The Use And Production Of Benzodiazepines (BZDs)

BZDs are effective drugs with numerous positive clinical values, widely used in treatment of anxiety, insomnia, and other psychological conditions, such as panic disorder [Rouby 2012]. However, this is only applicable if BZDs are used for their proper indications (Marriott 1993). In general, short term or intermittent prescription will avoid dependency and withdrawal problems (51- Chief Medical Officer 2004).

The costs of health care increase worldwide, with particularly rapid growth of pharmaceutical expenses (Vojvodić 2014). In the European Union countries, public and private outpatient spending on pharmaceuticals constitutes 1.6% of gross domestic product (Carone 2012).

The largest BZD manufacturers in the past decade were placed in Italy, India and Germany. Alprazolam, lorazepam and diazepam were the most manufactured psychotropic substances in 2016, in terms of S-DDD (Psychotropic Substances, 2018).

Although their per-unit price is low, BZDs play a significant role in the profitability of the companies that manufacture and distribute them. The drugs from this group are very high volume, inexpensive to manufacture, and have little remaining research and development costs (Lyons 1992).

The decision-making process of BZD prescription should be result of successful communication between the health care professional and the patient, with appropriate monitoring throughout tapering and after drug discontinuation. These steps have been confirmed as effective at minimizing adverse drug withdrawal reactions (Reeve 2017).

BZDs are widely prescribed drugs. The recent research conducted in France and Italy showed the prevalence of BZD use estimated to be 13.8 % (Bénard-Laribière 2016, Barbui 1996); in Sweden the reported prevalence varies between 10% and 42% (Madhusoodanan 2004, Bogunovic, 2004), while the prevalence of BZD current use in Brasil was 21.7% (Alvarenga 2008). Similar variations were found in USA, Canada and United Kingdom, were BZD were most often prescribed by primary care physicians (Aparasu 2003, Voyer 2010, Sonnenberg 2012). Previous studies conducted in city of Zagreb, capital of Croatia showed that BZDs accounted for more than 50% of the outpatient utilization of psychopharmaceuticals throughout the study period (Živković 2014).

This prescription pattern is also recognized in Croatia, confirmed by results in this study, with an average of 8.7 % in analyzed period. Croatian primary care physicians prefer BZDs because of good effectiveness and fast response with small number of initial side effects (Vlastelica 2012).

There is no internationally agreed consensus on the duration of BZD utilization (IFI: Drug policy in Croatia). Some treatment guidelines recommend that BZDs should be used intermittently for less than 2 weeks in the treatment of insomnia and should not be used for more than 6 weeks (including tapering before withdrawal) anxiety treatment [Brett 2015, Millar 2017, Siriwardena 2006]. BZD dependence is a frequent complication of regular prescriptions for 4 weeks or longer, occurring in almost one-third of patients (Marriot 1993). Long-term use individuals are at a higher risk of tolerance to drug effects, occasional drug seeking behavior and a withdrawal reaction (Vlastelica 2012, Glass 2005, van Eijk 2010).

Previous studies have shown that caution should be taken when prescribing BZDs to older people, (Cimolai, 2007), since long-term use individuals are at a higher risk of dependence and other well-known side effects (Johnell 2009). The results from this study have shown that BZD users were more likely to be older females, which confirms previously published data (Spanemberg 2011)

The recent data published by Agency for Medicinal Products and Medical Devices of Croatia showed that N group of drugs according to ATC classification were second most prescribed drugs in Croatia in 2016, with expenditure of 849 million kuna (approximately 115 million euro) (Halmed web str). Voshaar et al. (2003) claim that tapering off BZD use might lead to a reduction in the cost for mental healthcare since treatment costs would be paid back after 19 months of follow-up.

In terms of the prescriptions of BZD by primary care physicians in the analyzed period (years 2015 and 2016), the most prescribed drug from the group of a BZDs was diazepam, followed by alprazolam. This result is in line with previous studies conducted in Croatia, where the most common inappropriate drug prescribed in Croatia is diazepam (56% of all inappropriate drugs, with an overall prevalence of 1.2%) (Vlahović 2004). European data confirms this prescription habit, where Ireland, Serbia, Portugal and Croatia had the highest rates of calculated consumption (Psychotropic Substances, 2018, Divac 2004, Petrushevska 2015).