Abstract
Chronic use of benzodiazepines (BDZs) is a widespread phenomenon which can lead to side effects such as tolerance, dependence and cognitive impairment, as well as resulting in accidents at work. High-dose BDZ dependence (HD-BDZ) is little studied, and it is mainly attributed to major psychiatric disorders and polydrug abuse. To date, few studies have investigated HD-BDZ among active workers, with none among health-care professionals (HPs). Tapering from high doses of BDZs can cause severe withdrawal symptoms, including seizures. The Addiction Unit of the University Hospital in Verona uses a protocol based on flumazenil slow infusion (FLU-SI), the safest and most effective treatment for HD-BDZ. Since 2003, 1281 patients have been detoxified from long-term use of high doses of BDZ using FLU-SI. The sample includes 139 (10.8%) HPs. Mean daily doses were 336 mg diazepam equivalent among HPs and 365 mg diazepam equivalent among non-HPs (no statistically significant difference). HPs are at higher risk of sleep disorders and work-related stress. Most of these HPs experience difficulties at work due to cognitive impairment, but they are often afraid of the potential legal implications and too ashamed to ask for help. It is important to study the prevalence of HD-BDZ among HPs and to investigate the impact on their working skills and working eligibility.
Introduction
The first benzodiazepine (BDZ), chlordiazepoxide, was approved in 1960, primarily to treat anxiety and insomnia. 1 The 1960s saw a rapid spread of the use of this drug, soon joined by the still-popular diazepam and, gradually, by several others. In the 1970s, diazepam became the best-selling drug in the UK and the USA. 1 Because BDZs can produce tolerance and dependence, even after only a short time, their use was recommended for only a very limited time (two to four weeks). 1 These recommendations have often been disregarded by doctors and patients themselves. It is difficult to ignore the rapid benefits of these drugs coupled with such limited side effects. One of the keys to understanding the widespread use of BDZs is, in fact, their substantial lack of acute toxicity. However, chronic use can cause a number of serious side effects, including cognitive impairment, falls, traffic accidents and dependence. BDZ tolerance was reported in 1961 by Hollister, 2 but this and other reports during the 1960s and 1970s were obscured by the enthusiastic use of these drugs, which replaced barbiturates. BDZ tolerance has some specific characteristics when compared to other drugs of abuse. The very low toxicity of BDZs and their high potential for tolerance can result in consumption at extremely high doses.3–5
Contextualising BDZ dependence
One of the major obstacles preventing an appropriate analysis of BDZ dependence is that many have considered that in a world of increasing anxiety and sleeplessness, spending years taking one or two tablets every day is preferable to other ways of dealing with anxiety and insomnia. Long-term use of BDZs is a phenomenon that affects 2–7.5% of the population in developed countries. 6 Among these there are high-dose BDZ users (HDUs), usually categorised as people with major psychiatric disorders or drug addictions. This is inaccurate because a significant proportion of them do not have major psychiatric disorders. Few epidemiological studies have analysed the problem of HDUs. In a population-based cross-sectional study of 520,000 patients, Petitjean et al. estimated that 1.6% used BDZs in very high doses, exceeding the maximal recommended daily dose by more than twice. 7 Notably, surveys from France, Germany, Italy and the UK carried out during the 1990s showed that 3.9% and 3.2% of current hypnotic and anxiolytic users had been taking doses higher than the recommended therapeutic range. 8 In addition, few studies have evaluated the quality of life in long-term users, and there are even fewer less studying HDUs. 9 The phenomenon has been investigated in more detail among heroin addicts in methadone maintenance, with the conclusion that BDZs worsen the quality of life of these patients. 10
BDZ withdrawal management
The risk of dependence after long-term use has been described, as reflected in the appearance of a series of symptoms when the drug is abruptly withdrawn. Between 15% and 44% of chronic BDZ users experience protracted moderate to severe withdrawal symptoms upon cessation, including emergent anxiety and depressive symptoms.1,10 In some cases, a withdrawal syndrome can lead to serious events such as (potentially lethal) seizures.1,11
The severe discomfort experienced by patients by stopping long-term BDZ use led to the development of treatment strategies for discontinuing these medications. The common management of BDZ withdrawal syndrome includes, either individually or in combination: (a) a gradual tapering of the drug, (b) switching to an equivalent dose of a long half-life BDZ before tapering withdrawal and (c) adding medications prior to detoxification and continuing those medications after discontinuation. For HDUs with personality disorder and/or co-dependency on alcohol and illicit drugs, there is an increasing use of substitution treatment (with a slow onset of action BZD such as clonazepam), with an approach similar to methadone substitution in heroin users. 12
Flumazenil and the management of BDZ withdrawal
A potential approach of particular pharmacological interest is BDZ detoxification using flumazenil (FLU). FLU is commonly used in the treatment of BZD overdose; it is usually considered a BDZ antagonist. When compared to placebo, a bolus infusion of FLU (1 mg in five minutes) produced effects consistent with BDZ withdrawal in BDZ users. Nonetheless, results of studies in chronic BDZ users who have discontinued BDZ use suggest that multiple slow bolus infusions of FLU can reduce the symptoms of withdrawal.1,11,13 The mechanism of the FLU effect remains unclear. Its action may facilitate coupling of the GABAA and BZD receptor complexes, potentially reversing the down-regulation/uncoupling that occurs with long-term BZD misuse. This could explain its ability to attenuate withdrawal symptoms after chronic exposure to the drug, since it induces weak agonistic action.12,13 The first to propose and provide a treatment protocol in an outpatient hospital using intravenous infusion of FLU was Gerra et al., 14 showing better results than the standard tapering. Since then, until the report by Hood et al. described in this issue, few studies have been reported in the literature. 11 The recent experience of FLU subcutaneous infusion increased patient compliance and makes the treatment more ‘low risk’ for doctors, apparently removing barriers to treatment. 12
Subjects and methods
Since 2003, 1281 patients have been detoxified from long-term use of high doses of BDZ at the Addiction Unit of the University Hospital of Verona. The detoxification programme consisted of a continuous FLU infusion during a seven-day hospital admission, along with oral tapering doses of clonazepam (from 6 mg on the first day of hospitalisation to 0.5–2 mg on the last day), with anti-epileptic prophylaxis.3,11–14 Inclusion criteria were: age >18 years, diagnosis of BDZ dependence according to the Diagnostic and Statistical Manual of Mental Disorders (4th revision) criteria, with BDZ abuse lasting more than six months. The lack of a consensus among researchers regarding clinical criteria for high dose led us to define a high use of BDZ, such as to indicate inpatient treatment, as dose intake exceeding at least five times the maximum daily recommended dose. 3 We investigated the professional status of all patients by asking if they were working or had ever worked as a health-care professional (HP).
Results
The sample included 1281 patients with high-dose BDZ dependence (HD-BDZ) who were detoxified between 2003 and 2019 with FLU slow infusion (FLU-SI). As shown in Figure 1, 139 (10.8%) patients were HPs, including 71 nurses (51%), 43 medical doctors (31%) and 25 other HPs (18%), such as dentists, veterinarians, psychologists and physical therapists.
HPs and non HPs detoxified from HD-BDZ.
Table 1 shows the characteristics of HPs and non-HPs. No statistically significant differences were found between HPs and non-HPs, apart from sex distribution: among HPs, we reported a higher percentage of women compared to non HPs.
Patient characteristics (HPs vs. non HPs).
HP: health-care practitioner; SD: standard deviation.
Discussion
All patients in our sample were taking very high doses of BDZs, in keeping with those who had previously been admitted to the same unit. 3 It is known that HPs are at risk of work-related stress and sleep disorders, due in part to night shifts and the associated short recovery intervals. This could increase the risk of BDZ intake. Previous studies conducted among HDUs showed that they scored worse than healthy controls in all neuropsychological measures. 15 Most HDUs, including HPs, experience working difficulties due to cognitive impairment. However, their working status could prevent them from seeking treatment, as they are often afraid of legal implications and too ashamed to ask for help. It is extremely important to further investigate the prevalence of HD-BDZ among the working population and among HPs in particular, as well as determining the impact on their working skills and working eligibility.
Dependence on BDZs is a widespread phenomenon, and it is the most emblematic form of iatrogenic dependence. Data on abuse are still scarce, despite the potential problem with high doses of BDZ being predicted by Hollister et al. in 1961. 2 Dependence and abuse of these drugs have been ignored by most practitioners and official bodies. The common opinion that abuse of BDZ is associated with dependence on other drugs, or with major psychiatric illness, is not reflected in our experience, where HDUs often have a negative history of such disorders. The therapeutic offer consisting of tapering the drug, as commonly applied in the case of dependence by therapeutic doses of BDZ, may be inadequate in the case of HDUs, whether in co-addiction with other substances or not.
One of the most critical aspects of agonist substitution resides in the starting phase: it is rather difficult to keep patients compliant by proposing a substitution with a low-power BDZ. The reverse of tolerance obtained with a few days of FLU-SI allows patients to experience a full recovery rapidly with very small doses of a slow onset of action BDZ, which is then tapered and ultimately stopped after a few weeks. recovery
In recent years, the use of partial agonists such as buprenorphine and varenicline in the treatment of opioid and smoking dependence, respectively, has increased significantly. The diffusion of FLU use in the treatment of BDZ dependence is much slower. We hope that the treatment will receive more attention from researchers and clinicians.
We would like to quote a passage taken from a literature review undertaken very recently by a leading expert on BDZ, Malcolm Lader: The practical problems with BDZs have persisted for 50 years, but have been ignored by many practitioners and almost all official bodies. The risk–benefit ratio of BDZs remains positive in most patients in the short term (2–4 weeks) but is unestablished beyond that time, due mainly to the difficulty in preventing short-term use from extending indefinitely with the risk of dependence. Other research issues include the possibility of long-term brain changes and evaluating the role of the benzodiazepine antagonist, flumazenil, in aiding withdrawal.
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Footnotes
Declaration of conflicting interests
The authors declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.
Funding
The authors received no financial support for the research, authorship and/or publication of this article.
