# Evolution of the Addictovigilance Signal of Zopiclone: A 2014–2020 National Follow-up Study

Aurélie Aquizerate, Edouard-Jules Laforgue, Marion Istvan, Morgane

Rousselet, Marie Gérardin, Emilie Jouanjus, Frédéric Libert, Anne-Sylvie

Caous, Samira Djezzar, Alexandra Boucher, et al.

► To cite this version:

Aurélie Aquizerate, Edouard-Jules Laforgue, Marion Istvan, Morgane Rousselet, Marie Gérardin, et al. Evolution of the Addictovigilance Signal of Zopiclone: A 2014-2020 National Follow-up Study. International Journal of Mental Health and Addiction, 2023, 10.1007/s11469-023-01078-y. http://04795227

HAL Id: hal-04795227

https://nantes-universite.hal.science/hal-04795227v1

Submitted on 21 Nov 2024

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_1.png" /></figure>

Distributed under a Creative Commons Attribution 4.0 International License
# Evolution of the Addictovigilance Signal of Zopiclone: A 2014–2020 National Follow-up Study

Aurélie Aquizerate¹ ID · Edouard-Jules Laforgue¹,² ID · Marion Istvan¹,² ID ·

Morgane Rousselet¹,² ID · Marie Gérardin¹ ID · Emilie Jouanjus³ · Frédéric Libert⁴ ·

French Addictovigilance Network (FAN) · Anne-Sylvie Caous · Samira Djezzar ·

Alexandra Boucher · Amélie Daveluy · Céline Eiden · Bernard Fauconneau ·

Christine Fournier-Choma · Valérie Gibaja · Clémence Lacroix ·

Maryse Lapeyre-Mestre · Reynald Le Boisselier · Bruno Revol · Marylène Guerlais¹ ·

Caroline Victorri-Vigneau¹,² ID

Accepted: 10 May 2023

© The Author(s) 2023

## Abstract

Zopiclone, like zolpidem, is under surveillance in France due to its potential for dependence, abuse and misuse. However, part of the narcotics regulation was implemented in 2017 in France for zolpidem only, which has led to an increase in the number of zopiclone consumers. The objective of this article is to present French addictovigilance data regarding the evolution of the abuse, dependence and misuse profiles of zopiclone. We used the following 3 data sources over two periods: the 3-year period before the regulatory measure regarding zolpidem (2014–2016) and the 3-year period after the regulatory measure (2018–2020): (i) Medic’AM, a public database which provides a good overview of the number of boxes of zopiclone reimbursed in France; (ii) all French cases of drug dependence or abuse reported by health professionals to the French Addictovigilance Network (FAN); and (iii) a national epidemiological tool based on the surveillance of falsified prescriptions. Between the first and the second study periods (i) despite an increase in the exposure of the population to zopiclone, the proportion of reports to the FAN remained stable; (ii) the proportion of misusers increased significantly (*p* < 0.01), from 27% (*n* = 31) to 48.3% (*n* = 72); (iii) the profile of problematic users remained comparable with persistence of markers of problematic use; and (iv) there was a significant increase (*p* = 0.01) in zopiclone fraud for obtention, from 26.1% (*n* = 30) to 40.9% (*n* = 61), which mainly concerned nomadism. Prescribers should remain cautious in providing zopiclone prescriptions.

**Keywords** Zopiclone · Addictovigilance · Dependence · Abuse · Misuse · Hypnotics · Sedatives
## Zopiclone and Zolpidem (Z-Drugs): Continuous Monitoring

Zopiclone belongs to the cyclopyrrolone chemical family and is related to the benzodiazepine class. Specific subtypes of the GABA-A receptors mediate the pharmacological effects of benzodiazepines: the anxiolytic action by α2 subunit receptors, and the sedative effect by α1 subunit receptors (McKernan et al., 2000). Zopiclone acts by binding to the GABAergic receptor complex. Unlike zolpidem, the only other benzodiazepine-related molecule marketed in France, zopiclone is not selective for the α1 subunit and also binds to other α subunits (Olsen & Sieghart, 2008; Kralic et al., 2002). Zopiclone is indicated in adults for the treatment of transient or occasional insomnia and was initially marketed as an alternative to benzodiazepines without the same abuse and dependence potential (Holm & Zolpidem, 2000). The literature contains numerous studies on the risks of dependence, abuse and misuse of benzodiazepines and zolpidem (Sabe et al., 2019; Seldenrijk et al., 2017; Istvan et al., 2022; Victorri-Vigneau et al., 2007; Victorri-Vigneau et al., 2014; Aquizerate et al., 2023). However, few specific data are available on zopiclone, although this molecule is also under surveillance in France.

## Zopiclone: A Different Profile than That of Zolpidem

In France, the French Addictovigilance Network (FAN) is a special system composed of 13 centres spread over the national territory and is coordinated by the French Drug Agency (ANSM) (Baumevieille et al., 2001; Site de l'association du réseau fraçias d'addictovigilance, n.d.). The FAN collects and analyses the cases of abuse or dependence related to the use of psychoactive substances (Code de la Santé and Publique (CSP), n.d.); health professionals have a regulatory obligation to report cases of addictovigilance, called NOTS (for spontaneous notifications in French), to their centre. The FAN also analyses epidemiological surveillance tools, including Suspect Prescriptions Possibly Indicating Abuse (OSIAP), which is based on the national surveillance of falsified or forged prescriptions presented in community pharmacies (Site de l'association du réseau français d'addictovigilance, n.d.; Jouanjus et al., 2018). In 2002, the ANSM wanted to take stock of the abuse and dependence potential of zopiclone, and a national investigation was launched. Since then, the Addictovigilance Centre of Nantes is accountable to the French Health Authorities for providing national expertise of all cases of abuse, dependence and misuse reporting zopiclone. The first national addictovigilance surveys of zopiclone dependence, abuse and misuse cases reported to the FAN between 1993 and 2002 and between 2003 and 2014 did not identify specific problems with zopiclone, apart from dependence, abuse, chronic intake and withdrawal upon stopping common to hypnotics, with zopiclone having a much lower severity than zolpidem. Very few cases of an unap-proved route of administration were reported, and the main effect sought, other than the hypnotic effect, was anxiolysis (Schifano et al., 2019). Furthermore, a latent class analysis based on French regional health reimbursement databases did not specify a class of problematic consumers for zopiclone, whereas it indicated a subclass of zolpidem users prone to abuse (Victorri-Vigneau et al., 2013). In addition to this epidemiological study, Rousselet et al. clinically identified a higher prevalence of physical and compulsive signs of dependence and harmful consequences of dependence for zolpidem compared with zopiclone (Rousselet et al., 2017). For the OSIAP tool, in 2014, while zolpidem was present
on 38% of falsified prescriptions, thus becoming the most cited molecule, zopiclone was mentioned in only 10% of falsified prescriptions but was also reimbursed less frequently than zolpidem (Jouanjus et al., 2018; Rousselot et al., 2020).

## An Upheaval of Prescriptions in France

Zolpidem and zopiclone could only be obtained by prescription in France. However, zopiclone dependence did not appear to share the characteristics of zolpidem dependence, and based on the decision of the French health authorities in April 2017, part of the narcotics regulation was implemented for zolpidem-based drugs only. Since then, while zopiclone can be prescribed with a regular prescription, zolpidem must be prescribed with a secure, tamper-proof prescription to limit the risk of falsification. This difference in regulation between zolpidem and zopiclone, which is not found in other European countries, nor in the USA and Canada, seems to be a French specificity. This decision greatly changed the French population's exposure to sedative drug, especially Z-drugs, with a reversal of reimbursement trends: in 2016, compared to zolpidem, zopiclone was reimbursed at lower rates; after the regulatory change, zopiclone was reimbursed at a rate more than 2 times that of zolpidem (Rousselot et al., 2020). Following the change in zolpidem regulations in 2017, approximately 40% of subjects continued to use zolpidem, one-third stopped using any hypnotic and one in five chronic zolpidem users switched to zopiclone, the main carry-over molecule in cases of substitution. Thus, the reimbursement data for zopiclone increased significantly after the regulatory change affecting the prescription rules of zolpidem (Rousselot et al., 2020; Istvan et al., 2022).

## Necessary Monitoring

To our knowledge, no data from the past decade specific to zopiclone have been previously published. In this context, studying the evolution of the addictovigilance signal of zopiclone to evaluate the possible appearance of new problematic uses is necessary. The objective of this article is to present French addictovigilance data (NOTS and OSIAP) regarding the evolution of the abuse, dependence and misuse profile of zopiclone between 2 periods: 3 years before the regulatory change was applied to zolpidem in 2017 and 3 years after.

## Methods

### Study Oversight

In this national study, we used 3 data sources:

(i) Medic'AM is a public database, provided by the French national health care system, that indicates the number of tablets reimbursed in France each month and for each reimbursable drug. Zopiclone is a reimbursable and strictly prescribed drug in France, so Medic'AM provides a good proxy for the exposure of the French population to this molecule, even though it is an indirect indicator.
(ii) NOTS: we focused on the addictovigilance notification mentioning zopiclone as “suspected” reported by health professionals, collected by the FAN, analysed by medical pharmacologists working in the addictovigilance centres and recorded in the French national database. Those records include sociodemographic data, medical history and co-consumption data and data on the products consumed: route of administration, quantity, duration, search effects and method of obtention.

(iii) Data from the French epidemiological OSIAP survey. This national program continuously collects and analyses the forged or falsified prescriptions presented by patients in community pharmacies and ranks the most frequently identified drugs on falsified prescriptions. French pharmacists are not mandatory to declare to the FAN the falsified prescriptions that they detect: OSIAP relies on spontaneous declarations (Jouanjus et al., 2018). For this study, we analysed the positioning of zopiclone among the other most frequently cited drugs.

## Study Procedure

We defined two study periods: the 3-year period before the measure was applied to zolpidem, ranging from January 2014 to December 2016, called the “first study period”, and the 3-year period after the measure, ranging from January 2018 to December 2020, called the “second study period”. Data of the transition year 2017, in which the regulatory announcement (January) and change (April) occurred for zolpidem, are not presented.

## Outcomes

(i) **Zopiclone NOTS Volume and Importance**

- The number of annual notifications received by the FAN between 2014 and 2020, including zopiclone as a suspected substance, was implemented. These absolute values were related (i) to the zopiclone reimbursement data and (ii) to the total number (all substances) of annual cases reported to the addictovigilance system.

- The ranking of zopiclone among all drugs listed on falsified prescriptions during the first and the second study periods was analysed.

(ii) **Zopiclone NOTS Characteristics**

We compared the well-informed NOTS including zopiclone as a suspected substance reported to the FAN during the first study period (2014–2016) and the second study period (2018–2020). The following items were analysed for comparison:

- Patient-related factors:

(i) Age and gender

(ii) Vulnerability factors present in notifications defined by the mention of at least one risk factor for a substance use disorder: medical history of a psychiatric disorder and/or the presence of “related substances” i.e., the concomitant use of medication and/or illicit substance and/or alcohol classified as suspected and/or reported dependence

(iii) Unlawful method of obtention, including nomadism, prescription falsification and/or any other method of illicit procurement

- Items marking use outside the Summary of Product Characteristics (SPC) indications:
(i) Overuse, whether mentioned as the reason for declaration and/or calculated (maximum daily dose or maximum dose per intake greater than 7.5 mg per day in those under 65 years of age and 3.75 mg per day in those over 65 years of age; the dose used for the calculation was the maximum daily dose consumed when the daily dose consumed was variable); the doses indicated in tablets were converted to mg based on the highest dosage available in France: $1 \text{ tablet} = 7.5 \text{ mg zopiclone}$.

(ii) Anteriority of consumption, i.e. the minimum exposure time to zopiclone known at the time of notification.

(iii) Misuse, whether mentioned as the reason for declaration, and/or when at least one effect other than a hypnotic effect was sought, and/or defined as use by an unap-proved route of administration, and/or in the case of daytime use (at least one dose during the day). Problematic users meeting at least one criterion for misuse were defined as “misusers”. Other problematic consumers were defined as “nonmisusers”.

## Statistical Analysis

The evolution of zopiclone volume and importance was presented per year from 2014 to 2020. A description of zopiclone NOTS characteristics was performed for the 2 study periods for the total population and for each period according to the status misuser/nonmisuser. Quantitative and qualitative analysis of notification characteristics used continuous data expressed as the mean and categorical data expressed as numbers and percentages. Comparisons were used to assess evolution over time, using chi-squared test for proportions and Student's t-test for means. Analyses were carried out using R version 4.2 Software and statistical significance was fixed at *p* < 0.05.

## Ethical Consideration

In France, health professionals have a legal obligation, mentioned in the Public Health Code, to report observed cases of abuse or dependence involving a psychoactive substance to the FAN. This reporting obligation is a French specificity which makes the French addictovigilance database unique and allows the collection of a large amount of data from health professionals. These data are collected by the FAN and recorded anonymously in the national database. FAN pharmacologists are commissioned by the health authorities to analyse these cases of abuse and dependence. In accordance with the regulations in force, no further authorization is therefore needed.

## Results

### Zopiclone NOTS Volume and Importance

Figure 1 shows the evolution of reimbursement's data and the number of notifications reported to the FAN for zopiclone between 2014 and 2020.

Figure 1a shows the number of notifications including zopiclone as a suspected substance relative to the number of boxes reimbursed per year between 2014 and 2020. The average number of boxes reimbursed increased by 15.4% between the first study period (N=14,223,230) and the second study period (N=16,417,086). The average number of
<figure><img src="image_2.png" /><figcaption>**Fig. 1** a Number of zopiclone notifications relative to the number of boxes reimbursed, per year, from 2014 to 2020. The light grey histograms give the number of zopiclone boxes reimbursed and the dark grey line gives the number of zopiclone reports per 1000 boxes reimbursed. b Absolute number of zopiclone notifications and number of zopiclone notifications related to the total number of notifications reported to the French Addictovigilance Network (FAN), per year, from 2014 to 2020. The light grey histograms give the number of zopiclone reports and the dark grey line gives the percentage of total reports</figcaption></figure>

zopiclone reports per 1.000 boxes reimbursed seemed to increase (by 15.8%) between the first study period (N=0.57) and the second study period (N=0.66).

Figure 1b shows the absolute number of zopiclone notifications and the proportion of zopiclone notifications related to the total number of notifications reported to the FAN per year between 2014 and 2020. The average absolute number of zopiclone notifications increased by 32.8% between the first study period (N=81.3) and the second study period (N=108). Furthermore, the average proportion of zopiclone notifications related to the total number of notifications reported to the FAN decreased by 16.7% between the first study period (N=2.15) and the second study period (N=1.79).

Table 1 presents the percentage of citations for zopiclone out of total citations and the associated citation rank among the most cited drugs in the OSIAP tool, per year, during the first and the second study periods. Since 2014, zopiclone consistently represented less than 5% of all the molecules mentioned on the falsified prescriptions. In the second study period, zopiclone was not significantly more identified on falsified prescriptions than in the first study period, and its position among the most cited molecules remained stable at the 7th or 8th place.

## Zopiclone NOTS Characteristics

Table 2 presents the items evaluated as defined in the Methodology section over the 2 study periods.

<table><caption>**Table 1** Percentage of citations for zopiclone out of total citations and associated citation rank in the Suspect Prescriptions Possibly Indicating Abuse (OSIAP) tool per year during the first study period and the second study period</caption><thead><tr><th rowspan="2">Year</th><th colspan="3">First study period</th><th colspan="3">Second study period</th></tr><tr><th>2014</th><th>2015</th><th>2016</th><th>2018</th><th>2019</th><th>2020</th></tr></thead><tbody><tr><td>Proportion of zopiclone among all drugs</td><td>5.0%</td><td>2.9%</td><td>3.0%</td><td>4.6%</td><td>2.8%</td><td>2.2%</td></tr><tr><td>Citation rank</td><td>3</td><td>8</td><td>8</td><td>7</td><td>8</td><td>8</td></tr></tbody></table>
<table><caption>**Table 2** Evolution of the criteria studied in the spontaneous notification (NOTS) reported to the French Addictovigilance Network (FAN) between 2014 and 2020 by period</caption><thead><tr><th rowspan="2"></th><th rowspan="2"></th><th>First study period (2014–2016)</th><th>Second study period (2018–2020)</th><th colspan="2">First study period (2014–2016)</th><th colspan="2">Second study period (2018–2020)</th></tr><tr><th>Total</th><th>Total</th><th>Misusers</th><th>Nonmisusers</th><th>Misusers</th><th>Nonmisusers</th></tr></thead><tbody><tr><td rowspan="5">Patient-related factors</td><td>Number of reports</td><td>115</td><td>149</td><td>27% (31)</td><td>73% (84)</td><td>48.3% (72)</td><td>51.7% (77)</td></tr><tr><td>Mean age, years (n)</td><td>46.5 (113)</td><td>42.7 (146)</td><td>38.2 (31)</td><td>49.7 (82)**</td><td>37.9 (69)</td><td>46.9 (77)**</td></tr><tr><td>Female, % (n)</td><td>46.1% (53)</td><td>48.3% (72)</td><td>54.8% (17)</td><td>42.8% (36)</td><td>45.8% (33)</td><td>50.6% (39)</td></tr><tr><td>Vulnerability factors</td><td>Presence of at least one risk factor for substance use disorder, % (n)</td><td>86.1% (99)</td><td>89.9% (134)</td><td>96.8% (30)</td><td>82.1% (69)*</td><td>94.4% (68)</td><td>85.7% (66)</td></tr><tr><td>Medical history of psychiatric disorders, % (n)</td><td>43.5% (50)</td><td>44.9% (67)</td><td>61.3% (19)</td><td>36.9% (31)*</td><td>45.8% (33)</td><td>44.1% (34)</td></tr><tr><td rowspan="5">Patient-related factors</td><td>Related substances, % (n)</td><td>67% (77)</td><td>75.2% (112)</td><td>77.4% (24)</td><td>63.1% (53)</td><td>83.3% (60)</td><td>67.5% (52)*</td></tr><tr><td>Benzodiazepine or zolpidem, % (n)</td><td>43.5% (50)</td><td>50.3% (75)</td><td>61.3% (19)</td><td>36.9% (31)*</td><td>61.1% (44)</td><td>40.3% (31)*</td></tr><tr><td>Opioids (analgesics and/or maintenance treatment), % (n)</td><td>23.5% (27)</td><td>26.2% (39)</td><td>35.5% (11)</td><td>19% (16)</td><td>31.9% (23)</td><td>20.8% (16)</td></tr><tr><td>Controlled substances, % (n)</td><td>18.3% (21)</td><td>22.1% (33)</td><td>25.8% (8)</td><td>15.5% (13)</td><td>27.8% (20)</td><td>16.9% (13)</td></tr><tr><td>Alcohol, % (n)</td><td>13% (15)</td><td>20.1% (30)</td><td>19.3% (6)</td><td>10.7% (9)</td><td>23.6% (17)</td><td>16.9% (13)</td></tr><tr><td rowspan="2">Unlawful way of obtention, % (n)</td><td>Dependence, % (n)</td><td>68.7% (79)</td><td>67.1% (100)</td><td>90.3% (28)</td><td>60.7% (51)*</td><td>76.4% (55)</td><td>58.4% (45)*</td></tr><tr><td></td><td>26.1% (30)</td><td>40.9% (61)*</td><td>41.9% (13)</td><td>20.2% (17)*</td><td>41.7% (30)</td><td>40.3% (31)</td></tr></tbody></table>
<table><caption>Table 2 (continued)</caption><thead><tr><th rowspan="2">Items marking use<br>outside the scope of<br>the SPC</th><th rowspan="2">Overuse, % (n)</th><th rowspan="2">Number of data avail-<br>able</th><th rowspan="2">Med [25 percent-75<br>percent], mg/day<br>min-max, mg/day</th><th rowspan="2">Number of data<br>available</th><th rowspan="2">med [25 percent-75<br>percent], month<br>min—max, month</th><th rowspan="2">Unapproved route of<br>administration, % (n)</th><th rowspan="2">Unapproved indication,<br>% (n)</th><th rowspan="2">Misuse without further<br>information, % (n)</th><th colspan="2">First study period<br>(2014–2016)</th><th colspan="2">Second study period<br>(2018–2020)</th><th colspan="2">First study period<br>(2014–2016)</th><th colspan="2">Second study period<br>(2018–2020)</th></tr><tr><th>Total</th><th>Total</th><th>Misusers</th><th>Nonmisusers</th><th>Misusers</th><th>Nonmisusers</th></tr></thead><tbody><tr><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>70.4% (81)</td><td>77.8% (116)</td><td>90.3% (28)</td><td>63.1% (53)*</td><td>75.0% (54)</td><td>80.5% (62)</td><td></td><td></td></tr><tr><td></td><td>Dose</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>103</td><td>116</td><td>28</td><td>75</td><td>49</td><td>67</td><td></td><td></td></tr><tr><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>15 [7.5–30]</td><td>18.75 [15–45]</td><td>22.5 [15–63.75]</td><td>15 [7.5–22.5]**</td><td>37.5 [15–52.5]</td><td>15 [7.5–30]</td><td></td><td></td></tr><tr><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>3.75–412.5</td><td>3.75–450</td><td>7.5–412.5</td><td>3.75–210</td><td>7.5–375</td><td>3.75–450</td><td></td><td></td></tr><tr><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>56</td><td>81</td><td>12</td><td>44</td><td>36</td><td>45</td><td></td><td></td></tr><tr><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>36 [17.25–<br>96]</td><td>36 [12–108]</td><td>36 [24–51]</td><td>48 [14.5–120]</td><td>48 [22.5–120]</td><td>36 [10–84]</td><td></td><td></td></tr><tr><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>2–276</td><td>0–360</td><td>2–180</td><td>2–276</td><td>0–360</td><td>0–360</td><td></td><td></td></tr><tr><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>1.7% (2)</td><td>4% (6)</td><td>6.4% (2)</td><td></td><td>8% (6)</td><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>20.9% (24)</td><td>34.2% (51)*</td><td>77.4% (24)</td><td></td><td>70.8% (51)</td><td></td><td></td><td></td></tr><tr><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>4.34% (5)</td><td>10.1% (15)</td><td>16.1% (5)</td><td></td><td>20.8% (15)</td><td></td><td></td><td></td></tr></tbody></table>

<figure><img src="image_3.png" /></figure>

<footnote>*p < 0.05 using Chi-squared test; **p < 0.05 using Student's t-test</footnote>
(i) **Global analysis of the NOTS reported to the FAN over the periods from 2014 to 2016 and 2018 to 2020.**

Regarding the patient-related factors, in the second study period (2018–2020), relative to the first study period (2014–2016), the mean age of the patients tended to be lower (46.5 vs. 42.7, *p*=0.06), and the proportion of women appeared to be relatively stable (46.1% vs. 48.3%). Vulnerability factors did not change significantly over the 2 periods, with at least one risk factor for substance use disorder being reported in nearly 90% of NOTS: (i) a medical history of psychiatric disorders was mentioned in approximately 45% of NOTS, (ii) dependence was mentioned in nearly 2/3 of the cases analysed, and (iii) related substance use was mentioned in 67% (first period) and 75.2% (second period). When related substances were reported, benzodiazepines and/or zolpidem were most frequently cited in both study periods.

Concerning unlawful ways of obtention, there was a significant increase (*p*=0.01) in zopiclone fraud for obtention between the first (*n*=30, 26.1%) and second (*n*=61, 40.9%) study periods. While the proportion of cases mentioning fraud for obtention was relatively stable among misusers over the two study periods, it increased significantly between the first (*n*=17, 20.2%) and the second (*n*=31, 40.3%) study periods (*p*<0.01) among nonmisusers.

Transgressive behaviour mainly involved nomadism, whether medical and/or pharmaceutical, and was reported in 43.3% and 70.5% of NOTS mentioning fraud, respectively. Falsified prescriptions remained at a stable level over the 2 periods (approximately 1/5 of fraudulent behaviour cases). Purchases on the Internet remained marginal over the 2 periods and seemed to decrease, although the very small number was difficult to interpret, decreasing from 13.3% (*n*=4) of fraudulent behaviour cases to 3.3% (*n*=2). Other reported behaviours, including lying for obtaining, stealing, self-prescribing by health professionals and/or repeated overlapping prescriptions, decreased from 63.3% (*n*=19) over the first study period to 39.3% (*n*=24) over the second study period (data not shown in the table).

Concerning the items marking the use outside the SPC indications between the 2 study periods, while overuse was mentioned in 70.4% (*n*=81) of the NOTS analysed in the first study period and 77.8% (*n*=116) in the second period, the median doses consumed remained relatively low: 15 and 18.75 mg per day, respectively. Anteriority of consumption was stable over both periods, with a median of 36 months. However, the proportion of misusers increased significantly (*p*<0.01), from 27% (*n*=31) in the first period to 48.3% (*n*=72) in the second period. This increase concerned the use in an unapproved indication (*p*<0.02), with diversions of routes of administration remaining marginal.

(ii) **Focus on the NOTS reported to the FAN mentioning misuse**

Comparing misusers versus nonmisusers, misusers were significantly younger (*p*<0.01) and more vulnerable (*p*<0.1) in both the first and the second study periods: misusers had more dependence diagnoses (*p*<0.02), consumed more benzodiazepines and/or zolpidem (*p*<0.02) and seemed to have more psychiatric disorders than nonmisusers. In the first study period, misusers consumed higher doses than nonmisusers. Overuse was more frequent (*p*<0.01), reported in 90.3% of NOTS mentioning misuse, and the median dose was significantly higher (*p*<0.05): 22.5 mg per day, vs. 15 mg/day; however, in the second study period, even if the median dose consumed seemed to be higher for misusers, the overuse rate seemed to be balanced between the 2 groups. Similarly, in the first
study period, misusers fraudulently obtained zopiclone more frequently than nonmisusers (*p*=0.02); the unlawful ways of obtention were mentioned in a similar proportion of cases between the 2 groups in the second study period (approximately 40%).

Between the first and second study periods, while the proportion of misusers increased significantly (*p* < 0.01), the profile of misusers was relatively comparable, although the proportion of overconsumption seemed to decrease (90.3% vs. 75.0%) and the anteriority of consumption seemed to increase (36 vs. 48 months). The consumption of zopiclone by an unapproved route of administration remained marginal over the two study periods, reported in 2 to 6% of the NOTS analysed. Misuse by unapproved indication was reported in 20.9% (*n* = 24) of the NOTS in the first study period, and this proportion increased significantly (*p* = 0.02) in the second study period, where it was mentioned in 34.2% (*n* = 51) of the NOTS. When at least one effect, other than the hypnotic effect, was sought, the search for an anxiolytic effect was reported in almost half of the cases (45.8% over the first study period and 50.9% over the second); the search for a stimulating effect (mentioned as “stimulant” and/or “recreational” in the NOTS) was reported in 1/3 of the cases (*n* = 8) over the first study period and seemed to decrease over the second period, reported in 17.6% (*n* = 9) of cases of misuse for unapproved indication.

Discussion

A Consumption Profile Without Radical Modification...

The comparison of both quantitative and qualitative outcomes between the two study peri-
ods did not show any critical changes to the addictovigilance profile of zopiclone. (i) From
a quantitative point of view, even though the number of reports including zopiclone as a
suspected substance increased in absolute value between the first and the second study
periods, on the one hand, this increase was related to the increase in reimbursement data,
probably in connection with both a postponement of zolpidem (Rousselot et al., 2020; Ist-
van et al., 2022) and new treatment initiations, and on the other hand, to the increase in the
overall number of reports to the FAN. Thus, the proportion of zopiclone reports to the total
FAN decreased between the first and second study periods and remained at less than 2% of
the total notifications reported to the FAN over the 2 periods. (ii) From a qualitative point
of view, the general profile of problematic zopiclone users remained comparable between
the first and second study periods and consistent with the profile already identified in the
literature (Schifano et al., 2019; Victorri-Vigneau et al., 2013; Rousselet et al., 2017): the
presence of at least one risk factor for substance use disorder in approximately 3/4 of cases,
frequent overconsumption (mentioned in approximately 3/4 of cases) and a moderate, but
very rare diversion of the route of administration. Even though the proportion of misusers
increased significantly between the first and second study periods, this quantitative increase
was not accompanied by major qualitative changes between the 2 study periods: in both
periods, misusers had more vulnerability factors than nonmisusers; they consumed higher
doses of zopiclone and were significantly younger. In the literature, several studies have
found that the age of misusers is significantly lower than that of nonmisusers, whether for
benzodiazepines and related (alprazolam (Diaz et al., 2011), zolpidem (Aquizerate et al.,
2023)) and opioids (tramadol (Roussin et al., 2013)).
## ... but Still Problematic

Nevertheless, over the two study periods, the markers of problematic consumption were still present: a diagnosis of dependence was reported in more than 2/3 of the cases, overuse was mentioned in 3/4 of the cases notified to the network, the anteriority of consumption went far beyond the scope of the SPC (median anteriority of 36 months) and misuse progressed. In view of these results, healthcare professionals should remain cautious in prescribing and dispensing zopiclone, communicate to reduce as much as possible the prescription of zopiclone in particular and of hypnotics in general and, when prescribing, if it proves to be necessary, establish a “contract” with the patient for the limitation of the prescription to a short duration in accordance with recommendations. In France, the High Authority of Health has published good practices for prescribing benzodiazepines to avoid the overconsumption and misuse of these molecules in anxiety and insomnia (Haute Autorité de Santé (HAS), 2007). Zopiclone has a maximum prescription duration of 28 days, including the gradual reduction of doses. The question could be raised of applying the zopiclone legislation to all benzodiazepines (whose maximum prescription duration is currently 12 weeks in France), since (i) they share common characteristics of abuse and dependence, (ii) the risk of dependence increases with the duration of exposure and (iii) the restricted and time limited indications of these molecules.

## The Impact of the Regulatory Measure

The obligation to prescribe zolpidem on a secure prescription in 2017 logically decreased its presence on falsified prescriptions, with zolpidem moving from the 1st to the 7th place among the most cited drugs in OSIAP (Aquizerate et al., 2023). This evolution has not been accompanied by an increase in citations of zopiclone in this national tool; the proportion of falsified prescriptions mentioning zopiclone has remained stable and even seemed to begin to decrease in 2019. There is, however, a significant increase in the unlawful ways of obtention, particularly notable among nonmisusers, which mainly concerns nomadism, whether medical or pharmaceutical. Laforgue et al. highlighted an association between the perception of the new regulation of zolpidem prescription by General Practitioners (GPs) and their strategy of prescription (Laforgue et al., 2022). According to the authors, the regulatory change concerning zolpidem in 2017 led to awareness of the risk of hypnotics for 13% of GPs. From an epidemiological point of view, it has already been observed that a regulatory measure on a specific molecule can impact its entire class. Thus, in January 2001, the frequent misuse of flunitrazepam led ANSM to implement part of the narcotics regulation for this drug. Victorri et al. showed that nearly half of the 738 patients selected in this study (who had received at least one flunitrazepam prescription in January 2001) stopped using hypnotics over a period of 8 months (Victorri-Vigneau et al., 2003). We can thus assume that the regulatory measure applied to zolpidem could be perceived as an alert regarding the prescription of hypnotics in general, which may lead chronic zopiclone users, but nonmisusers, who have a diagnosis of dependence in 2/3 cases, to try to fraudulently obtain zopiclone because it became more difficult to get a prescription.

## Strengths and Limitations

This study presents an analysis of all FAN reported French cases of problematic consumption of zopiclone on the basis of clinical and consumption data. In France, health
professionals have an obligation to report cases of abuse and dependence that they observe. Although we cannot guarantee the exhaustiveness of this database, and even though serious or unexpected cases are probably reported more than nonserious cases, this system remains an effective monitoring system and a good whistleblower.

## Conclusion

While the regulatory measure applied to zolpidem in 2017 in France resulted in an increase in the exposure of the population to zopiclone, new problematic uses for zopiclone have not been observed. However, in the face of the persistence of problematic use markers, the significant increase in the number of misusers and the increase in fraud for obtention, healthcare professionals should remain cautious in prescribing and dispensing zopiclone.

**Acknowledgements** We wish to thank the French Addictovigilance Network (FAN) for making this work possible: Anne-Sylvie Caous, Samira Djezzar, Alexandra Boucher, Amélie Daveluy, Céline Eiden, Bernard Fauconneau, Christine Fournier-Choma, Valérie Gibaja, Clémence Lacroix, Maryse Lapeyre-Mestre, Reynald Le Boisselier, Bruno Revol.

**Author Contribution** Conception or design of the work: CVV.

Acquisition and analysis: AA.

Interpretation of data for the work: all authors.

Drafting the work or revising it critically for important intellectual content: all authors.

Final approval of the version to be published: all authors.

**Data Availability** In France, health professionals have a legal obligation, mentioned in the Public Health Code, to report observed cases of abuse or dependence involving a psychoactive substance to the French Addictovigilance Network. These data are collected by the FAN and recorded anonymously in the national database of ANSM (French National Agency for the Safety of Medicines).

Data sources: French National Agency for Medicines and Health Product Safety (ANSM). The content of this article is the sole responsibility of the authors and has not been validated by the ANSM.

**Code Availability** Code can be transmitted by the corresponding author upon reasonable request.

## Declarations

**Ethics Approval** Not applicable.

**Consent to Participate** Not applicable.

**Consent for Publication** Not applicable.

**Conflict of Interest** The authors declare no competing interests.

**Open Access** This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
References

Aquizerate, A., Laforgue, E.J., Istvan, M., Rousselet, M., Gerardin, M., Jouanjus, E., et al. (2023). French national addictovigilance follow-up of zolpidem between 2014 and 2020: evolution of drug abuse, misuse and dependence before and after the regulatory change. *European Journal of Public Health*, **33**(2), 169–175. https://doi.org/10.1093/eurpub/ckad003/7030751.

Baumevieille, M., Miremont, G., Haramburu, F., Maurain, C., & Begaud, B. (2001). Le système français d’évaluation de la pharmacodépendance et de l’abus : Consécration juridique. *Thérapie*, **56**, 15–22.

Code de la Santé Publique (CSP), Sous-section 4 : Centres d’évaluation et d’information sur la pharmacodépendance et d’addictovigilance (Articles R5132–112 à R5132–116) : obligation de déclaration.

Diaz, L., Eiden, C., Jouanjus, E., Frauger, E., Fouilhé, N., Djezzar, S., et al. (2023). Alprazolam misuse: Analysis of French Addictovigilance Network data from 2011 to 2020. *Therapies*, 2023. https://linkinghub.elsevier.com/retrieve/pii/S0040595723000306

Haute Autorité de Santé (HAS) Recommandation de bonne pratique. Prise en charge du patient adulte se plaignant d'insomnie en médecine générale 2007, May. https://www.has-sante.fr/jcms/c_522637/fr/prise-en-charge-du-patient-adulte-se-plaignant-d-insomnie-en-medecine-generale.

Holm, K.J., Goa, K.L., Zolpidem. (2022). An update of its pharmacology, therapeutic efficacy and tolerability in the treatment of insomnia. *Drugs*, **59**(4), 865–89. https://doi.org/10.2165/00003495-200059040-00014

Istvan, M., Rousselet, M., Laforgue, E. J., Guerlais, M., Gérardin, M., Jolliet, P., Feuillet, F., & Victorri-Vigneau, C. (2022). Did the pattern of use of zolpidem change since the enforcement of a new prescription rule? A latent class analysis using the French health insurance database. *Expert Opinion Drug Safety*, **8**, 1–10. https://doi.org/10.1080/14740338.2022.2047930

Istvan, M., Rousselet, M., Laforgue, E.J., Guerlais, M., Gérardin, M., Jolliet, P., et al. (2022). Did the pattern of use of zolpidem change since the enforcement of a new prescription rule? A latent class analysis using the French health insurance database. *Expert Opinion Drug Safety*. 8 mars 1–10.

Jouanjus, E., Guernec, G., Lapeyre-Mestre, M., French Addictovigilance Network. (2018). Medical prescriptions falsified by the patients: A 12-year national monitoring to assess prescription drug diversion. *Fundamental Clinic Pharmacology*, **32**(3), 306–322. https://doi.org/10.1111/fcp.12356

Kralic, J.E., Korpi, E.R., O'Buckley, T.K., Homanics, G.E., Morrow, A.L., (2022). Molecular and pharmacological characterization of GABA<sub>A</sub> receptor α1 subunit knockout mice. *Journal of Pharmacology and Experimental Therapeutics*, **302**(3), 1037–45 (2022). https://doi.org/10.1124/jpet.102.036665

Laforgue, E. J., Istvan, M., Schreck, B., Mainguy, M., Jolliet, P., Grall-Bronnec, M., & Victorri-Vigneau, C. (2022). Perception of the regulatory change for zolpidem prescription by French general practitioners and its relation to prescription behavior. *Journal of Clinical Medicine*, **11**(8), 2176. https://doi.org/10.3390/jcm11082176

McKernan, R.M., Rosahl, T.W., Reynolds, D.S., Sur, C., Wafford, K.A., Atack, J.R., et al. (2000). Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABAA receptor α1 sub-type. *Nature Neuroscience*, **3**(6), 587–92. http://www.nature.com/articles/nn0600_587

Olsen, R.W., Sieghart, W. (2008). International Union of Pharmacology. LXX. Subtypes of γ-aminobutyric acid <sub>A</sub> receptors: Classification on the basis of subunit composition, pharmacology, and function. Update. *Pharmacological Reviews*, **60**(3), 243–60 (2008). https://doi.org/10.1124/pr.108.00505

Rousselet, M., Feuillet, F., Gerardin, M., Jolliet, P., Hardouin, J. B., & Victorri-Vigneau, C. (2017). The French addictovigilance network clinical assessment: Z-drugs, true false twins. *Expert Opinion on Drug Safety*, **16**(9), 1063–1069. https://doi.org/10.1080/14740338.2017.1346084

Rousselot, N., Pariente, A., Mansiaux, Y., & Victorri-Vigneau, C. (2020). Impact of secured prescription implementation for zolpidem on hypnotics use in France: A time-series analysis on national data. *Annals of Family Medicine*, **18**(4), 345–348. https://doi.org/10.1370/afm.2556

Roussin, A., Soeiro, T., Fouque, C., Jouanjus, E., Frauger, E., Fouilhé, N., et al. (2022). Increase of high-risk tramadol use and harmful consequences in France from 2013 to 2018: Evidence from the triangulation of addictovigilance data. *British Journal of Clinical Pharmacology*, **88**(8), 3789–802. https://doi.org/10.1111/bcp.15323

Sabe, M., Kashef, H., Gironi, C., Sentissi, O. (2022). Zolpidem stimulant effect: Induced mania case report and systematic review of cases. *Progress in Neuro-Psychopharmacology and Biological Psychiatry*, **94**, 109643. https://linkinghub.elsevier.com/retrieve/pii/S0278584618308595

Schifano, F., Chiappini, S., Corkery, J.M., Guirguis, A. (2019). An insight into Z-drug abuse and dependence: An examination of reports to the European medicines agency database of suspected adverse drug reactions. *International Journal of Neuropsychopharmacology*, **22**(4), 270–7. https://academic.oup.com/ijnp/article/22/4/270/5306970
Seldenrijk, A., Vis, R., Henstra, M., Ho Pian, K., van Grootheest, D., Salomons, T., et al. (2017). Systematic review of the side effects of benzodiazepines. *Nederlands Tijdschrift Voor Geneeskunde*, **161**, D1052.

Site de l'association du réseau fraçias d'addictovigilance (n.d.) www.addictovigilance.fr.

Victorri-Vigneau, C., Basset, G., Bourin, M., Jolliet, P. (2022). Impacts de la nouvelle réglementation du flunitrazépam sur la consommation d'hypnotiques. *Therapies*, **58**(5), 425-30. https://linkinghub.elsevier.com/retrieve/pii/S0040595716301263

Victorri-Vigneau, C., Dailly, E., Veyrac, G., Jolliet, P. (2007). Evidence of zolpidem abuse and dependence: Results of the French Centre for Evaluation and Information on Pharmacodependence (CEIP) network survey. *British Journal of Clinical Pharmacology*, **64**(2), 198-209. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2000636/

Victorri-Vigneau, C., Feuillet, F., Wainstein, L., Grall-Bronnec, M., Pivette, J., Chaslerie, A., et al. (2022). Pharmacoepidemiological characterisation of zolpidem and zopiclone usage. *European Journal of Clinical Pharmacology*, **69**(11), 1965-72. https://doi.org/10.1007/s00228-013-1557-x

Victorri-Vigneau, C., Gérardin, M., Rousselet, M., Guerlais, M., Grall-Bronnec, M., & Jolliet, P. (2014). An update on zolpidem abuse and dependence. *Journal of Addiction Disorder*, **33**(1), 15-23. https://doi.org/10.1080/105508872014882725.

**Publisher's Note** Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

## Authors and Affiliations

Aurélie Aquizerate¹ ID, Edouard-Jules Laforgue¹,² ID, Marion Istvan¹,² ID,

Morgane Rousselet¹,² ID, Marie Gérardin¹ ID, Emilie Jouanjus³, Frédéric Libert⁴,

French Addictovigilance Network (FAN) · Anne-Sylvie Caous · Samira Djezzar ·

Alexandra Boucher · Amélie Daveluy · Céline Eiden · Bernard Fauconneau ·

Christine Fournier-Choma · Valérie Gibaja · Clémence Lacroix ·

Maryse Lapeyre-Mestre · Reynald Le Boisselier · Bruno Revol · Marylène Guerlais¹ ·

Caroline Victorri-Vigneau¹,² ID

<figure><img src="image_4.png" /></figure>

Aurélie Aquizerate
aurelie.aquizerate@chu-nantes.fr

Edouard-Jules Laforgue
edouard.laforgue@chu-nantes.fr

Marion Istvan
marion.istvan@chu-nantes.fr

Morgane Rousselet
morgane.rousselet@chu-nantes.fr

Marie Gérardin
marie.gerardin@chu-nantes.fr

Emilie Jouanjus
emilie.jouanjus@univ-tlse3.fr

Frédéric Libert
flibert@chu-clermontferrand.fr
Marylène Guerlais
marylene.guerlais@chu-nantes.fr

Caroline Victorri-Vigneau
caroline.vigneau@chu-nantes.fr

1 Nantes Université, CHU Nantes, Centre d'Evaluation Et d'Information Sur La Pharmacodépendance-Addictovigilance (CEIP-A), Service de Pharmacologie Clinique, 9 Quai Moncousu, 44000 Nantes, France

2 INSERM U1246 SPHERE "methods in Patient-Centered Outcomes and Health Research", Nantes and Tours University, Nantes, France

3 Centre for Evaluation and Information On Pharmacodependence, Clinical Pharmacology Department, Toulouse University Hospital, Toulouse, France

4 Centre for Evaluation and Information On Pharmacodependence, Clinical Pharmacology Department, Clermont-Ferrand University Hospital, Clermont-Ferrand, France