Use of Antidepressant and Anxiolytic Drugs in Scandinavian Countries between 2006 and 2021: A Prescription Database Study

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Introduction
Globally, it is estimated that over 700 million people suffer from mental health disorders [1], putting them among the leading causes of health and economic losses [2].Antidepressants and anxiolytics are psychotropic drugs, effective and often recommended as first-line treatment of various mental health disorders [3].In recent decades, there has been a global rise in antidepressant and anxiolytic use, particularly in highly developed countries [4].This trend may be attributed to the increasing prevalence of relevant mental health disorders [5], expanded drug indications [6], and the introduction of generic alternatives to the market [7].A comprehensive study across more than 65 regions worldwide revealed significant variations in the consumption of psychotropic drugs between 2008 and 2019, with the highest use in high-and middle-high-income countries [4].Among European countries outside Scandinavia, the study reported the highest use of antidepressants in the United Kingdom (UK), Portugal, Ireland, and Spain, ranging from 87 to 124 daily-defined doses per 1000 inhabitants per day.Despite the geographical proximity and similar income levels, the same study showed a significant variation in drug use across countries.Notably, the UK has seen higher antidepressant use than Germany and France (124 vs. 11 daily defined doses per 1000 inhabitants per day), while both the UK and Germany had similar anxiolytic use, both lower than France (11 vs. 29 daily defined doses per 1000 inhabitants per day) in 2019 [4].Thus, the observed disparities in antidepressant and anxiolytic drug use among countries can only be partially explained by geographical location and income [4].Other socioeconomic and demographic factors affecting drug use trends may include, but are not restricted to, the country-level burdens of mental illness [4,5], life expectancy [2], and health expenditure [2,4].
In 2020, Scandinavian countries ranked among the top ten users of antidepressants in Europe while exhibiting lower anxiolytic use compared to other countries [8].Despite their comparable culture, economies [9], and prevalence of common mental health disorders (i.e., depression and anxiety) [10], recent studies suggest differences both in overall use and age-specific use of antidepressants and anxiolytics between Scandinavian countries over the last two decades [11][12][13].Notably, the use of anxiolytics reduced overall in Scandinavia from 2004 to 2020, but the decrease was most marked in Denmark, compared to Norway and Sweden [11].A population-based study including nearly one million individuals aged 5-19 years reported an over twofold increase in the prevalence of antidepressant users (from 9.3 to 18.0 users per 1000 inhabitants) in Sweden and a smaller rise in Norway, while there was a decrease in Denmark from 2007 to 2017 [12].The observed discrepancies in antidepressant and anxiolytic use may be attributed to various factors, such as public attitudes and awareness about mental health disorders [14], availability of mental health treatment options [5], and prescribing practices [10] that may differ between countries.There are growing concerns about the appropriate use of these drugs in relation to long-term treatment [15], the potential for overprescribing [16], and their safety among paediatric [17,18] and elderly users [19,20].
The available register data [21] and compatibility between Norway, Sweden, and Denmark [10] allow us to examine and compare trends in antidepressant and anxiolytic use across countries and over time.Earlier studies have been limited to specific populations [12,15,22], one drug class [11,15], one country [15,23,24], or had shorter study periods [15,23].To inform future initiatives on drug prescription, revision of clinical guidelines, or allocation of economic resources, investigations of variation in drug use in general populations are needed.This study investigates the use of antidepressant and anxiolytic drugs in Scandinavian countries between 2006 and 2021 in order to describe and compare their use between the countries, overall, by drug classes and across age groups.

2.
1. Data Sources.Data material was collected from the national prescription registers in Norway [25], Sweden [26], and Denmark [27].These national prescription registers include dispensed drug prescriptions from community pharmacies (i.e., expressed in the number of users and doses) by drug classes and age groups.98-99% of prescriptions can be identified individually, thus providing valid estimates of drug use [21].As data on the total amount of drugs dispensed are not available from the Swedish Prescription Drug Register, the Nordic Medico-Statistical Committees (NOMESCO) database was used as a supplementary data source.NOMESCO data are described elsewhere (see https://nhwstat.org/health/pharmaceutical-products).
See Table 1 for more information on the data sources.

Main Measures.
To investigate drug use in terms of the number of users and the amount used, the following measurements were calculated: (i) period (one-year) prevalence as the number of users per 1000 inhabitants per year and (ii) therapeutic intensity (TI) as the number of WHOdefined daily doses (DDD) used per 1000 inhabitants per day.DDD is a standardized measure of drug amount used based on the "assumed average maintenance dose per day for a drug used for its main indication in adults" [28].

Statistical Analysis.
The analysis included all available antidepressant and anxiolytic drugs in the Scandinavian countries, overall and by each drug class.Prevalence was analyzed overall and by the following age groups: 5-19, 20-64, and ≥65 years.Supplementary analysis, overall and by sexes, included other age groups: 5-14, 15-19, 20-44, 45-64, 65-74, and ≥75 years.Sex stratification for the age group 5-14 years was excluded due to a low number of users per 1000 inhabitants.For further information on supplementary analysis, see section description of supplementary material.Prevalence of drug use was calculated as the number of individuals with one or more drug prescriptions within a calendar year divided by the number of inhabitants in thousands in that year (yielding users per 1000 inhabitants).TI was calculated as the total number of DDDs used per calendar year divided by the total number of inhabitants in the same year and divided by 365 days per year (yielding DDD per 1000 inhabitants per day).
The calculations were based on data from prescription registers and available national statistics.For Sweden, data on drug use in DDD per 1000 inhabitants per day were only available for anxiolytics overall and for the subgroup BZDs from NOMESCO.Therefore, prescriptions per 1000 inhabitants per year collected from the National Swedish Drug Registry were used in the calculations.DDD per 1000 inhabitants per day was calculated as the product of the number of prescriptions, drug mass, and average dispensed quantity multiplied by 1000 and divided by DDD, population, and days in the year [29].The TI and total dose (as 1000 DDD) were calculated for two specific ATC level 5 approved drug groups in Sweden: diphenylmet.derivatives (N05BB01) and azasp.derivatives (N05BE).
The changes in one-year prevalence and TI over time were calculated as relative changes in percentage.Trend analysis included a test for trend with associated p values for the hypothesis of no trend.The results in tables and figures display data at three-year intervals for ease of presentation.However, the statistical trend analysis utilizes data from each year.All calculations were done with STATA release 17 (StataCorp, College Station, TX, USA).
2.5.Ethics.This descriptive drug utilization study used routinely collected (deidentified) data from publicly available sources for which no informed consent or ethical approval is necessary.

3.1.
Trends in Antidepressant and Anxiolytic Drug Use.The overall use of antidepressant and anxiolytic drug groups was presented in the total number of users, one-year prevalence (users per 1000 inhabitants), and relative changes in prevalence (Tables 2 and 3).Figures 1 and 2 show the time trend in the prevalence of antidepressant and anxiolytic drug use (number of users per 1000 inhabitants) by drug class and country from 2006 to 2021.
During the study period, the use of antidepressants increased steadily across Scandinavia (Figure 1).The prevalence of antidepressant use was consistently highest in Sweden (from 78 to 107 users per 1000 inhabitants), followed by Denmark, and lowest in Norway (from 60 to 69 users per 1000 inhabitants) (Figure 1).However, in terms of relative change in the prevalence of antidepressant use, Sweden had the greatest increase by 34%, while the lowest increase was in Denmark by 5% (Table 2).SSRIs had the highest prevalence throughout the study but with notable variations between the countries.The prevalence of SSRI use increased by 15% in Sweden, reduced by nearly 13% in Denmark, and remained relatively stable in Norway (Table 2 and Figure 1).However, the prevalence of "other antidepressant" use increased steadily across all three countries; the relative increase in Sweden was nearly three times greater than in Norway or Denmark.Conversely, the prevalence of TCA use increased in Sweden and Norway but decreased in Denmark.Among group "other antidepressants," there has been a notable increase in the use of serotonin-norepinephrine reuptake inhibitors, SNRIs (i.e., duloxetine and venlafaxine) and atypical antidepressant mirtazapine across countries (Table S3).This rise has coincided with a concurrent decrease in the utilization of tetracyclic antidepressants (i.e., mianserin).
The prevalence of anxiolytic use declined consistently across Scandinavia (Figure 2); however, the largest decline was in Denmark (64%), followed by Norway (26%) and Sweden (10%).BZDs accounted for the most anxiolytic use in all three countries.However, the prevalence of diphenylmet.derivatives increased markedly, with Sweden showing the highest relative increase (47%, from 15 to 22 users per 1000 inhabitants) compared to Norway and Denmark (Table 3).
Overall, the TI of antidepressants increased across all three countries, but with notable differences in levels of TI and relative change throughout the period (Table 4).In Norway and Sweden, the TI of antidepressants rose consistently, while in Denmark, it increased initially (from 2006 to 2012), followed by a decline to 2021.However, the largest relative change in TI was in Sweden with a 56% increase, followed by Denmark (31%) and Norway (13%).Sweden had the highest TI of antidepressants in both 2006 and 2021 (from 69.7 and 108.9 DDD per 1000 inhabitants per day, respectively), while the levels of TI of antidepressants were consistently lowest in Norway.TI of SSRI use increased in all countries, with the largest relative increase in Sweden (41%) and the lowest in Norway (6%).Notably, there was a rising trend in TI of "other antidepressants" across the three countries, most markedly in Sweden (119%), followed by Denmark (81%) and Norway (36%).TI of anxiolytics decreased in all three countries, mainly attributed to reduced BZD use; this trend was most marked in Denmark (75%) then Norway (44%) and Sweden (39%) (Table 5).

The Antidepressant and Anxiolytic Drug Use across Age
Groups.The use of antidepressants and anxiolytic drugs increased with age across the three countries, with the highest prevalence observed in adults ≥65 years (Figures 3 and  4).In contrast to Norway and Denmark, there was a rising trend in the prevalence of antidepressant use across all age groups in Sweden from 2006 to 2021.This was sharpest in  3 and Table S1).
SSRIs dominated antidepressant use across age groups in all three countries.However, there was a decrease in the prevalence of SSRI use among individuals ≥65 years, most markedly in Denmark (by 33%; from 101 to 68 users per 1000 inhabitants), but this was accompanied by an increase in the prevalence of "other antidepressant" use.The prevalence of antidepressants used showed very small differences between the age groups 45-65 and 65-75 years; however, the highest was those ≥75 years throughout the period in all three countries (Figure S1).
The prevalence of anxiolytic use declined across all age groups in Denmark and Norway, but this trend was only observed in the age group ≥65 years in Sweden (Figure 4 and Table S2).Notably, anxiolytic use increased markedly among Swedish individuals aged 5-19 years, and this contributed to the increasing use of diphenylmeth derivatives.Age differences in the prevalence of anxiolytic drug use, mainly due to BZDs, were the largest in Sweden and were minimal in Denmark.However, the prevalence of BZD use consistently remained highest in adults aged ≥75 years in all three countries throughout the study period (Figure S2).
Throughout the study period, women consistently exhibited approximately two times higher prevalence of overall antidepressant and anxiolytic use compared to men across all age groups and countries (Supplementary analysis Tables S4-S7).Overall, younger individuals (15-19 years and 20-44 years) experienced a higher relative increase in total  S4 and S5 S6 and S7).

Discussion
This study showed that overall antidepressant use in Scandinavia between 2006 and 2021 increased, but anxiolytic use decreased; however, there were notable differences between the countries and between age groups.Sweden consistently had the highest use of antidepressant drugs in Scandinavia, while the relative decline in anxiolytic drug use was highest in Denmark.Overall, antidepressant and anxiolytic drug use increased with increasing age and was highest in older age groups (≥75 years).Antidepressant use showed increases across all age groups in Sweden and particularly in individuals aged 15-19 years in Norway during the study period, but no such trend was observed in Denmark.There was a marked increase in anxiolytic drug use in individuals aged 15-19 years in Sweden, in contrast to their Danish and Norwegian peers.Across all age groups and countries, women consistently exhibited a higher prevalence of overall antidepressant and anxiolytic use compared to men, the trend notably pronounced among young Swedish women.
As antidepressants are the first-line treatment for depression and anxiety disorders [6], it is likely that these disorders are driving the increasing use of antidepressants in Scandinavian and other European countries [4].Hence, the growing trend of antidepressant use in Norway, Sweden, and Denmark may be partly attributed to the increased prevalence of current mental health disorders (i.e., depression The table displays data points every three years for ease of presentation, but the statistical trend analysis and graphs are based on data from each year.a Percentage differences in the year 2021 compared to the year 2006.b Jonckheere-Terpstra trend test P value for trend analysis ≥ 0 05.

Depression and Anxiety
and anxiety) in Scandinavia [10].This, in turn, may reflect the global mental health burden in the developed countries [30,31].The availability of new-generation antidepressants with improved risk-benefit profiles and expansion of their indications to other psychiatric disorders (insomnia, manic-depressive disorders, eating disorders, etc.) and phys-ical conditions (e.g., peripheral neuropathic pain, migraine, etc.) [6] has probably contributed to increased antidepressant use.The changes in guidelines for treating anxiety, which recommend antidepressants as a first-line treatment during the study period (see Table 6), could be partly responsible for the increasing antidepressant use observed  6 Depression and Anxiety in all three studied countries.Moreover, the emergence of "other antidepressants" (ATC: N06AX) with diverse mechanisms of action provides an alternative treatment avenue, particularly for patients resistant to standard therapies like SSRIs.In line with this study's findings (Table S3), there has been a noticeable shift towards using SNRIs (i.e., duloxetine and venlafaxine) to treat major depressive disorders in Scandinavian countries, following the use of SSRIs [10].In line with our findings, newer classes of antidepressants, including SSRIs, SNRIs, and other antidepressants, are preferred over older TCA globally, although there is a growing trend in lower-middle-income countries favouring older, potentially more affordable antidepressants [4].However, atypical tetracyclic antidepressants like mirtazapine are prescribed for conditions beyond depression or anxiety, such as chronic pain and sleep disorders.This broader usage might contribute to the rise in their use in Scandinavia, as indicated by the findings of this study.Scandinavian countries share strong cultural, economic, and health service similarities (e.g., free access to healthcare and funding for medication) [9,32].All three countries also have increased public awareness of and decreasing social stigma towards mental health disorders [33].These factors collectively may have led to more individuals seeking help and receiving antidepressants over the past few years and contributed to the increased use of antidepressants in these countries.On the other hand, the results of this study showed a markedly higher overall use of antidepressants in Sweden throughout the period (2006)(2007)(2008)(2009)(2010)(2011)(2012)(2013)(2014)(2015)(2016)(2017)(2018)(2019)(2020)(2021).A crosscountry comparison between Baltic and Nordic countries reported a similar trend in antidepressant use in the Baltic region (containing the countries Estonia, Latvia, and Lithuania) in 2010-2015, while Sweden ranked highest in antidepressant use compared to Norway, Denmark, and Baltic countries in 2015, albeit below Iceland and Finland [13].
The reasons for the varying antidepressant use in Scandinavian countries remain unknown.There is a comparable prevalence of psychiatric disease diagnosis, and there are similar treatment guidelines for depression and anxiety disorders in these countries.A recent prescription database study showed a much higher prevalence of common psychiatric disorders (e.g., anxiety and depression) and certain clinical outcomes (e.g., major depressive disorders and generalized anxiety disorders) in Sweden compared to Norway and Denmark [10].There was also a higher frequency of mental health visits to and antidepressant prescriptions made in specialized rather than primary healthcare compared to Norway and Denmark [10].Access to healthcare in Norway and Denmark is largely centralized through general practitioners (GPs), whereas patients in Sweden often seek direct access to specialist services and psychiatrists [32].All these variations in prevalence, access to services, and treatment approaches (including diagnosis Abbreviations: DDD: defined daily doses; TCA: tricyclic antidepressants; SSRI: selective serotonin reuptake inhibitors.The table displays data points every three years for ease of presentation, but the statistical trend analysis and graphs are based on data from each year.Notes: * Data in the 2021 column and relative change (%) for Norway were calculated for 2020 as this was the last year with publicly available prescription data.Data in the 2021 column and relative change (%) for remaining countries were calculated for 2021.* * Data from Sweden include both sales at community pharmacies and hospital use, while data from remaining countries cover only sales at community pharmacies.a Percentage differences in the year 2021 compared to the year 2006.b Jonckheere-Terpstra trend test P value for trend analysis ≥ 0 05.
7 Depression and Anxiety and healthcare pathways) in Scandinavia may contribute to differences in antidepressant use between the countries.
The overall reduction in anxiolytic drug use, mainly driven by BZD use, may reflect the several recommendations and regulations initiated in Scandinavian countries before and during the study period (see Table 6).These were aligned with international recommendations and perceptions of BZD-related risks [34].However, this alone does not explain the notably higher drop in anxiolytic use, mainly BZD, in Denmark.There was a large number of local and national public health initiatives addressing BZDs in Denmark from 2003 to 2013 [35].These could have resulted in a greater reduction in their use compared to the other two countries.Despite documented adverse events in the older population, including increased risk of falls [19] and cognitive impairment [36], BZD use still remains high in these age groups in Europe [11], Canada [37], and the USA [38].A recent drug use study showed that the highest BZD use was in older age groups (≥80 years) in all Nordic countries [11], and the results are in agreement with the findings in this study.Unfortunately, the drivers of these age-specific patterns in BZD use are still unclear; they could be due to the increasing number of new users and/or insufficient deprescribing for long-term users in the older population [39].
Furthermore, previous studies have also highlighted the increasing trend in overall antidepressant and anxiolytic use [22] and BZD use in younger age groups (i.e., children and adolescents (0-17 years) and young adults (18-24 years)) in Sweden [15], specifically among females, the findings supported by this study.A Swedish population-based register study showed that the substantial rise in the prevalence of BZD use in younger age groups between 2006 and 2013 was followed by high prevalence of off-label and long-term (>6 months) use, psychotropic drug polypharmacy and prescriptions from primary care or nonpsychiatric institutions, which may indicate nonadherence to BZD prescribing guidelines [15].However, when we interpret the results of BZD use in younger age groups, it is important to remember that there is no firmly established indication for BZD treatment in children and adolescents in psychiatry [17]-and that is also true in Sweden.
Unlike prior studies restricted by short timeframes [15], singular drug class analyses [11,12], age group [16][17][18], or focusing on a single country [16], this study is a leap forward.Examining both antidepressants and anxiolytics across countries, ages, and sexes in a unified framework offers a more comprehensive picture of trends in the use of the primary medications for treating depression and anxiety in Scandinavia, where these conditions pose a substantial burden of disease.These results may provide thorough information on similarities and differences in the use of these drugs across Scandinavia that may have been overlooked in isolated or fragmented analyses.Other strengths The table displays data points every three years for ease of presentation, but the statistical trend analysis and graphs are based on data from each year.Notes: * Data in the 2021 column and relative change (%) for Norway were calculated for 2020 as this was the last year with publicly available prescription data.Data in the 2021 column and relative change (%) for remaining countries were calculated for 2021.* * Data from Sweden include both sales at community pharmacies and hospital use, while data from remaining countries cover only sales at community pharmacies.a Percentage differences in the year 2021 compared to the year 2006.b Jonckheere-Terpstra trend test P value for trend analysis ≥ 0 05. 9 Depression and Anxiety of this study include the use of three nationwide population databases with validated and nearly complete data on drug use in the entire population.There is minimal (no) selection and recall bias or loss of follow-up.However, there are some limitations in the use of these data sources which include a lack of information on indications and duration of drug treatment and whether the decline in drug use was due to changing to other drug classes (e.g., from BZDs to antidepressants, antihistamines, or low dose antipsychotics) or change in therapy.The data utilized in this study are aggregated and deidentified, meaning that prescriptions of studied drugs cannot be linked to specific individuals, making it not  10 Depression and Anxiety possible to distinguish between those using a single drug from those using several drugs (i.e., polypharmacy).Consequently, drug subgroups are not mutually exclusive.The prevalence of drug use did not include drugs dispensed to patients in hospitals or secondary health institutions.This could lead to underestimation without necessarily affecting the observed trends.Moreover, this study could not differentiate new users (i.e., incident users) from individuals already using antidepressants or anxiolytics, or those using several antidepressants or anxiolytics (i.e., engaging in polypharmacy), so overestimation of the point prevalence for the use of each drug is likely.Importantly, DDD is not the clinically recommended therapeutic dose but is the daily maintenance dose used for the drug's main indication in adults; hence, different doses may be recommended for different conditions.For example, TCA amitriptyline is used in higher doses for depression (main indication) than in neuropathic pain or migraine, which may overestimate TI for this drug class.Therefore, the TI of antidepressant and anxiolytic use should be interpreted as suggestive.Furthermore, antidepressant and anxiolytic drug use in the age group 5-14 years may be underestimated because of the lack of paediatric drug formulations within these drug classes.Finally, the absence of other factors (e.g., education, cohabitation status, income, alcohol intake, and health conditions) that impact drug use at both individual and population levels [40][41][42] is an important limitation in this study that needs to be considered in the interpretation of the findings.

Depression and Anxiety
In conclusion, antidepressant use increased while anxiolytic use decreased between 2006 and 2021 in Scandinavia, but with differences by country and age group.The high prevalence of antidepressant and anxiolytic use among older adults (≥75 years) and the rising trend in their use among Swedish young people (15-19 years) are urgent reasons for research and public health interventions.These findings highlight the need for drug use studies that include socioeconomic, demographic, and health-related characteristics as important determinants of drug use on individual and population levels to inform public health initiatives and development of better guidelines.Moreover, future drug utilization studies need to thoroughly explore social, economic, and geographical (e.g., rural vs. urban) characteristics within each country's basic health zones to fully understand the factors behind increased drug use, moving beyond mere country-level analysis.The guide replaces the following guides: National Professional Guide for addictive drugs 2014-requisition and professional soundness and national professional guide for the use of opioids for long-term noncancer-related pain.
The main lines of the professional recommendations for symptom-relieving treatment with benzodiazepines, benzodiazepine-like drugs, and opioids are continued.The new guide is concise and more user-friendly than previous versions.The guide gives a reminder to treating physicians that there is room for quality improvements both in treatment choices and in follow-up of patients with especially anxiety, sleep problems, or long-term pain conditions that are not due to cancer.
). Swedish women aged 15-19 years and 20-44 years consistently showed the highest prevalence of antidepressant use compared to their counterparts in Denmark and Norway.In 2021, young women aged 15-19 years in Sweden showed an antidepressant use prevalence almost three times higher than their counterparts of the same age in Norway and Denmark.In contrast to their Norwegian and Danish peers, there has been an increase in the prevalence of overall anxiolytic use among young women and men (aged 15-19 years and 20-44 years) in Sweden from 2006 to 2021 (Table

Figure 1 :
Figure 1: Time trend in the prevalence of antidepressant drug use (number of users per 1000 inhabitants) by drug class and country from 2006 to 2021.Note: variation in y-axes.ATC: Anatomical Therapeutic Chemical Classification.

Figure 2 :
Figure 2: Time trend in the prevalence of anxiolytic drug use (number of users per 1000 inhabitants) by drug class and country from 2006 to 2021.Note: variation in y-axes.ATC: Anatomical Therapeutic Chemical Classification.

Figure 3 :
Figure 3: Time trend in the prevalence of antidepressant drug use (number of users per 1000 inhabitants) by age groups, drug class, and country.Note: y-axis differs between countries.ATC: Anatomical Therapeutic Chemical Classification.

Figure 4 :
Figure 4: Time trend in the prevalence of anxiolytic drug use (number of users per 1000 inhabitants) by age groups, drug class, and country.Note: y-axis differs between countries.ATC: Anatomical Therapeutic Chemical Classification.

Table 1 :
Description of registers, coverage, and obtained data.

Table 2 :
Total number of users (users; no) and prevalence (prev.; users per 1000 inhabitants) of antidepressants by drug class and country from 2006 to 2021.Users Prev.Users Prev.Users Prev.Users Prev.Users Prev.Users Prev.

Table 3 :
Total number of users (users; no) and prevalence (prev.; users per 1000 inhabitants) of anxiolytics by drug class and country from 2006 to 2021.Users Prev.Users Prev.Users Prev.Users Prev.Users Prev.Users Prev.

Table 4 :
Time trends in therapeutic intensity (TI; DDD per 1000 inhabitants per day) and relative change in TI (in %) of antidepressants by drug class and country from 2006 to 2021.

Table 5 :
Time trends in therapeutic intensity (TI; DDD per 1000 inhabitants per day) and relative change in TI (%) of anxiolytics by drug class and country from 2006 to 2021.

Table 6 :
Timeline of specific recommendations or regulations in Scandinavian countries on the use of psychotropic drugs.Guide to the prescription of addictive drugs 2001 Revised guide on addictive drugs.Prescribing and justification, only in electronic format 2003 Restriction in the prescription status from group B (addictive) to A (highly addictive) for flunitrazepam 2014 Guide to the prescription of addictive drugs 2021