Non‐medical use of benzodiazepines and GABA analogues in Europe

We investigated the prevalence of non‐medical use (NMU) of benzodiazepines and GABA analogues in Europe.

gamma-aminobutyric acid (GABA) analogues gabapentin and pregabalin have become popular alternatives for anxiety and treatment of neuropathic pain. 46 Baclofen, another GABA analogue, is currently used for the treatment of spastic movement disorders and also has potential in the treatment of alcohol and gamma-hydroxybutyrate/gamma-butyrolactone withdrawal syndrome. 710 NMU of benzodiazepines has long been recognised and more recently NMU of pregabalin and gabapentin has been noted, along with deaths related to this NMU, particularly associated with concomitant opioid use. 1115 While concern regarding NMU of benzodiazepines and GABA analogues have been documented, there has currently been limited research focusing on the prevalence and causes of NMU of these drug classes within Europe.
The primary aim of this study was to determine the prevalence of use and NMU of benzodiazepines and GABA analogues through data collected by an online cross-sectional survey on drug use in five European countries. Additionally, we studied factors associated with NMU of these drugs to determine associations between personspecific factors (demographics, medical history and previous drug use) or place-specific factors (availability of drugs) and the prevalence of NMU of benzodiazepines or GABA analogues. Post-stratification weights were applied to each survey population (based on region, gender and age) to be representative of the demographic distribution of the national adult populations. The methodology of this program has been described elsewhere. 16,17 The countries included in this study are the five most populous located entirely within Europe: Germany, the United Kingdom (UK), France, Italy and Spain. 18  Respondents were asked if they had ever used benzodiazepines or specific GABA analogues (baclofen, gabapentin or pregabalin) for any reason in their lifetime; a yes response classified lifetime use. If respondents reported lifetime use, they were asked about lifetime NMU, where NMU was defined as using a medication without a doctors prescription or for any reason other than what was recommended by their doctor. If respondents reported lifetime benzodiazepine NMU they were asked to select which specific drug substance they used.
Respondents were then asked substance-specific questions including the frequency of recent NMU, motivations for NMU and methods of drug acquisition. The individual national surveys were tailored to specifically ask only about drugs available via prescription in that country (see Supporting information).
Basic demographics were collated together with data on prevalence of illicit drug use. Participants were asked about whether they had used a range of illicit drugs, which varied based on the drugs and slang terms specific to individual survey countries (see Supporting information). Additionally, the prevalence of respondents scoring six or greater out of ten questions used to identify problematic drug use (see Supporting information), indicating substantial or severe problematic drug use, or reporting they had sought professional help for substance abuse, was calculated. 19 Respondents were also asked if they had ever been diagnosed with chronic pain or a mental health disorder (see Supporting information).

| Drug utilisation analysis
Association between NMU and legitimate drug availability was investigated using drug utilisation data obtained from IQVIA (Durham, NC, USA). To create comparable timeframes, last 12-month NMU was correlated with 12-month drug utilisation data for quarter four 2016 to quarter three 2017 for the UK and quarter one to four 2017 for other countries. To enable comparison between types of units sold, number of standard units sold was used where a standard unit for a tablet was a single tablet, a standard unit for a patch was a single patch, and a standard unit for liquids was 5 ml of liquid. Sales data for available benzodiazepines and GABA analogues were analysed (with the exception of clorazepate which was not included for any country) and ranked to provide the top four benzodiazepine/GABA analogue drugs with the highest estimated standard units sold by country.

What is already known
• There is limited data available on the prevalence of nonmedical use (NMU) of benzodiazepines and GABA analogues in Europe.

What this adds
• Benzodiazepine lifetime NMU is higher than GABA analogue NMU in France, Italy and Spain while the reverse is observed in Germany and UK.
• Lifetime NMU is associated with younger adults and a history of a mental health diagnosis or illicit drug use.
• Last 12-month NMU of specific drugs varied by country and is strongly associated with drug availability.

| Statistical analysis
The weighted proportion and 95% confidence intervals (CIs) of select demographic and respondent characteristics were calculated to describe the population. Weighted prevalence estimates and 95% CIs were calculated for lifetime use, lifetime NMU and last 12-month NMU of benzodiazepines and/or GABA analogues in each country.
Additionally, characteristics of those endorsing lifetime NMU or lifetime use without NMU of benzodiazepines and/or GABA analogues were calculated and compared. Characteristics comprised the estimated proportion and 95% CIs by age, gender, previous history of a mental health disorder, chronic pain, lifetime illicit drug use, problematic drug use and seeking help for substance abuse. The prevalence and 95% CIs of last 12-month NMU of individual drugs were also calculated to identify the top four benzodiazepine or GABA analogue drugs reported for NMU per country. Analyses were conducted in SPSS Version 25.0 (Armonk, NY). In order to investigate association between drug availability and NMU, Spearmans correlation coefficient was used to measure the strength of a relationship between rank NMU prevalence and rank standard units sold for the top drugs reported for last 12-month NMU (alprazolam, bromazepam, diazepam, lorazepam, baclofen, gabapentin and pregabalin). Analysis was conducted in SAS Version 9.4 (Cary, NC). Statistical significance was determined by non-overlapping CIs.  Table 1, there is variation in the general population characteristics between countries, including higher prevalence of chronic pain in Germany and the UK and higher prevalence of mental health disorders in Spain and the UK.

| Prevalence of lifetime use and non-medical use
The prevalence of lifetime use of benzodiazepines was higher than lifetime use of GABA analogues in all countries ( Figure 1). The overall lifetime prevalence estimates of benzodiazepine and GABA analogue use were similar in Germany but varied more among other countries.
The prevalence of lifetime benzodiazepine use and NMU was highest in Spain and lowest in Germany. The prevalence of lifetime GABA analogue use was highest in Spain and lowest in Italy, while the prevalence of lifetime GABA analogue NMU was highest in Germany and lowest in France and the UK. Less than one in five of lifetime benzodiazepine users reported lifetime NMU, while over one in five of GABA analogue lifetime users reported lifetime NMU, two-thirds in Germany.

| Factors associated with lifetime use and nonmedical use
Among those reporting lifetime use but not NMU of benzodiazepines or GABA analogues, approximately 80% were aged 35 years or older (see Table 2). Among lifetime users, the proportion aged Lifetime use without NMU of benzodiazepines and GABA analogues was more common among females than males, significantly so in all countries except for GABA analogues in Germany (see Table 2). Lifetime NMU of benzodiazepines was also more common among females in all countries except the UK but only significantly so in France. Conversely, lifetime NMU of GABA analogues was more common among males than females, significantly different in all countries except Italy.
Mental health diagnoses and a history of chronic pain were significantly more common among those reporting both lifetime NMU and lifetime use without NMU of benzodiazepines or GABA analogues than among the general population (see Tables 1 and 2. Mental health diagnoses were more common among those   A history of lifetime illicit drug use, problematic drug use and seeking substance abuse help were significantly more common for lifetime NMU than for lifetime use without NMU of benzodiazepines in all countries (see Table 2). For GABA analogues, a history of lifetime illicit drug use, problematic drug use and seeking substance abuse help were also more common among those reporting NMU, although significant difference was observed only in France, Spain and the UK.
Lifetime illicit drug use was highest in the UK with approximately three-quarters of individuals reporting lifetime NMU of benzodiazepines or GABA analogues also reporting illicit drug use. The highest prevalence of problematic drug use and seeking substance abuse help was also observed in the UK with over a fifth of benzodiazepine/ GABA analogue NMU endorsers having problematic drug use or having sought help for substance abuse.

| Prevalence of last 12-month non-medical use
While no notable difference was observed for France or the UK, there was a higher prevalence of last 12-month NMU of benzodiazepines compared to GABA analogues in Italy (2.4 times higher) and Spain (3.0 times higher) and a higher prevalence of NMU of GABA analogues compared to benzodiazepines in Germany (2.6 times higher) (see Figure 2). NMU of GABA analogues in Germany was at least double that seen in other countries.

| Association of 12-month non-medical use with legitimate availability
The highest selling benzodiazepine/GABA analogue drugs per country were examined from last 12-month sales data corresponding to each   F I G U R E 2 Prevalence of last 12-month non-medical use of prescription benzodiazepines and GABA analogues in France, Germany, Italy, Spain and the UK respectively (see Figure 3). In France, Italy and Spain, alprazolam and bromazepam were among the most commonly reported drugs for NMU but these two drugs did not feature for Germany or the

| DISCUSSION
This study documents differences in the prevalence of lifetime and last 12-month NMU of benzodiazepines and GABA analogues across five European countries. While the prevalence of lifetime use of benzodiazepines is higher than lifetime use of GABA analogues in all countries and the prevalence of lifetime NMU of benzodiazepines is higher in France, Italy and Spain, the proportion of users that also non-medically used GABA analogues is higher in all countries. Therefore, while the absolute number of people nonmedically using GABA analogues may be lower than for benzodiazepines in some countries, it is important to recognise that these Among both benzodiazepine and GABA analogue lifetime users, the proportion aged 34 years or younger was higher for those who had non-medically used than those who had not, while the reverse was true for those over the age of 60 years. Lifetime NMU of GABA analogues was more common among males than females in all countries, while lifetime NMU of benzodiazepines was more common among females in all countries except the UK.
In most countries use of benzodiazepines increases with age and is more common among women. 2024  reports of abuse, dependence or product misuse related to gabapentin or pregabalin among females than males, but the authors suggested this may be due to the fact that the indicated uses of GABA analogues (including neuropathic pain, generalised anxiety disorder and fibromyalgia) are more typically identified with female individuals. 12 General population estimates for a history of previous mental health or chronic pain diagnosis were approximately one in three to one in four, while lifetime illicit drug use was approximately one in four to one in five for all countries; these estimates are comparable to previous studies. 3034 Perhaps not surprisingly, due to their use to treat neuropathic pain or general anxiety disorder, a higher prevalence of mental health diagnoses and chronic pain were observed among those reporting both lifetime use but not NMU, and lifetime NMU of benzodiazepines or GABA analogues, than the general population.
No association was seen between NMU and a history of chronic We declare no competing interests.

DATA AVAILABILITY STATEMENT
Research data are not shared.