P
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
fetal 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, twelve 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 characterised 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 behavioural disinhibition. " [p. 451]

" Caution is essential when using medications that have not been used frequently in certain
populations. The fact that specific side effects 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 Generalised 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 behaviour, 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 unrecognised 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 severely 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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