L
Lader M.
Benzos and Memory Loss: More Than Just "Old Age".
Prescriber 1992; 3: 13.

" Amnesic effects were recognised early on by anaesthetists who, indeed, welcomed a
premedicant drug that resulted in the patient forgetting unpleasant diagnostic or operative
procedures such as gastroscopy. In this usage, fairly large doses of benzodiazepines are given
intravenously.

However, many reports have accrued over the years of patients taking oral doses of a
benzodiazepine and then suffering from an amnesic episode, a lapse of memory or "black-out".
The patient behaves quite purposefully, e.g. changes planes at an airport, but has no recollection of
events subsequently. Such reports have involved all the benzodiazepine but lorazepam and
triazolam seem particularly implicated. The amnesic episodes usually follow the sporadic use of a
high dose of benzodiazepine, and are particularly likely if alcohol is taken as well. In some rare
instances antisocial behaviour, even involving homicide, seems to have occurred during such an
episode.

Reports have also accrued of more persistent memory impairments in patients taking a
benzodiazepine on a regular basis. The elderly taking a hypnotic seem particularly at risk: about
15 per cent of the over-65s take hypnotic drugs, and of those 75 per cent have used them
regularly for over a year, 25 per cent (i.e. about 4 per cent of the total) for over 10 years. As these
chronic users age, they become more sensitive to the benzodiazepine and have lapses of memory,
ending up in a chronically confused state. "

[Key words; amnesia, memory impairment, confusion, aggression, paradoxical effects, hypnotics]

Lader M.
History of Benzodiazepine Dependence.
Journal of Substance Abuse Treatment 1991; 8: 53-59.

" The widespread usage of the benzodiazepines has inevitably led to thousands of people
becoming dependent, perhaps 500,000 in the UK and twice that number in the USA where
long-term use is less common. Patients who have become dependent and have either been unable
to withdraw or have only done so with great symptomatic distress justifiably feel aggrieved
against their doctors and the benzodiazepine manufacturers for not warning them about the risk.
In the UK about 2000 people have started legal proceedings, co-ordinated by about 300 firms
of lawyers. It is the largest civil action ever. " [p. 58]

" Along with withdrawal and rebound at the end of alprazolam treatment, attention has been
drawn to daytime interdose symptom recurrence with an increasingly short period of drug
effectiveness, so-called" clock-watching". Presumably tolerance with rebound occurs after each
dose: this is characteristic of shorter-acting benzodiazepines. Related to this is early morning
"rebound" - patients wake feeling anxious and shaky until they take their first dose of the day.

Will history repeat itself with alprazolam and will the last decade of the 20th century see a major
dependence problem in U.S.A. and elsewhere? Let us hope that this time we are sufficiently
forewarned to limit duration and the dosage of alprazolam to the minima. " [p. 58 ]

[Key words; Xanax, alprazolam, addiction, dependence, withdrawal, tolerance, drug
manufacturers]

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

Benzodiazepine present problems related to both unwanted and withdrawal effects. Dosage
adjustments usually obviate unwanted effects except for paradoxical reactions such as hostility.
Patients with apparent benzodiazepine dependence need careful assessment with respect to
personality, social situation and psychiatric disorder. The patient must be motivated and carefully
prepared for withdrawal and taught anxiety management techniques. Withdrawal must always be
gradual over at least 6 weeks but very prolonged schedules are counter-productive. Substituting
a long-acting for a medium-acting benzodiazepine may be helpful in the more intractable cases. An
antidepressant may be needed if a depressive disorder supervenes, but other adjunctive therapies
are usually helpful. [ABSTRACT p. 823]

" Most withdrawal symptoms have subsided by 3 months after final discontinuation. In a few
unfortunate patients symptoms may persist and include feelings of unsteadiness, neck tension, a
"bursting" head, perceptual distortions and muscle spasm. The strange nature of these symptoms
distresses the patient, perplexes the doctor and may lead to the patient being regarded as a
hopeless neurotic or even a malingerer. We believe this to be a genuine part of a protracted
withdrawal syndrome as the symptoms are identical with those seen earlier in withdrawal. " [ p.
828]

[Key words; addiction, dependence, withdrawal, protracted withdrawal syndrome]

Lader M.
Anxiety or Depression During Withdrawal of Hypnotic Treatments.
Journal of Psychosomatic Research 1994; 38 (suppl 1): 113-123.

" In a few unfortunate individuals, the withdrawal symptoms either return or more commonly
persist. The existence of this so-called "Persistent Withdrawal Syndrome" is unestablished but
many experienced practitioners are convinced of its reality.

The syndrome is dominated by anxiety, either generalised or phobic or sometimes both, phobic
behavioural disorder, and panic attacks. Many of the litigants involved in the large UK court
case have suffered from prolonged disabilities of this type. " [p. 116S]

[Key words; addiction, dependence, withdrawal, phobias, OCD, protracted withdrawal
syndrome]

Lader M.
Clinical Pharmacology of Anxiolytic Drugs: Past, Present and Future.
Advances in Biochemical Psychopharmacology 1995; 48: 135-152.

" A converse, paradoxical psychological effect is the release of anxiety or hostility by therapeutic
doses of a benzodiazepine. Reactions include uncontrollable weeping or uncharacteristic
antisocial acts like sexual improprieties, impulsive thefts and unprovoked aggression. The feelings
and impulses may puzzle the patient who fails to connect them to his medication. Opinions differ
as to the frequency of such paradoxical reactions, some regarding them as rare, others as fairly
common. " [p. 137]

[Key words; aggression, paradoxical effects]

Laegreid L, Hagberg G, Lundberg A.
The Effect of Benzodiazepines on the Fetus and the Newborn.
Neuropediatrics 1992; 23: 18-23.

The effect of the maternal use of benzodiazepines (BZD) on the fetus and the new-born infant has
been studied in a representative series of 17 new-born infants (BZD group). The pregnancy and
the perinatal period were characterized by 20 items. On the 2nd day of life, a neurologic
investigation was performed and comprised a total of 38 items, subgrouped into items of
reflexes/reactions, tonus, and other symptoms and signs. An optimum finding for each item was
selected. The results were compared with a group of 21 newborns fetally exposed to
psychotropic drugs other than BZD (drug group) and a reference group of 29 new-borns with no
known fetal exposure to drugs. Infants in the BZD group had a lower birth weight for birth length,
as compared to both the drug group and the reference group. Significant differences in frequency
of pre- and perinatal complications and in neuro-behavior between the BZD group and the
reference group were found in all groups of items. We conclude that the use of BZD during
pregnancy is associated with impaired intrauterine growth and an increased frequency of pre- and
perinatal events. It affects the newborn infant neurologically mainly in the form of intoxication and
withdrawal symptoms. [ ABSTRACT p. 18]

" In conclusion, the results of this study indicate t h a t mothers using BZD alone continuously
throughout pregnancy do not deviate much from mothers in general in social terms, t h a t their
newborn infants tend to be wasted, have a significantly increased frequency of perinatal
complications and a significantly deviating neuro-behavior. " [p. 22]

[Key words; teratogenic effects, infants]

Lapornik R, Lehofer M, Rous F, Klampfer H, Hofmann P, Zapotoczky HG.
[ Drug-Screening in an Austrian Prison.]
Nervenarzt 1994; 65: 633-634.

" In the Austrian prison Graz, a randomized group of 64 prisoners... was selected to investigate
patterns of drug abuse. From this group, 60 consented to drug-screening in urine. While opiates,
cocaine, alcohol and amphetamines screened negative, cannabis (in 8.4%) and benzodiazepines
(in 20%) had positive results. " [p. 634]

[Key words; addiction, abuse, dependence]

Lennane KJ.
Treatment of Benzodiazepine Dependence.
Medical Journal of Australia 1986; 144: 594-597.

" A high proportion of long-term normal-dose users are physically dependent, and will suffer
significant symptoms if the drug is withdrawn. Two studies by Tyrer et al. suggest that the
frequency of significant dependence is between 27% and 45%. " [p. 594]

" ... dependence can occur in less than three months. Occasional patients - particularly those who
have been dependent on other drugs - give anecdotal reports of almost instantaneous
dependence on benzodiazepine drugs, and many such patients develop obvious dependence in
five to 10 days. Withdrawal symptoms have been noted in patients who have received
benzodiazepine agents for three weeks. " [p. 594]

" Therefore, it seems that the occurrence of withdrawal symptoms if patients try to decrease or
stop benzodiazepine agents is keeping up to half the patients taking the tablets. " [p. 595]

" Anxiety, insomnia, irritability, tremulousness, gastrointestinal disturbances and dysphoria occur
much as in the withdrawal of any tranquilliser or sedative drug. Other symptoms appear to be
more specific. Perceptual distortions occur in all modalities. Sounds may be unduly loud and
patients may hear non-existent thumps or tunes. Sights are distorted and may be misinterpreted,
with occasional brief visual hallucinations. The most common complaint is of feelings of unreality
and depersonalisation, and of seeing "through a veil".

Paraesthesia is common, as are distortions of smell and taste. Paranoid thoughts and feelings
occur frequently.

Pain and stiffness in various parts of the body, especially the face, are common, with muscular
spasms which may appear as myoclonic jerks, or as local tremors and fasciculation. (---) Ashton
also reports a flu-like illness in 10 of her 12 patients that was reminiscent of narcotic withdrawal,
and also menorrhagia and breast pain. Marked weight loss is common. " [p. 595]

" What makes withdrawal so bad, apart from the perceptual disturbances which make patients
feel they are going mad, is that it goes on for so long. (---) Benzodiazepine withdrawal symptoms
typically last at least four weeks. Ashtons study suggests that many symptoms, though improved
by four weeks, may continue intermittently for months. " [p. 595]

" It is clear that patients who are dependent and want to withdraw may face a very
unpleasant illness - in most cases, very much worse than the condition for which they were
prescribed benzodiazepine drugs in the first place. " [p. 595]

" One [difficulty] is the risk of accumulation in elderly patients, who may develop apathy and
confusion, that are attributed erroneously to dementia. Another is the risk that withdrawal
symptoms may develop inconveniently and dangerously after admission to hospital for other
reasons (for example, surgery). Yet a third is the risk of permanent brain damage, analogous to
alcohol-related damage, which it seems may occur with long-term usage. " [p. 595]

" There is a period of a few days to a few months during which the benzodiazepine drug has an
active effect. A period of months to years then occurs when there is no longer any active effect,
but the drug in normal dosage prevents the occurrence of withdrawal symptoms. Some patients
then progress to the "problem" phase. when withdrawal symptoms start to occur although they
are still taking the medication. The great majority of such patients do not attempt to compensate
for this tolerance by increasing their dosage, and this phase may continue for months or years -
until someone realises that the benzodiazepine drug is actually making the patient ill. " [p. 595]

" Patients who keep on taking the tablets must be carefully monitored for the appearance of such
"neurotic" symptoms, and the doctor must be aware, if they appear, that the answer is not more
medication, but benzodiazepine withdrawal. [p. 595]

"... the patients with the clearest psychological indications for benzodiazepine therapy are those
who are most likely to get into trouble with them. " [p. 596]

" It is my personal opinion that it would be helpful if the profession as a whole could accept the
evidence and alter their prescribing habits. " [p. 596]

" Primum non nocere is an excellent precept, and is often the best we can do. It is unfortunate that
we sometimes fail to achieve even that. " [p. 596]

[Key words; addiction, abuse, dependence, withdrawal, withdrawal psychosis, protracted
withdrawal syndrome, tolerance, drug accumulation, hallucinations, confusion, long-term effects]

Levander S.
Psychophysiology and Anxiety - Current Issue and Trends.
In: Pharmacological Treatment of Anxiety. National Board of Health and Welfare, Drug
Information Committee, Sweden 1988; 1: 43-51.

" However, it cannot be excluded that treatment with benzodiazepines may have negative
therapeutic long-time effects, and may induce neuropsychological impairment, which in the worst
case can be permanent. " [p. 49]

"The amount of prescription of benzodiazepines in general practice is considerable, both for
treating sleep disturbances and anxiety. There are a number of studies suggesting that
benzodiazepines may have negative neuropsychological consequences. Because of the large
prescription volume it is particularly important to investigate these suggestions, even if the
impairment in the individual case is moderate. It will have important consequences for a
cost-benefit analysis of treatment by drugs versus psychotherapy of anxiety disorders if such
impairments can be demonstrated in a significant number of cases. " [p. 50]

[Key words; cognitive impairment, long-term effects]

Lobo BL, Miwa LJ.
Midazolam Disinhibition Reaction.
DICP 1988; 22: 725.

" Some studies suggest that benzodiazepines have an inherent potential to cause aggression. In a
double-blind, placebo-controlled, cross-over study, Gardner and Cowdry showed that
alprazolam produced a significant increase in behavioural loss of control in patients with a
borderline personality disorder. Wilkinson demonstrated an aggression-enhancing effect with
diazepam, especially in the low-anxiety group. Other studies have demonstrated that
chlordiazepoxide and diazepam may decrease anxiety but increase affective hostility. " [p. 725]

" In addition, some studies show aggression-enhancing effects of benzodiazepines in laboratory
animals. Rats given benzodiazepines tend to kill significantly more mice than those given placebo."
[p. 725]

[Key words; Xanax, Valium, alprazolam, diazepam, aggression, paradoxical effects]

Lydiard RB, Laraia MT, Ballenger JC, Howell EF.
Emergence of Depressive Symptoms in Patients Receiving Alprazolam for
Panic Disorder.
American Journal of Psychiatry 1987; 144: 664-665.

The authors relate their clinical experience with 46 panic disorder patients who were receiving
3-10 mg/day of alprazolam. Fifteen (33%) developed symptoms consistent with DSM-III criteria
for major depression despite remission of their panic symptoms. Clinicians should be alert to this
potentially reversible complication. [ SUMMARY p. 664 ]

[Key words; Xanax, alprazolam, depression]

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