For over 50 years, benzodiazepines have been a veritable "best seller". The key to their continued success is due not only to their easy management and widespread prescription, but also to their potential to induce dependence and tolerance, which is why their use is only recommended for a very limited time. These recommendations, however, have been largely disregarded by medical practitioners, the government regulatory bodies and, last but not least, by patients themselves.
It is not easy to ignore the rapid benefit that these drugs bring for widespread conditions such as anxiety and insomnia, with limited adverse effects. One of the keys to understanding the widespread use of benzodiazepines is their substantial lack of acute toxicity (except in cases of overdose). At the same time, however, chronic use often involves numerous relevant adverse effects, including cognitive impairment, risk of accidents and falls, and addiction.
One of the obstacles to proper understanding of the problem of benzodiazepines dependency was the tacit acceptance by physicians and patients of long-term use of these drugs, a phenomenon that affects between 2-7.5% of the population of countries with high economic development. Also underestimated was the plight of those who use high doses of benzodiazepines permanently, a phenomenon known but summarily relegated to the marginal world of serious psychiatric disorders and drug addicts. This view is restricted. Tolerance, in the case of benzodiazepines, has some unique characteristics when compared to other drugs of abuse. The very low toxicity of benzodiazepines (different from opiates or alcohol) and the ability to induce tolerance may in fact lead to an often really surprising overdose. For reasons not yet clarified (genetic? linked to certain types of benzodiazepines?) there are a significant proportion of monodependent users of high benzodiazepine doses who develops tolerance, but do not display any serious psychiatric disorders.
Epidemiological research has largely neglected users of high benzodiazepine doses. To date, few studies have assessed quality of life in people taking benzodiazepines long-term, and even fewer in users of high doses in the general population, despite the significant size of the phenomenon. From the sparse existing data, 1.6% of the Swiss population uses higher than maximally permitted doses, a country where it is much more difficult to obtain a benzodiazepine prescription compared to Italy. If these data applied to the Italian population, one would expect several hundred thousand Italians to be involved, with differing intensity and severity. A significant proportion of these drugs evade prescription, and a source of supply can be found without a regular prescription.
Failure to focus on benzodiazepine dependence has allowed the practice of gradually decreasing the benzodiazepine to become the only system for its withdrawal. Generally, a slow decrease, when correctly applied, works in long-term users but much less so in the case of high dose users. In other words, whilst the drop to therapeutic doses for dependents is long and rather challenging, it becomes almost impossible for those who use high doses.
The problem is relevant because abstinence in patients taking high doses of benzodiazepines is a phenomenon very poorly tolerated and constitutes a health risk, with disturbances at the nervous- and sensory systems levels. In some cases you may experience serious events such as seizures, which are potentially (directly or indirectly) lethal.
For users of high doses of benzodiazepines hospitalisation should be imposed to manage the discontinuation of treatment. The traditional approach in these cases generally involves replacement by a long half-life benzodiazepines with decreasing doses, but this procedure is burdened by high costs for the length of the hospitalization, and by a high percentage of dropouts and relapses. It is an area in which the use of flumazenil as a slow infusion is indicated.
Flumazenil, via rapid parenteral administration, is used around the world to treat benzodiazepine overdoses. It is in fact considered to be a benzodiazepine antagonist. Experimental data, however, has demonstrated that if flumazenil is administered slowly an in a prolonged way to patients with benzodiazepine tolerance, its action is partial agonism of the benzodiazepine receptors, significantly reducing the signs and symptoms of withdrawal. When used for benzodiazepine detoxification in tolerant patients, flumazenil has shown the following pharmacological actions:
- rapid relief of the signs and symptoms of withdrawal;
- rapid normalization and up-regulation of benzodiazepine receptors;
- reduction of craving;
- limited relapse rates.
Since the first experiences in the eighties on small series of patients to date, few publications have appeared in the literature, and even fewer centres have practiced detoxification with flumazenil. Detoxification with slow infusions of flumazenil have struggled to become "good practice", perhaps due to the lack of literature, or because of disinterest from the academic world, despite benzodiazepine dependence being the most typical form of iatrogenic dependency. In addition, the pharmaceutical industry has no interest in exploring such problems in relation to benzodiazepines: these old molecules are indeed still among the best-selling drugs in the world.
Fabio Lugoboni, Marco Faccini, Rebecca Casari, Lorenzo Zamboni
Addiction Medicine, University Hospital of Verona
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