Baker PM, Bartholomeusz DB, Siskind M, Whitlock FA.
Drug-Induced Depression and Attempted Suicide.
Medical Journal of Australia 1977; 2: 322-324.

" A study of 135 cases of suicide in Brisbane revealed that many of the victims were taking one or more drugs, particularly alcohol, barbiturates, benzodiazepines and analgesics, before their deaths. Most of these subjects were deeply depressed and it seemed possible that their disturbances of mood were partly caused by the mixture of medicaments being consumed
beforehand. " [p. 322]

" In the end, two important prophylactic factors have to be considered when treating emotionally disturbed patients; the assessment of suicidal risk, and the hazard of giving potentially depressant drugs to patients with a past or present history of depression, suicidal attempt, or alcoholism. In
such cases, multiple prescribing should be avoided lest the outcome be the death of the patient being treated. " [p. 324]

Key words; depression, suicide, multiple prescribing]

Ban TA, Da Silva T, Gagnon MA, Lamont CT, Lehmann HE, Lowy FH, Ruedy J,Sellers EM.
Therapeutic Monograph on Anxiolytic-Sedative Drugs.
Canadian Medical Association Journal 1981; 124: 1439-1446.

" Various unusual responses have been documented, including nightmares, paradoxical delirium and confusion, depression, aggression and hostile behaviour. Some patients experience a dry mouth, a metallic taste or headaches.

Awareness of the sometimes bizarre effects of these drugs is important. " [p. 1443]

[Key words; addiction, dependence, depression, aggression, hostility, nightmares, headaches,
paradoxical effects]

Bayer AJ, Bayer EM, Pathy MSJ, Stoker MJ.
A Double-Blind Controlled Study of Chlormethiazole and Triazolam in the Elderly.
Acta Psychiatrica Scandinavica 1986; 73 (suppl 329): 104-111.

This study compared the hypnotic efficacy and the psychometric effects of treatment with either chlormethiazole or triazolam for 9 weeks in elderly patients with sleep disturbance. Chlormethiazole and triazolam were found to be similarly effective in short-term use. However, evidence of sustained hypnotic efficacy throughout the 9 weeks of treatment was obtained for
chlormethiazole but not for triazolam. There were daytime withdrawal effects with triazolam, but none with chlormethiazole. [ ABSTRACT p. 104 ]

" Our study suggests that the use of triazolam in older patients, even in conservative doses, may have significant disadvantages and gives further support to the view that chlormethiazole is, at present, the hypno tic drug of choice for use in this age group. " [p. 111]

[Key words; Halcion, triazolam, dependence, withdrawal, the elderly]

Beeley L.
Benzodiazepines and Tinnitus.
BMJ 1991; 302: 1465.

" In his discussion of the causes and managements of tinnitus Mr M Hawthorne points out that benzodiazepines should not be used to treat tinnitus because their long term use is detrimental.

I should like to add to this that withdrawal of benzodiazepines after long term use is a well documented but often unrecognized cause of tinnitus. It may be realated to the hyperacusis characteristic of benzodiazepine withdrawal, and it usually disappears once withdrawal is complete - but I have seen patients in whom tinnitus persisted for many months after withdrawal from benzodiazepines was complete, and similar cases have been reported. In one of the reported cases the tinnitus was relieved by diazepam.

Tinnitus is common and has many causes, but questioning patients about their use of benzodiazepines may elicit a cause that usually has a good prognosis. "

[Key words; addiction, dependence, withdrawal, tinnitus]

Berger R, Green G, Melnick A.
Cardiac Arrest Caused by Oral Diazepam Intoxication.
Clinical Pediatrics 1975; 14: 842-844.

Respiratory an cardiac effects have been reported as manifestations of diazepam toxicity. Cardiac arrest may occur in the intravenous administration of diazepam, but we believe this case to be the first reported episode of cardiac arrest caused by oral ingestion in a child. [ABSTRACT p. 842]

[Key words; Valium, diazepam, poisoning, children]

Bergman H, Borg S, Engelbrektson K, Vikander B.
Dependence on Sedative-Hypnotics: Neuropsychological Impairment, Field Dependence and Clinical Course in a 5-Year Follow- Up Study.
British Journal of Addiction 1989; 84: 547-553.

" Despite some neuropsychological improvement in a group of 30 patients who had been hospitalised for primary abuse of sedatives or hypnotics 4-6 years earlier, the prevalence of intellectual impairment was still increased and about as high as before.

As in alcoholic patients CAT scan of the brain showed an increased prevalence of dilatation of the ventricular system, but unlike alcoholics not of widened cortical sulci. Field dependence and visuo-spatial skills during treatment predicted abuse status at follow-up. Patients with improved
drug habits had less pronounced withdrawal symptoms during treatment and a better social situation at follow-up than patients without improvement of drug habits. The results suggest that despite some neuropsychological improvement cerebral disorder diagnosed in patients abusing sedatives or hypnotics is often permanent through the years and that neuropsychological status is linked to long-term prognosis. [SUMMARY p. 547]

[Key words; addiction, abuse, dependence, cognitive impairment]

Bergman U, Griffiths RR.
Relative Abuse of Diazepam and Oxazepam: Prescription Forgeries and Theft/Loss Reports in Sweden.
Drug and Alcohol Dependence 1988; 16: 293-301.

" The classic drug-seeking patterns through different physician which are sometimes asociated with drugs of abuse been reported to be unusual for the benzodiazepines, However, in Sweden, which has had a low use of barbiturates in recent years, rate of prescription forgeries (corrected
for usage) for diazepam were similar to those for barbiturates (Bergman, unpublished data).
Surveys in Iceland, another country with low use of barbiturates at that time, revealed drug seeking with the 10-mg tablets of diazepam by a substantial number of patients. This observation led to removal of 10-mg diazepam tablets from the Icelandic market. As use of the psychotropic barbiturates

[Key words; Valium, Serax, Serenid, Serepax, diazepam, oxazepam, addiction, abuse,

Bergman U.
Anxiety and Antianxiety Drug Use in Sweden.
In: Pharmacological Treatment of Anxiety. National Board of Health and Welfare, Drug Information Committee, Sweden 1988; 1: 63-74.

"... there remain marked inter- and intra-regional differences in the utilisation of these drugs which are not easily accounted for." [p. 63]

"... a previously unknown problem with benzodiazepine dependence developing with therapeutic doses has become generally recognised."           [p. 72]

" The large geographic variations within Sweden in the sales of these anxiolytic drugs, most of which have an inherent abuse potential, however remain a source of concern. This points to the need for local therapeutic auditing, to obtain and maintain an acceptable standard of prescribing. "
[p. 72]

[Key words; addiction, dependence, low-dose-dependence]

Bergman U.
Insomnia and Pills in Sweden.
In: Treatment of Sleep Disorders. National Board of Health and Welfare, Drug Information
Committee, Sweden 1988; 4: 65-80.

"... large geographical differences in the utilisation of hypnotics/sedatives exist within Sweden. The close relation between misuse and availability of these drugs demonstrated in the county of Malmö in the period 1975-1984, emphasises the need at the local level for regular surveillance of drugs with an inherent abuse potential, to obtain and maintain an acceptable standard of
prescribing. However, according to a legal statement from June 1986 (...) there is probably no such surveillance of psychotropic drug utilisation being performed anywhere in Sweden today. "
[p. 73]

" Swift et al conclude that " the desirability of protracted benzodiazepine hypnotic use in the elderly must continue to be questioned, particularly in view of the doubtful rationale for continued use found in the case of so many patients. " [p. 75]

" Hypnotics are also subject to abuse. This is an adverse reaction rarely reported in voluntary adverse drug reaction reporting systems. " [p. 75]

" The discrepancy found in the province of Saskatchewan, Canada between the recommendation of short-term treatment and the extent of chronic use, may actually be explained by post-treatment re- bound symptoms seen when discontinuing treatment with triazolam. " [p. 76]

[Key words; Halcion, triazolam, addiction, abuse, dependence, the elderly]

Berlin RM, Conell LJ.
Withdrawal Symptoms after Long-Term Treatment with Therapeutic Doses of Flurazepam: A Case Report.
American Journal of Psychiatry 1983; 140: 488-490.

A male patient with chronic insomnia experienced withdrawal symptoms when flurazepam (30 mg h.s.), which he had taken nightly for 8 years, was abruptly discontinued. Problems associated with sedative-hypnotic medication and the long-term treatment of chronic insomnia are discussed. [SUMMARY p. 488]

[Key words; Dalmane, flurazepam, addiction, dependence, withdrawal]

Betts TA, Birtle J.
Effect of Two Hypnotic Drugs on Actual Driving Performance Next
BMJ 1982; 285: 852.

[ regarding flurazepam and temazepam ]
" A single night-time dose of both hypnotics caused changes in driving behaviour next morning that increased the chance of a road accident. Whether the effect wears off in the day (and if so, when), whether subjects adapt to repeated dosing, whether the effect is dose dependent, and
whether men would be affected we cannot say; we suggest, however, that doctors should advise patients to avoid morning driving for the first few days of taking one of these hypnotics. " [p. 852]

[Key words; Dalmane, Euhypnos, flurazepam, temazepam, driving, accidents]

Binder RL.
Three Case Reports of Behavioural Disinhibition with Clonazepam. General Hospital Psychiatry 1987; 9: 151-153.

" These three patients had worsening symptoms while their dose of clonazepam was being increased. " [p. 152]

" Clinicians should be careful that additional clonazepam is not given as this would obviously worsen the situation." [p. 152]

[Key words; Klonopin, clonazepam, disinhibition, paradoxical effects]

Bitnun S.
Possible Effect of Chlordiazepoxide on the Fetus.
Canadian Medical Association Journal 1969; 100: 351.

" Cerebral haemorrhage would not cause leukopenia, and since all cultures were negative, it was felt that the depression and leukopenia could both best be explained by chlordiazepoxide toxicity. It is conceivable, of course, that some underlying neurological disorder is present but not apparent at this time. " [p. 351]

[Key words; Librium, chlordiazepoxide, pregnancy]

Bleich A, Grinspoon A, Garb R.
Paranoid Reaction Following Alprazolam Withdrawal.
Psychosomatics 1987; 28: 599-600.

"Since the clinical course of our case is so strongly suggestive of a withdrawal reaction, we believe it imperative to call attention to the unanticipated possibility that even a modest and gradual reduction of this short-acting minor tranquilliser may provoke a paranoid reaction."              [p.600]

[Key words; Xanax, alprazolam, addiction, dependence, withdrawal, paranoia]

Blennow G, Romelsö A, Leifman H, Leifman A, Karlsson G.
Sedatives and Hypnotics in Stockholm: Social Factors and Kinds of Use.
American Journal of Public Health 1994; 84: 242-246.

" It is reasonable to believe that being unemployed or on a disability pension may be associated with number of psychological problems caused by, for instance, social isolation. However, drug use in itself may be the reason for unemployment or a disability pension. [p. 245]

[Key words; addiction, dependence]

Borg S.
Dependence on Hypnotic/Sedative Drugs.
In: Pharmacological Treatment of Anxiety. National Board of Health and Welfare, Drug Information Committee, Sweden 1988; 1: 135-143.

" In spite of good socio-economic conditions the long-term prognosis for patients with hypnotic/sedative dependence seems to be similar to that encountered in e.g. alcohol abuse. " [p.137]

[Key words; addiction, abuse, dependence, social decline, long-term effects

Breier A, Charney DS, Nelson JC.
Seizures Induced by Abrupt Discontinuation of Alprazolam.
American Journal of Psychiatry 1984; 141: 1606-1607.

Two patients had grand mal seizures following abrupt discontinuation of short-term treatment with alprazolam. Alprazolams pharmacokinetic and clinical properties are discussed in relation to withdrawal reactions. [ABSTRACT p. 1601]

[Key words; Xanax, alprazolam, addiction, dependence, withdrawal, seizures]

British National Formulary
1993; 26: 132-136.

"Most anxiolytics ('sedatives') will induce sleep when given in large doses at night and most hypnotics will sedate when given in divided doses during the day. Prescribing of these drugs is widespread but dependence (either physical or psychological) and tolerance to their effects occurs. This may lead to difficulty in withdrawing the drug after the patient has been taking it
regularly for more than a few weeks (---). Hypnotics and anxiolytics should not therefore be precribed indiscriminately and should, instead, be reserved for short courses to alleviate acute conditions after causal factors have been established.

Prescribing of more than one anxiolytic or hypnotic at the same time is not recommended. It may constitute a hazard and there is no evidence that side-effects are minimised.

Benzodiazepines are the most commonly used anxiolytics and hypnotics; they act at benzodiazepine receptors which are associated with gamma-aminobutyric acid (GABA) receptors. Barbiturates are no longer recommended. Benzodiazepines have fewer side-effects than barbiturates and are much less dangerous in overdosage. They are also less likely to interact with other drugs because unlike barbiturates they do not induce liver microsomal enzymes.

A paradoxical increase in hostility and aggression may be reported by patients taking benzodiazepines. The effects range from talkativeness and excitement, to aggressive and antisocial acts. Adjustment of the dose (up or down) usually attenuates the impulses. Increased anxiety and perceptual disorders are other paradoxical effects. Increased hostility and aggression
after barbiturates and alcohol usually indicate intoxication.

DEPENDENCE AND WITHDRAWAL. The benzodiazepine withdrawal syndrome may not develop until up till 3 weeks after stopping a long-acting benzodiazepine, but may occur within a few hours in the case of a short-acting one. It is characterised by insomnia, anxiety, loss of
appetite, and body weight, tremor, perspiration, tinnitus, and perceptual disturbances. These symptoms may be similar to the original complaint and encourage further prescribing. Some symptoms may continue for weeks or months after stopping benzodiazepines entirely. Withdrawal of a benzodiazepine should be gradual as abrupt withdrawal may produce confusion, toxic psychosis, convulsions, or a condition resembling delirium tremens.

DRIVING. Hypnotics an anxiolytics may impair judgement and increase reaction time, and so affect ability to drive or operate machinery; they increase the effects of alcohol. Moreover the hangover effects of a night dose may impair driving on the following day."

[Key words; addiction, dependence, withdrawal, tolerance, anxiety, confusion, aggression,
hostility, tinnitus, paradoxical effect, disinhibition, traffic]

Brown CR.
The Use of Benzodiazepines in Prison Populations.
Journal of Clinical Psychiatry 1978; 39: 219-222.

" Experiences at the Utah State Prison with the use of psychotropic medication... indicated that the indiscriminate use of benzodiazepines could lead to more detriment than benefit." [p. 220]

" During 1974 when several tranquillizers and pain killers were being used relatively indiscriminately... the incidence of riots, stabbings, cuttings, murders and attempted suicides and self-mutilations were extremely high. 22 cases of sputum injections, deliberate self-mutilations, were reported during that period. In addition there were two major riots and five minor riots, one
murder, two suicides, 44 self mutilations, 6 stabbings of other individuals, 8 attacks on guards, and innumerable verbal assaults on guards and other inmates. [p. 221]

" Several prisoners had acute withdrawal symptoms and some who were addicted to Valium and other benzodiazepines had a prolonged withdrawal effect, much longer than even the heroin and methadon addicts. " [p. 221]

[Key words; Valium, diazepam, addiction, dependence, abuse, withdrawal, depression, suicide,
aggression, hostility]

Browne JL, Hauge KJ.
A Review of Alprazolam Withdrawal.
DICP 1986; 20: 837-841.

" A cumulative review of case reports in the literature describing withdrawal reactions secondary to alprazolam is presented. In four of eight reports, the primary withdrawal reactions were grand mal seizures. One case was characterized by painful myoclonos. In the remaining three cases, the
major complications consisted of rebound anxiety with psychotic features. Despite tapering of the daily dosage according to manufacturer guidelines, a withdrawal syndrome was precipitated in three cases.

As a result of alprazolams atypical pharmacodynamic profile, the issue is raised as to whether alprazolam is pharmacologically cross-tolerant with other benzodiazepines. " [SUMMARY p. 837]

[Key words; Xanax, alprazolam, addiction, abuse, dependence, anxiety, withdrawal]

Burke KC, Meek WJ, Krych R, Nisbet R, Burke JD.
Medical Services Use by Patients before and after Detoxification from Benzodiazepine Dependence.
Psychiatric Services 1995; 46: 157-160.

Objective: The authors examined use of medical and mental health services before and after detoxification among a group of patients detoxified from benzodiazepines to see if the data suggested a reduction in service use and costs after detoxification, the so-called offset effect observed for treatment of alcohol and mental disorders. Methods: Through a medical record
review, information was collected about medical service use for patients aged 40 and older who were detoxified from benzodiazepines at Scott and White Clinic and Hospital between 1997 and 1991. Results: Among the 76 patients, medical and mental health outpatient visits fell from an average rate of 25.4 visits per year before detoxification to 4.4 per year after detoxification. For the 44 patients with at least one inpatient stay besides the admission for detoxification, the mean number of inpatient days remained constant at three days per year before and after detoxification.
Conclusions: Although a retrospective review suffers from a range of limitations, the findings suggest that detoxification from benzodiazepines may be effective in reducing use of outpatient medical and mental health services and presumably in reducing costs of care. " [\~SUMMARY
p. 157]

[Key words; addiction, dependence, costs, detoxification]

Burnakis TG, Berman DE.
Hostility and Hallucinations as a Consequence of Midazolam Administration.
DICP 1989; 23: 671-672.

A 74-year-old woman experienced an apparent psychotic reaction several hours after administration of iv midazolam as a predimedicant for gastroscopty. The reaction included confusion, hallucinations, and hostility and required administration of haloperidol to calm her. The woman subsequently underwent colonoscopy with meperidine as a premedication and experienced no behavioral changes. Although other causes cannot be completely ruled out, the evidence points strongly to midazolam as the precipitating agent for the psychotic reaction.
[ABSTRACT p. 671]

[Key words; Versed, midazolam, aggression, hostility, psychosis, hallucinations, confusion,
paradoxical effects]

Busto U, Fornazzari L, Naranjo CA.
Protracted Tinnitus after Discontinuation of Long-Term Therapeutic Use Off Benzodiazepines.
Journal of Clinical Psychopharmacology 1988; 8: 359-362.

The presence of protracted tinnitus after discontinuation of long-term therapeutic doses of diazepam (---) is described in three patients. In one of these patients, the association of the tinnitus appearance with the drug discontinuation was documented in a double-blind, randomized,
crossover single case study. Objective confirmation of drug use or of abstinence was performed by obtaining plasma benzodiazepine concentrations. The findings provide further documentation that sensory disturbances of short- and long-term duration are among the most distinctive clinical features of the benzodiazepine withdrawal syndrome. [ SUMMARY p. 359]

[Key words; Valium, diazepam, dependence, withdrawal, protracted withdrawal syndrome,

Byrd JC.
Alprazolam-Induced Rage Reaction.
Journal of Clinical Psychopharmacology 1985; 5: 186-188.

" ... this case lends support to the observation that alprazolam shares with other benzodiazepines the capacity to produce rage reactions at therapeutic drug levels. " [p. 187]

" ... it seems that alprazolam should be used at least as cautiously as other benzodiazepines in patients who experience anxiety in the context of suppressed rage at hostile or conflict-ridden environments. " [p. 188]

[Key words; Xanax, alprazolam, aggression, hostility, paradoxical reactions]

Byrne A.
Benzodiazepines: The End of a Dream.
Australian Family Physician 1994; 23: 1584-1585.

" Benzodiazepine tranquillisers were introduced in 1960 after brief clinical tests at the University of Texas in 1959. Controlled trials were not required for evaluation and "efficacy" was demonstrated by anectdotes and testimonials. If introduced today they would probably only be approved for limited indications." [p. 1584]

" Some critical authors have suggested that the medical profession and drug companies have been guilty of knowingly ignoring the dangers of tranquillisers. " [p. 1584)

Side-effects, including instability and falls in the elderly, memory disturbance, abnormal sleep patterns, sexual disturbance, depression, fatigue and habituation are all well documented. " [p. 1584]

" Use of these drugs for minor complaints, or as first line of management is no longer justified. " [p. 1584]

"Some patients can withdraw from these drugs rapidly without great trouble. For others, it is a long, harrowing experience. " [p. 1585]

" The dream of the perfect sedative has not come true. For some, it has become a recurrent nightmare. Chloral, bromides, barbiturates, meprobamate and even heroin were all touted in their turn as the ideal, non addictive calming agents. There is still no perfect drug for primary insomnia
or anxiety. Benzodiazepines are a limited tool in the pharmacopoeia, but not the panacea once thought. " [p. 1585]

[Key words; addiction, dependence, withdrawal, amnesia, memory impairment, depression,
fatigue, drug manufacturers]


Byrne A.
Medications and Fractures.
Australian Family Physician 1997; 26: 475.

"I wish to emphasise...that medications may add to the risk of falls. Australian and overseas data now confirm the strong associaction between benzodiazepines and fractures. Patients taking 10 mg daily of temazepam are three times more likely to have a serious fall than those who are not taking medication.

If this is a causative relationship, which would appear likely, then large numbers of hip fractures could be prevented by weaning patients off their tranquillisers. We must give our patients honest information about the new found risks of such medications. They can then decide if and when they are ready to address reductions, and do so with our assistance."

[Key words; fractures, the elderly]



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