High Doses Of Benzodiazepines Research Articles

Benzodiazepines and the developing rat: A critical review

This paper reviews: (1) the development of benzodiazepine binding-sites and the GABA system; (2) the evidence that prenatal exposure to benzodiazepines can cause malformations; (3) other persisting effects of developmental exposure to benzodiazepines; and (4) the behavioral effects of benzodiazepines (and other relevant drugs) in immature animals. The review concentrates on the rat, since fundamental work in other species is scarce. The data on neurochemical development are found to be generally consistent; however, reports that the enhancement of benzodiazepine binding by GABA varies with age are controversial. The physical development of the rat is disturbed only by extremely high doses of benzodiazepines. The evidence for persisting effects after early exposure to benzodiazepines is impressive at first sight, but in most studies, confounding variables have not been eliminated. Startle and some learning tasks are affected by prenatal diazepam; submissiveness is affected by neonatal lorazepam; social behaviour and convulsions are affected by neonatal CGS 8216. Benzodiazepines inhibit chemically-induced seizures in neonatal rats, but the developmental profile of sensitivity to the convulsants is disputed. Benzodiazepines stimulate motor behavior in the neonatal rat.

Imaging of [ 11C]-labelled RO 15-1788 binding to benzodiazepine receptors in the human brain by positron emission tomography

The benzodiazepine antagonist Ro 15-1788 was labelled with [ 11C] and examined for possible use as ligand for PET scan studies on benzodiazepine receptors in the brain of cynomolgus monkeys and human subjects. [ 11C] Ro 15-1788 allowed the in vivo visualization of benzodiazepine receptor binding in cerebral and cerebellar cortical areas as well as in basal brain nuclei in PET scan images. [ 11C] Ro 15-1788 exhibited a high ratio of specific benzodiazepine receptor binding (cerebral cortex) to non-specific binding (pons) and the kinetics of binding should be satisfactory for quantitative clinical PET scan studies using [ 11C]. The in vivo binding of [ 11C] Ro 15-1788 in the cerebral cortex of cynomolgus monkeys and healthy human subjects was reduced by approximately 90% within 10 min after the intravenous injection of a high dose of unlabelled Ro 15-1788 (0.5 mg/kg i.v.). Different areas of the healthy human brain showed an approximately 10-fold variation in maximal [ 11C] Ro 15-1788 binding that corresponded to the previously known distribution of benzodiazepine receptors in these regions. The highest degree of binding was obtained in the medial occipital cerebral cortex followed by frontal cortex, cerebellum, thalamus, striatum and pons. Two psychiatric patients with anxiety syndromes who had been treated for a long time with high doses of benzodiazepines had roughly the same degree of maximal [ 11C] Ro 15-1788 binding in brain regions as the healthy subjects but the rate of decline of [ 11C] Ro 15-1788 in the brain was higher. This indicates that there is measurable competition between [ 11C] Ro 15-1788 binding and clinical benzodiazepine concentrations in the body fluids of psychiatric patients. The results demonstrate that [ 11C] Ro 15-1788 should be a valuable tool for quantitative analyses of benzodiazepine receptor characteristics and receptor occupancy in the brain of patients with neuropsychiatric disorders.

Diazepam tapering in detoxification for high-dose benzodiazepine abuse.

The clinical characteristics and management of patients who abuse high doses of benzodiazepines are not well described. In a prospective open study, 23 subjects who abused high doses of benzodiazepines were admitted for detoxification. Urine or blood test results confirmed benzodiazepine use in all but one subject and multiple drug use in eight (35%). Median benzodiazepine dose was 150 mg (range 40 to 500 mg) of diazepam equivalent. Initial plasma concentrations (diazepam: median = 1245 ng/ml; desmethyldiazepam: median = 2961 ng/ml) were 400% to 800% higher than usual therapeutic concentrations. For detoxification, subjects were given a loading dose of diazepam equal to approximately 40% their reported daily consumption. This was followed with daily tapering of diazepam by 10%. This regimen resulted in a slow and gradual decline in drug concentrations. Withdrawal symptoms were assessed daily. Sixteen subjects completed detoxification in the hospital without complications. One subject became paranoid and confused on day 7 of withdrawal. This was attributed to a too-low initial loading dose and too-rapid tapering, which resulted in rapid drug elimination. Gradual reduction of diazepam dose appears to be an effective and safe approach for detoxifying abusers of high doses of benzodiazepines.

Intracranial self-stimulation distinguishes between two benzodiazepine antagonists

Low doses of Ro 15–1788 and CGS 8216 were without effect on variable-interval self-stimulation, but completely abolished the enhancement of responding produced by chlordiazepoxide (5 mg/kg). Higher doses of Ro 15–1788, unlike other benzodiazepine receptor antagonists, produced an increase in response rates similar to that found after chlordiazepoxide. This result is consistent with its suggested action as a partial agonist. The combination of a high (benzodiazepine-like) dose of Ro 15–1788 with chlordiazepoxide produced a depression of responding similar to that seen with high doses of benzodiazepines. High doses of CGS 8216 produced a depression of self-stimulation, which was not reversed by chlordiazepoxide (5 mg/kg). Thus, the present procedure is able to distinguish contrasting behavioural effects of benzodiazepine antagonists.

Dépendance physique aux benzodiazépines dans un contexte traumatologique

During the last years, there have been more and more observations of physical dependence on the benzodiazepines. This paper emphasizes the seriousness of this syndrome, its similarity with delirium trements and its optimal treatment by high doses of benzodiazepines. This article shows also the misuse of drugs lowering the epiloptogenic threshold and suggests in replacement the peranaesthesic administration of benzodiazepines or barbiturates. Finally the treatment should be started with a gradual and slow withdrawal so as to avoid undesirable neurological signs.

Benzodiazepine dependence

1. Dependence to benzodiazepines is difficult to induce in animals but has been induced by high doses in man. Case reports of benzodiazepine dependence are rare compared with the usage of these drugs, but provide no proper epidemiological framework for the estimation of risk. Patients taking these drugs for four months or more may develop symptoms on withdrawal, characterized by anxiety, dysphoria, malaise, depersonalization, and by perceptual changes such as hyperacusis and unsteadiness. 2. In our first study we compared four patients withdrawing from high doses of benzodiazepines with six patients withdrawing from therapeutic doses. In all patients the typical withdrawal syndrome was noted and was equal in intensity in both groups. 3. In the second study, long-term, normal-dose benzodiazepine treatment was discontinued in 24 patients believed to be dependent on their medication. The withdrawal was gradual, placebo-controlled and double-blind. All experienced some form of withdrawal reaction, which ranged from anxiety and dysphoria to moderate affective and perceptual changes. Symptom ratings rose as the drugs were discontinued, but usually subsided to pre-withdrawal levels over the next two to four weeks. Electroencephalographic (EEG) changes comprised marked reduction in fast-wave activity as the drugs were withdrawn, and an improvement in psychological performance was noted. 4. It is concluded that a risk of dependence is present in all patients taking benzodiazepines even in therapeutic doses for more than a few months. Caution is urged in the prescribing of these drugs.

Tranquilizers and driving

The consumption of tranquilizers has increased throughout the 1960s. At present more than 100 million prescriptions of tranquilizers are written annually in the U.S.A. In a Norwegian study diazepam was found in the blood of 18% of people injured in traffic accidents. Other epidemiological studies have demonstrated an increased traffic accident risk to be associated with the use of tranquilizers. The combined use of tranquilizers and alcohol, which is common among patients, increases one's accident risk from that due to either agent alone. Laboratory studies concerning the effects of tranquilizers on skills related to driving have demonstrated impaired information processing capacity and eye-hand coordination due to these agents. Neuroleptics impair information processing especially at the onset of the treatment whereas the hazards of benzodiazepines become evident during long term treatment. Most of the tranquilizers increase the deleterious effects of alcohol on skills related to driving. Particularly strong is the interaction between diazepam and alcohol. At present the best countermeasure against accidents caused by tranquilizers seems to be easily available information about the effects of drugs on driving. At the onset of treatment with a neuroleptic or during long term treatment with a high dose of benzodiazepines, one should cease driving.