest with the cumulative long-acting benzodiazepines since effects may persist for many hours or days after the last dose. The patient who takes nitrazepam at night will still have about 85% of the dose in his body as he drives his car to work the following morning. " [p. 256]

" It is the prescribing doctor's clear responsibility to warn patients accordingly. Unfortunately many patients who had been prescribed these drugs do not seem to have been warned of the possible risks by their doctors. I have encountered drivers of double-decker buses, heavy goods vehicles, and even the operator of a very large dockside crane who stated they had been prescribed benzodiazepines without any warnings or restrictions. " [p. 256]
[ Key words; Mogadon, nitrazepam, depression, suicide, poisoning, cognitive impairment, psychomotor impairment, drug accumulation, the elderly]

Priest RG, Montgomery SA.
Benzodiazepines and Dependence: A College Statement.
Bulletin of the Royal College of Psychiatrists 1988; 12: 107-109.
" Amnesia is frequently a real side effect of the use of benzodiazepines and not just a figment of the individual's imagination or a coincident symptom of emotional disorder.

It is often inadvisable to prescribe benzodiazepines to a patient in an acute crisis as the amnestic property of these compounds may not allow patients to make an optimum response to the situation which they are facing. In cases of loss or bereavement, the psychological adjustment to this trauma may be severly inhibited by benzodiazepines and any tendency to denial could be reinforced. " [p. 107]

" It is recognised that the use of benzodiazepines has been (and is still) far too widespread and they are frequently prescribed for trivial and imprecise indications. This has arisen from the belief that benzodiazepines were safe compounds.

It is now acknowledged that the risks of benzodiazepines far outweigh the benefits in many cases and we would recommend that benzodiazepines should not be used in general for vague or mild disorders and should be prescribed for short-term relief when the problem is (i) disabling (ii) severe or (iii) subjecting the individual to unacceptable distress and even then should ideally be prescribed for no more than one month. " [p. 108]

" The prescribing of benzodiazepines in cases of depression may have serious consequences and may precipitate suicide. Withdrawal from benzodiazepines in many cases may precipitate depression. " [p. 108]
[Key words; amnesia, memory impairment, depression, suicide]

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Key words:
abuse, accidents, addiction, adolescents, aggression, amnesia, anxiety, apnea, children, cognitive impairment, confusion, costs, dependence, depersonalization, depression, detoxific ation, driving, drug accumulation, drug manufacturers, the elderly, encephalopathy, fatigue, fractures, hallucinations, headaches, hostility, hypnotics, infants, insomnia, long-term effects, low Apgar scores, mania, memory impairment, mult iple prescribing, nightmares, OCD, oral cleft, paranoia, paradoxical effects, phobias, poisoning, polypharmacy, pregnancy, protracted withdrawal syndrome, psychomotor impairment, psychosis, rebound, respiratory depression, seizures, shop-lifting, social decline, suicide, teratogenic effects, tinnitus, tolerance, traffic, withdrawal, withdrawal psychosis.

Trade Names:
Ativan, Dalmane, Euhypnos, Halcion, Klonopin, Lexotan, Librium, Mogadon, Noctamid, Normison, Rohypnol, Serax, Serenid, Serepax, Tranxene, Valium, Versed, Xanax.

Generic Names:
alprazolam, bromazepam, chlordiazepoxide, clonazepam, clorazepate, diazepam, flunitrazepam, flurazepam, lorazepam, lormetazepam, nitrazepam, midazolam, oxazepam, temazepam, triazolam.

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