Select a psychoactive drug that is of pharmacological interest to you, but not one you will review as part of your Critical Review. For this paper, you may choose drugs of abuse; however, the paper mu

doi: 10.1111/j.1472-8206.2010.00882.x ORIGINAL ARTICLE Evidence of clonazepam abuse liability:

results of the tools developed by the French Centers for Evaluation and Information on Pharmacodependence (CEIP) network Elisabeth Frauger a, Vanessa Pauly b, Vincent Pradel a,b , Frank Rouby a, Jocelyne Arditti c, Xavier Thirion b, Maryse Lapeyre Mestre d, Joe ¨ lle Micallef a* aCEIP – Centre Associe ´ ,Fe ´ de ´ ration de Pharmacologie et de Toxicologie, CHU Timone, Marseille & Institut des Neurosciences Cognitives de la Me ´ diterrane ´ e, Faculte ´ de Me ´ decine, UMR 6193 Universite ´ de la Me ´ diterrane ´ e-CNRS, Marseille, FrancebCEIP – Centre Associe ´ , Laboratoire de Sante ´ Publique, Faculte ´ de me ´ decine, Marseille, France cCEIP de Marseille, Centre Antipoison, Ho ˆ pital Salvator, Marseille, France dCEIP de Toulouse, Service de pharmacologie clinique, Unite ´ de pharmacoepidemiologie EA3696, Universite ´ Paul Sabatier, Toulouse, France INTRODUCTION Like all benzodiazepines (BZD), clonazepam has hyp- notic, sedative, anxiolytic, anticonvulsant, muscle relax- ant and amnesic properties. Clonazepam is rapidly and completely absorbed after oral administration. According to the summary of product characteristics (SPC), the elimination half-life of clonazepam is typically around 20–60 h. Marketed in several countries, it is available under different formulations (oral tablets, liquid solu- tions, injectable solution) and is classi ed on the schedule IV controlled substance in United States and in the psychotropic substance list in France. In France, according to the SPC, clonazepam is indicated in Keywords benzodiazepines, Centers for Evaluation and Information on Pharmaco- dependence, clonazepam, drug abuse, Pharmacoepidemiology Received 30 June 2009; revised 13 July 2010; accepted 13 September 2010 *Correspondence and reprints: [email protected] ABSTRACT Recent observations suggest the existence of clonazepam abuse. To determine its importance in France, a quantitative and systematic synthesis of all clonazepam data of several epidemiological tools of the Centers for Evaluation and Information on Pharmacodependence (CEIP) network has been performed in comparison with data on others benzodiazepines (BZD). Data on clonazepam and other BZD have been analysed from different epidemiological tools: OSIAP survey that identi es drugs obtained by means of falsi ed prescriptions, Observation of Illegal Drugs and Misuse of Psychotropic Medications (OPPIDUM) survey that describes modalities of use and data from regional French health reimbursement system. In OSIAP survey, the proportion of clonazepam falsi ed prescriptions among all BZD falsi ed prescriptions increased. During the 2006 OPPIDUM survey, the analysis of the BZD modalities of use highlights clonazepam abuse liability (for example 23% of illegal acquisition), in second rank after unitrazepam. Studies based on data from the French health reimbursed system show that 1.5% of subjects with clonazepam dispensing had a deviant behaviour. Among BZD, clonazepam has the second most important doctor- shopping indicator (3%) after unitrazepam. All these data provide some arguments in favour of clonazepam abuse liability in real life and the necessity to reinforce its monitoring. ª 2010 The Authors Fundamental and Clinical Pharmacology ª2010 Socie ´ te ´ Franc ¸ aise de Pharmacologie et de The ´ rapeutique Fundamental & Clinical Pharmacology 25 (2011) 633–641 633 Fundam ental & Clinical P h a r m a c o lo gy treatment of partial or generalized seizure disorders, for adults and children, with a recommended daily dose at 0.05–0.1 mg/kg per day. In the United States, clonaze- pam is also approved for treatment of panic disorders.

Some published studies have reported the use of clonazepam for pain or in some psychiatric diseases, as bipolar disorder, acute mania, panic disorder, depression and BZD withdrawal [1–6].

The nonmedical use or abuse of prescription drugs is a serious and growing public health especially with opioids, central nervous system depressants (mainly BZD) and stimulants [7–12]. Indeed, BZD, like clonaze- pam, can induce dependence [13–15]. Some observa- tions from several countries have suggested clonazepam abuse liability in real life [16–22]. For example, the public health surveillance system ‘Drug Abuse Warning Network’ (DAWN) has highlighted that clonazepam reports have increased among drug-related hospital emergency department visits for its medical conse- quences of abuse [11].

In France, a national network of Centers for Evaluation and Information on Pharmacodependence (CEIP) was created in 1990 by the Ministry of Health. This network is closely related and funded by the French Medicine Agency (Afssaps) with speci c aims in particular: (i) to ensure collection and evaluation of clinical data concern- ing drug abuse or dependence; (ii) to perform experimen- tal, clinical and epidemiological studies [23,24]. This network has implemented different surveillance systems to monitor abuse liability of psychoactive drugs [25–30] and has developed a complementary pharmacoepidemi- ological approach using reimbursed drug database (from French health reimbursement system) [31–40]. Follow- ing a warning on a given psychoactive drug, the network investigates its abuse liability based on these different surveillance systems [24]. Because such a warning appears with clonazepam, Afssaps has decided to launch an of cial enquiry to determine the magnitude of its abuse liability.

The work presented here summarizes the quantitative and systematic synthesis performed of all clonazepam data. The aim was to assess the abuse liability of clonazepam in particular in comparison with other available data on BZD and benzodiazepines like from the CEIP pharmacoepidemiological tools.

MATERIALS AND METHODS For this work, the following tools have been used [23– 30,38,39]:OSIAP (‘Ordonnances Suspectes Indicateur d’Abus et de Pharmacodependance in French’): is an identi cation of drug abuse by means of falsi ed prescriptions presented to dispensing pharmacies [26,27]. This survey allows to identify drugs liable to be diverted and to determine the rank of most diverted drugs when compared with sales data. For this work, only BZD or BZD like falsi ed prescriptions have been analysed in 2002, 2004 and 2006. This survey gives the number of clonazepam falsi ed prescriptions in comparison with the most other reported BZD or BZD like. Moreover, a falsi cation ratio has been calculated for clonazepam in 2002, 2004 and 2006, this ratio was obtained by dividing the number of falsi ed prescriptions by its sales data in the same period.

In 2006, the falsi cation ratio has been also calculated for the most reported BZD or BZD like to compare them. The falsi cation ratio is expressed in number of falsi ed prescription/million daily de ned dose (DDD) per day.

The DDD is a technical unit of measurement de ned as the assumed average maintenance dose per day for a prescription drug used for its main indication in adults [41]. The DDD methodology was developed in response to the need to convert and standardize readily available volume data from sales statistics or pharmacy inventory data into medically meaningful units [42].

OPPIDUM (Observation of illegal drugs and misuse of psychotropic medications; ‘Observation des Produits Psychotropes Illicites ou De´ tourne´ s de leur Utilisation Me´ dicamenteuse’ in French): is a cross-sectional national pharmacoepidemiological study, repeated each year in October [25,28–30]. It is based on specialized addiction care centres who recruited subjects with a drug depen- dency as de ned by DSM IV or bene ting of an opiate maintenance treatment. For every subject, modalities of consumption of each psychoactive drugs consumed during the previous week are collected i.e. name of drug, daily dose, methods of acquisition (illegal or not), concomitant alcohol use, withdrawal symptoms and modality of use (adequate use,abuse, dependence). In this work, rst, proportion of each BZD declarations among all drugs declarations has been analysed from 1998 to 2006. Then, clonazepam modalities of con- sumption were compared with the most reported BZD and BZD like in 2006.

Those data were completed with results obtained from speci c studies based on reimbursed drugs database. This database includes dispensings of reimbursed drugs to all subjects enrolled with the general health insurance scheme of two southern France areas [31–40]. This database covers approximately 74% of the population 634 E. Fraugeret al. ª2010 The Authors Fundamental and Clinical Pharmacologyª2010 Socie´ te´ Franc¸ aise de Pharmacologie et de The´ rapeutique Fundamental & Clinical Pharmacology25(2011) 633–641 protected by French health insurance schemes (these areas are count around 5 millions inhabitants). Two methods were used to evaluate clonazepam abuse liability. On the one hand, clustering method has been used to discriminate, among all subjects with a clonaze- pam dispensing during a speci c period in 2001, subjects with deviant behaviour (subjects that have an important dosage and/or an important number of dispensing during one followed period and/or an important number of different prescribers and/or pharmacies) [38]. On the other hand, a speci c indicator of doctor shopping has been developed. For each patient who has a clonazepam dispensing in 2005, two quantities were computed: total dispensed quantity and total quantity obtained by doctor shopping [36,37,39,40]. From these data, a doctor- shopping indicator (DSI) is calculated (percentage of the prescription drugs obtained through doctor shopping among the total dispensed quantity). The doctor-shop- ping quantity re ects the degree of overlaps of prescrip- tions issued by different physicians to a single patient.

Quantities were expressed in DDD to allow comparison between drugs. According to the WHO Collaborating Centre for Drug Statistics Methodology, clonazepam DDD is 8 mg [41]. For this work, the different quantities and the DSI have been calculated for clonazepam and for all other BZD and BZD like. These two methods have been previously used to measure the importance of drug abuse liability like high-dosage buprenorphine [36,37] or trihexyphenidyle [34].

Statistical analysis A descriptive analysis has been carried out on clonaze- pam and other BZD or BZD like data. Usual statistical tests were performed to compare groups (chi-square tests). All signi cance levels were set atP< 0.05.

RESULTS OSIAP: A total of 1246 suspicious prescriptions were analysed (400 in 2002, 517 in 2004 and 329 in 2006).

Most of the suspect prescriptions involved at least one drug for the nervous system [26]. Among all suspicious prescriptions, BZD or BZD like represented 47% in 2002, 40% in 2004 and 46% in 2006. Among BZD, clonaze- pam suspicious prescriptions represent 2.1% in 2002 (ranked eighth), 5.3% in 2004 (ranked sixth) and 7.2% in 2006 (ranked fth) (Table I).

The clonazepam falsi cation ratio is obtained by relating the number of its falsi cation reports to its sales during the same period. Clonazepam ratio was 1.3/million DDD per day in 2002, 2.0/million DDD per day in 2004 and 1.4/million DDD per day in 2006. In 2006 among all BZD and BZD like, ve BZD have a falsi cation ratio higher than 1/million DDD per day. Among them, unitrazepam ranks rst on falsi cation ratio (8.84/ million DDD per day), clonazepam second (1.42/million DDD per day), zolpidem branded form third (1.15/ million DDD per day), bromazepam branded form fourth (1.13/million DDD per day) and alprazolam branded form fth (1.11/million DDD per day). The other BZD have a falsi cation ratio lower than 1/million DDD per day.

OPPIDUM: From 1998 to 2006 in the OPPIDUM survey, patterns of BZD consumption changed with a decrease in reports of unitrazepam use and an increase in clonazepam use. Indeed, clonazepam switched from the 11th to the fourth rank for BZD use with ve reports in 1998, 59 in 2001, 88 in 2003 and 119 in 2006 (Figure 1).

In 2006, several modalities of BZD use have been analysed. Even if its number of report has decreased, unitrazepam ranks rst in several modalities of use like daily dose twice over maximum recommended dose, proportion of illegal acquisition, proportion of abuse/ dependence and proportion of withdrawal symptoms (Table II). Comparing with the other most reported BZD data, the proportion of users with daily dose twice over maximum recommended dose was higher with clonaze- pam than with the other most reported BZD excepted unitrazepam (12 vs. 3%,P< 0.001), the proportion of illegal acquisition was higher with clonazepam (23 vs.

14%,P< 0.01) and the proportion of abuse/dependence was higher with clonazepam (64 vs. 50%,P< 0.01).

Nevertheless, there were no signi cant differences Table IMost frequently reported benzodiazepines and benzodiaze- pine-like in suspicious prescriptions in 2002, 2004 and 2006 (OSIAP survey).

Name of drugs2002 n= 188 (%)2004 n= 206 (%)2006 n= 152 (%) Bromazepam 12.2 17.0 23.7 Zolpidem 21.3 25.2 20.4 Alprazolam 4.3 4.9 9.9 Zopiclone 6.9 9.2 9.2 Clonazepam 2.1 5.3 7.2 Flunitrazepam 30.3 12.6 7.2 Oxazepam 1.6 2.9 6.6 Lorazepam 5.9 5.3 5.9 Clonazepam abuse liability in France 635 ª2010 The Authors Fundamental and Clinical Pharmacologyª2010 Socie´ te´ Franc¸ aise de Pharmacologie et de The´ rapeutique Fundamental & Clinical Pharmacology25(2011) 633–641 between clonazepam and the most reported other BZD expected unitrazepam for the modalities ‘alcohol use concomitant’ and ‘withdrawal symptoms’.

Reimbursed drugs database of all subjects enrolled with the general health insurance scheme in two areas:

the rst study has been carried out to estimate the proportion of subjects with deviant behaviour among all the clonazepam consumers and to describe their char- acteristics [38]. In 2001, 9381 clonazepam users have been selected and their dispensings have been monitored over a 9-month period. A clustering method identi ed a sub-group of 1.5% of users with deviant behaviour.These subjects were younger than the others and mostly man. Clonazepam dosage was higher (10.8 vs. 2.1 mg/ day), so the number of dispensings (19.4 vs. 5.9) and the number of different prescribers (4.5 vs. 1.5) and phar- macies (5.9 vs. 1.3) during the 9-month period. The second study has been carried out to analyse in 2005 for each BZD and BZD like the total dispensed quantity, the total doctor-shopping quantity and their DSI [39].

Among all BZD, zolpidem and bromazepam have the most important total dispensed quantity, clonazepam ranks 12th (2005 kilo DDD) and unitrazepam 15th (1443 kilo DDD) (Figure 2). 0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 1998 1999 2000 2001 2002 2003 2004 2005 2006 % of declarations of drugs Flunitrazepam Bromazepam Clonazepam Clorazepate dipotassique Diazepam Oxazepam Zopiclone Zolpidem Figure 1Most reported benzodiazepines and benzodiazepine like among psychoactive drugs declared in OPPIDUM survey from 1998 to 2006. Table IIModalities of consumption of the most reported benzodiazepines and benzodiazepine-like in OPPIDUM study 2006. DDa> 2RDD b, (%)Concomitant alcohol use, (%)Illegal acquisition, (%)Abuse/dependence, (%)Withdrawal symptoms, (%) Bromazepam (n= 150) 1 35 17 51 52 Oxazepam (n= 143) 4 33 13 59 53 Diazepam (n= 122) 4 43 23 58 48 Clonazepam (n= 119) 12 31 23 64 56 Clorazepate dipotassique (n= 116) 1 24 17 54 50 Zopiclone (n= 106) 1 11 3 38 51 Alprazolam (n= 96) 0 26 8 47 51 Zolpidem (n= 68) 9 15 3 36 34 Flunitrazepam (n= 57) 40 38 47 82 69 aDaily dose.bMaximum recommended daily dose: the recommended daily dose in France for clonazepam is 0.05–0.1 mg/kg per day. In the OPPIDUM survey, the maximum recommended daily dose has been xed at 9 mg/day. 636 E. Fraugeret al. ª2010 The Authors Fundamental and Clinical Pharmacologyª2010 Socie´ te´ Franc¸ aise de Pharmacologie et de The´ rapeutique Fundamental & Clinical Pharmacology25(2011) 633–641 Concerning the DSI of each BZD, clonazepam pre- sented the second most important DSI (3%) after unitrazepam (30.2%) (Figure 3).

The clonazepam DSI was different according to the formulations: 6.2% for tablets and 0.7% for oral solutions.

DISCUSSION The assessment of abuse liability, including in particular preclinical and human laboratory studies, is an impor- tant element of drugs safety. Nevertheless, abuse liability is not determined only by its pharmacology character- istics but also by nonpharmacological factors (as indi- vidual, economic, cultural and social factors) [43–45].

Thus, it is important to complete these experimental results by data collected in the ‘real-life’ context. To assess the magnitude of drug abuse in France, a nationalsystem of drug abuse and dependence monitoring was set up in the 1990s [23]. Following a warning on a psychoactive drug, the network has to investigate the magnitude of its abuse liability using their different surveillance systems [24]. Because such a warning appears with clonazepam, Afssaps has decided to launch an of cial enquiry to assess clonazepam abuse liability based on a quantitative synthesis and analysis of available data using their epidemiological tools. The aim of the work presented here was to collect and analyse these data and to compare them with other BZD and BZD like.

First, this work con rms the important abuse liability of unitrazepam in France. Indeed, unitrazepam is known to be the most abused BZD and the most liked by drug users in France and in other countries [21,29,40,46,47]. This BZD has the higher DSI (30.2% in the two southern France areas studied and 42.8% in an other area) [39,40]. Moreover, in the OPPIDUM survey, this BZD ranks rst in several modalities of consumption that suggest an abuse liability. However, although it seems to be the most abused BZD, it is one of the less prescribed BZD according to OPPIDUM survey (ninth consumed BZD) or reimbursement database [48].

Moreover, its prescription has decreased in France as a consequence of the application of narcotic regulation in 2001. In parallel, there is an increase in clonazepam prescriptions and clonazepam might have replaced some unitrazepam prescriptions to drug addicts. This trend was also observed in Denmark [21].

Clonazepam abuse liability has been highlighted by each epidemiological tool analysed in this study. In OSIAP survey among all BZD reported, the number of clonazepam suspicious prescriptions has increased. More- over, in 2006, clonazepam has the second falsi cation ratio (1.42/million DDD per day) after unitrazepam 0 2500 5000 7500 10 000 12 500 15 000 17 500 20 000 22 500 25 000 Total dispensed quantity (KDDD) Zolpidem Bromazepam Lorazepam Alprazolam Lormetazepam Zopiclone Clorazepate Tetrazepam Prazepam Oxazepam Diazepam Clonazepam Clobazam Loprazolam Flunitrazepam Nordazepam Figure 2Total dispensed quantity (measured in kilo de ned daily dose ‘KDDD’) for the most delivered ben- zodiazepines and benzodiazepines like in 2005 (drugs reimbursed database of two areas). 0 1 2 3 4 5 6 7 8 9 10Doctor shopping indicator Benzodiazepines Real value 30.2 % Figure 3Benzodiazepines and benzodiazepines-like with a doctor- shopping indicator superior to 1.5% in 2005 (drugs reimbursed database of two areas).

Clonazepam abuse liability in France 637 ª2010 The Authors Fundamental and Clinical Pharmacologyª2010 Socie´ te´ Franc¸ aise de Pharmacologie et de The´ rapeutique Fundamental & Clinical Pharmacology25(2011) 633–641 (8.84/million DDD per day). In the OPPIDUM survey in 2006, clonazepam ranks second after unitrazepam on several modalities of consumption (12% of daily dose twice over maximum recommended dose, 23% of illegal acquisition, 64% of abuse/dependence). These data are signi cantly higher with clonazepam than with other BZD excepted unitrazepam. The particular place of clonazepam among BZD was con rmed by data from health reimbursement system. Indeed, clonazepam has the second most important DSI (3.0%) after unitraze- pam (30.2%) and before zolpidem (2.2%).

When evaluating drug abuse liability in ‘real life’, it is also important to take into account other factors as regulation, prescription habits or pharmacology.

Concerning regulation, among all BZD, two of them ( unitrazepam in 2001 and clorazepate in 2005) are concerning by the application of narcotic regulation.

Moreover, in France, because its only indications are partial or generalized seizure disorders, clonazepam is not included in hypnotic or anxiolytic drugs list like other BZD [49]. This list limits its prescription to several weeks (4 weeks maximum for hypnotics and 12 for anxiolytics).

Concerning prescription habits, OSIAP survey and reimbursement database take into account this factor.

Indeed, in OSIAP survey, the falsi cation ratio denomi- nator is the BZD sales and in reimbursed database, the DSI denominator is the total dispensed quantity. Among all BZD dispensed to subjects af liated to the general health insurance system of two areas in 2005, clonaze- pam has the 12th total dispensed quantity whereas zolpidem ranks rst and bromazepam second. Zolpidem abuse and dependence has already been described by the CEIP network [24]. Nevertheless, according to the data presented in this work, its abuse ability seems to be less important than clonazepam. Indeed, in OSIAP survey, although zolpidem is the second most reported BZD among suspicious prescriptions in 2006, its falsi cation ratio is 1.15/million DDD per day for the branded form. In the OPPIDUM survey, 9% of zolpidem consumers have used it at a daily dose twice over maximum recommended dose and 3% have acquired zolpidem illegally. According to regional or national reimbursement/sales data, clo- nazepam is not the most prescribed BZD, nevertheless, its consumption has increased for several years, whereas BZD consumption (anxiolytics and hypnotics) has de- creased [48,50,51]. According to all these data, it seems important to follow clonazepam use because its use has increased and the increase in the drug availability can be a factor in uencing its misuse [45].Concerning pharmacology proprieties, clonazepam is a BZD with a pharmacodynamic activity similar to the others (hypnotic, sedative, amnesic properties…); how- ever, it has speci c pharmacodynamic properties (potent BZD) and speci c pharmacokinetic properties (long half- life…) [13,22,52]. According to its properties, some authors suggest that clonazepam could present a lower potential for abuse and dependence than other BZD [13].

However, clonazepam is an extremely potent drug (it can explain its potential abuse liability), it is eliminated much faster than other drugs [22]. Moreover, clonazepam is frequently detected in chemical submission cases (owing of its sedative activity) [53,54]. A recent published article by Steentoft et al. [21] has revealed that there was a vefold increase in forensic cases involving clonazepam in Denmark during the period 2002–2007.

It will be interesting to complete all these data with human abuse liability studies to compared the behavio- ural, subjective and reinforcing effects of clonazepam to those of other BZD [43,55,56].

Clonazepam abuse liability has been also highlighted in other countries [16–22]. In the United States, clonaze- pam is approved for use in treatment of panic disorders and seizures disorders. Concerning its abuse liability, according to DAWN network, among all BZD, clonaze- pam ranks in second position after alprazolam [57].

Each epidemiologic tool developed to improve the knowledge of drug use in the real-life conditions presents some limits. For example, the main limitation of OSIAP is the dif culty in achieving exhaustive detection of falsi ed prescriptions [26]. For OPPIDUM, the main limits may be the representativeness of the survey centres and the value of the self-reported drug use by drugs addicts. This survey is based on data from specialized addiction care centres. Although the included subjects may have more comorbidities and be more often polydrug users, all the described psychoactive drugs used are not necessarily problematic and can be appropriate. Indeed, in 2006, 36% of clonazepam consumption is used adequately (i.e.

out of abuse or dependence). The adequate use of BZD by opiate-dependent patients has already been described in an other study where, among buprenorphine users, 15% were BZD simple users and their characteristics were distinct from BZD problematic users (31% of the subjects) but not from BZD nonusers (54% of the subjects) [58]. In order not to focus only on data from specialized addiction care centres, this work takes into account data from general population. Nevertheless, the reimbursed drug database is not an exhaustive record of all the dispen- sings of clonazepam because a part of the population is 638 E. Fraugeret al. ª2010 The Authors Fundamental and Clinical Pharmacologyª2010 Socie´ te´ Franc¸ aise de Pharmacologie et de The´ rapeutique Fundamental & Clinical Pharmacology25(2011) 633–641 not covered by the general health insurance scheme (self-employed, farmers…) [33,38]. An other limitation is that some dispensed drugs can be not consumed but stolen, given or resale…[31,38]. Despite these limita- tions, the results obtained through each data source are concordant and strongly suggest the abuse liability of clonazepam in real life.

CONCLUSION Prescription drug abuse liability is affected by different factors as pharmacology, economic or sociocultural.

Abuse liability can be evaluated by data collected in ‘real life’. Concerning clonazepam, those data provide several arguments in favour of its abuse liability, which seems to be important in comparison with other BZD excepted unitrazepam. It will be interesting to complete those data by human abuse liability studies. Concerning other factors, clonazepam has speci c pharmacology proper- ties, its prescription has increased this last years and it is not submit to a speci c regulation. Regarding all these elements, Afssaps has taken several measures. A ‘Direct Health Care Professional Communication’ concerning the indications of clonazepam and the risk of its abuse liability has been sent to all health care providers as a rst warning [59]. Because this BZD is marketed in other several countries, it is also important to give this useful information to health care providers.

ACKNOWLEDGEMENTS The authors thank the network of CEIP. They gratefully acknowledge all specialized addiction care centres and all pharmacists who took part respectively in OPPIDUM and OSIAP surveys. We also thank Veronica Orleans for her work related to OPPIDUM database, Laure Pourcel for her work related to OSIAP database, Patrick Reggio and Franc¸ ois Natali for their helpful contribution and assis- tance concerning data from regional health reimbursed system.

CONFLICT OF INTEREST None.

REFERENCES 1 Wiffen P., Collins S., McQuay H., Carroll D., Jadad A., Moore A.

Anticonvulsant drugs for acute and chronic pain. Cochrane Database Syst. Rev. (2005)3CD001133.2 Wolkove N., Elkholy O., Baltzan M., Palayew M. Sleep and aging: 2. Management of sleep disorders in older people. CMAJ (2007)1761449–1454.

3 Smith P.F., Darlington C.L. Recent developments in drug therapy for multiple sclerosis. Mult. Scler. (1999)5110–120.

4 Winkler D., Willeit M., Wolf R. et al. Clonazepam in the long- term treatment of patients with unipolar depression, bipolar and schizoaffective disorder. Eur. Neuropsychopharmacol. (2003) 13129–134.

5 Curtin F., Schulz P. Clonazepam and lorazepam in acute mania:

a Bayesian meta-analysis. J. Affect. Disord. (2004)78201–208.

6 Patterson J.F. Withdrawal from alprazolam dependency using clonazepam: clinical observations. J. Clin. Psychiatry (1990)51 50–53.

7 National Institute on Drug Abuse. Prescription drugs abuse and addiction. National Institutes of Health publication. (2005) http://www.drugabuse.gov/PDF/RRPrescription.pdf [accessed on 2010 January 25].

8 McCabe S.E., Boyd C.J., Teter C.J. Subtypes of nonmedical prescription drug misuse. Drug Alcohol Depend. (2009)102 63–70.

9 Manchikanti L. Prescription drug abuse: what is being done to address this new drug epidemic? Testimony before the Sub- committee on Criminal Justice, Drug Policy and Human Resources. Pain Physician (2006)9287–321.

10 Manchikanti L., Singh A. Therapeutic opioids: a ten-year perspective on the complexities and complications of the escalating use, abuse, and nonmedical use of opioids. Pain Physician (2008)11S63–S88.

11 DAWN. National Estimates, Drug-Related Emergency Depart- ment Visits for 2004–2008. https://dawninfo.samhsa.gov/ data/ed/Nation/Nation_2008_NMUP.xls [accessed on 2010 July 01].

12 NSDUH. Results from the 2008 National Survey on Drug Use and Health: National Findings. http://oas.samhsa.gov/nsduh/ 2k8nsduh/2k8Results.pdf [accessed on 2010 July 01].

13 Chouinard G. Issues in the clinical use of benzodiazepines:

potency, withdrawal, and rebound. J. Clin. Psychiatry (2004) 657–12.

14 Buchanan N., Sharpe C. Clonazepam withdrawal in 13 patients with active epilepsy and drug side effects. Seizure (1994)3 271–275.

15 Galpern W.R., Lumpkin M., Greenblatt D.J., Shader R.I., Miller L.G. Chronic benzodiazepine administration. VII. Behavioral tolerance and withdrawal and receptor alterations associated with clonazepam administration. Psychopharmacology (1991) 104225–230.

16 Trudeau D.L. Clonazepam prescribing patterns and abuse by methadone patients in a medical center setting. J. Addict. Dis.

(1994)1399–107.

17 Manchikanti L., Brown K.R., Singh V. National All Schedules Prescription Electronic Reporting Act (NASPER): balancing substance abuse and medical necessity. Pain Physician (2002) 5294–319.

18 Sein Anand J., Chodorowski Z., Habrat B. Recreational ami- triptyline abuse. Przegl. Lek. (2005)62397–398.

Clonazepam abuse liability in France 639 ª2010 The Authors Fundamental and Clinical Pharmacologyª2010 Socie´ te´ Franc¸ aise de Pharmacologie et de The´ rapeutique Fundamental & Clinical Pharmacology25(2011) 633–641 19 Micallef J., Pradel V., Thirion X., Frauger E. and the CEIP Network. Indicators abuse and liabilities of benzodiazepines using OPPIDUM program. Fundam. Clin. Pharmacol. (2006) 20,150.

20 Mowla A., Firoozabadi A., Haghighi A.B., Sahraian A. Mega- dose clonazepam dependence: a case report. J. Clin. Psycho- pharmacol. (2007)27542–543.

21 Steentoft A., Linnet K. Blood concentrations of clonazepam and 7-aminoclonazepam in forensic cases in Denmark for the period 2002–2007. Forensic Sci. Int. (2009)18474–79.

22 Longo L.P., Johnson B. Addiction: Part I. Benzodiazepines – side effects, abuse risk and alternatives. Am. Fam. Physician (2000) 612121–2128.

23 Micaleff J., Jolliet P., Victorri-Vigneau C. et al. First Meeting of the French CEIP. Assessment of the abuse and pharmacode- pendence potential during drug development. Therapie (2008) 6355–65.

24 Victorri-Vigneau C., Dailly E., Veyrac G., Jolliet P. Evidence of zolpidem abuse and dependence: results of the French Centre for Evaluation and Information on Pharmacodependence (CEIP) network survey. Br. J. Clin. Pharmacol. (2007)64 198–209.

25 Thirion X., Micallef J., Barrau K., Djezzar S., Sanmarco J.L., Lagier G. Observation of psychoactive substance consumption:

methods and results of the French OPPIDUM programme. Eur.

Addict. Res. (2001)732–36.

26 Boeuf O., Lapeyre-Mestre M.; French Network of Centers for Evaluation and Information Pharmacodependence (CEIP).

Survey of forged prescriptions to investigate risk of psychoactive medications abuse in France: results of OSIAP survey. Drug Saf..

(2007)30,265–276.

27 Llau M.E., Lapeyre-Mestre M., Plas L. et al. Forged medical prescriptions in a community pharmacy network in Midi-Pyrenees area: assessment of a falsi cation ratio. Eur. J.

Clin. Pharmacol. (2002)57911–912.

28 Barrau K., Thirion X., Micallef J., Chuniaud-Louche C., Bellemin B., San Marco J.L. Comparison of methadone and high dosage buprenorphine users in French care centres. Addiction (2001) 961433–1441.

29 Modelon H., Frauger E., Laurenceau D., Thirion X., Mallaret M., Micallef J. Psychotropic drug addiction: consumption study of speci c population by the survey OPPIDUM 2004 from the CEIP network. Therapie (2007)62337–346.

30 Frauger E., Vigneau C., Orle´ ans V. et al. Consumption of cannabis among subjects with history of abuse/dependence or under an opiate maintenance therapy: OPPIDUM data in 2006 and main trends since 2004. Therapie (2008)63119– 127.

31 Micallef J., Pradel V., Thirion X. et al. Use of the health insurance database by the centres for evaluation and informa- tion on pharmacodependance: examples, interests and future prospects. Therapie (2004)59581–588.

32 Lapeyre-Mestre M., Llau M.E., Gony M. et al. Opiate mainte- nance with buprenorphine in ambulatory care: a 24-week follow-up study of new users. Drug Alcohol Depend. (2003)72 297–303.33 Thirion X., Lapierre V., Micallef J. et al. Buprenorphine prescription by general practitioners in a French region. Drug Alcohol Depend. (2002)65197–204.

34 Frauger E., Thirion X., Chanut C. et al. Misuse of trihexyphen- idyl (Artane, Parkinane): recent trends. Therapie (2003)58 541–547.

35 Victorri-Vigneau C., Basset G., Jolliet P. How a novel programme for increasing awareness of health professionals resulted in a 14% decrease in patients using excessive doses of psychotropic drugs in western France. Eur. J. Clin. Pharmacol.

(2006)62311–316.

36 Pradel V., Thirion X., Ron e E. et al. Assessment of doctor- shopping for high dosage buprenorphine maintenance treat- ment in a French region: development of a new method for prescription database. Pharmacoepidemiol. Drug Saf. (2004)13 473–481.

37 Pradel V., Frauger E., Thirion X. et al. Impact of a prescription monitoring program on doctor-shopping for high dosage buprenorphine. Pharmacoepidemiol. Drug Saf. (2009)1836– 43.

38 Frauger E., Pradel V., Natali F., Thirion X., Reggio P., Micallef J.

Misuse of clonazepam (Rivotril): recent trends. Therapie (2006) 6149–55.

39 Pradel V., Frauger E., Thirion X. et al. Comparaison of abuse potential of psychotropic medication in real life setting (abstract). Fundam. Clin. Pharmacol. (2007)2150. 40 Pradel V., Delga C., Rouby F., Micallef J., Lapeyre-Mestre M.

Assessment of abuse potential of benzodiazepines from a prescription database using ‘‘doctor shopping’’ as an indicator.

CNS Drugs. (2010)21611–620.

41 Guidelines for ATC Classi cation and DDD Assignment. Oslo, Norway: WHO Collaborating Centre for Drug Statistics Meth- odology. Available at: http://www.whocc.no/atcddd/ [accessed on 2010 January 25].

42 Strom B.L. Pharmacoepidemiology, 3rd edn. John Wiley & Sons, Ltd, West Sussex, England, 2000.

43 Carter L.P., Grif ths R.R. Principles of laboratory assessment of drug abuse liability and implications for clinical development.

Drug Alcohol Depend. (2009)105(Suppl 1) S14–S25.

44 Brady K.T., Lydiard R.B., Brady J.V. Assessing abuse liability in clinical trials. Drug Alcohol Depend. (2003)3(Suppl) S87–S95.

45 Gerada C., Ashworth M. ABC of mental health. Addiction and dependence – I: illicit drugs. BMJ (1997)315297–300.

46 Mintzer M.Z., Grif ths R.R. An abuse liability comparison of unitrazepam and triazolam in sedative drug abusers. Behav.

Pharmacol. (2005)16579–584.

47 Woods J.H., Winger G. Abuse liability of unitrazepam. J. Clin.

Psychopharmacol. (1997)31S–57S.

48 Health reimbursed national system: data on reimbursed drug from 2002 to 2007. http://www.ameli.fr/l-assurance-maladie/ statistiques-et-publications/donnees-statistiques/medic-am- generic-am-biolam-lpp-am/medic-am-2002-2007.php [accessed on 2010 January 25].

49 Ministe` re de l’emploi et de la solidarite´ . Arreˆ te´ du 7 octobre 1991 xant la liste des substances de la liste I des substances ve´ ne´ neuses a` proprie´ te´ s hypnotique et/ou anxiolytique dont la 640 E. Fraugeret al. ª2010 The Authors Fundamental and Clinical Pharmacologyª2010 Socie´ te´ Franc¸ aise de Pharmacologie et de The´ rapeutique Fundamental & Clinical Pharmacology25(2011) 633–641 dure´ e de prescription est re´ duite [determining the list of substances with hypnotic properties and / or anxiolytic whose duration of prescription is reduced]. http://www.legifrance.

gouv.fr/jopdf/common/jo_pdf.jsp?numJO=0&dateJO= 19911121&pageDebut=15173&pageFin=&pageCourante= 15173 (accessed on 2010 January 25).

50 French Medicine Agency. Drugs data sales reports in hospitals and pharmacy from 1997 to 2007. Avril 2009.

51 Frauger E., Pauly V., Thirion X. et al. Estimation of clonazepam abuse liability: a new method using a reimbursed drug database. Int. Clin. Psychopharmacol. (2009)24318–324 http://www.afssaps.fr/var/afssaps_site/storage/original/ application/bf1436c1cc9d8e8d8771ab85c410dc.pdf [accessed on 2010 January 25].

52 O’brien C.P. Benzodiazepine use, abuse, and dependence. J. Clin.

Psychiatry (2005)6628–33.

53 Che` ze M., Duffort G., Deveaux M., Pe´ pin G. Hair analysis by liquid chromatography–tandem mass spectrometry in toxico- logical investigation of drug-facilitated crimes: report of 128 cases over the period June 2003–May 2004 in metropolitan Paris. Forensic Sci. Int. (2005)1533–10.

54 Djezzar S., Questel F., Burin E., Dally S.; the French Network of Centers for Evaluation and Information on Pharmacodepen-dence. Chemical submission: results of 4-year French inquiry.

Int. J. Legal Med.. (2009)123,213–219.

55 Busto U.E., Kaplan H.L., Wright C.E. et al. A comparative pharmacokinetic and dynamic evaluation of alprazolam sus- tained-release, bromazepam, and lorazepam. J. Clin. Psycho- pharmacol. (2000)20628–635.

56 Farre´ M., Tera´ n M.T., Cam ´ J. A comparison of the acute behavioral effects of unitrazepam and triazolam in healthy volunteers. Psychopharmacology (Berl). (1996)125 1–12.

57 Drug Abuse Warning Network, 2006: National Estimates of Drug-Related Emergency Department Visits – 2008. http:// dawninfo.samhsa.gov/ les/ED2006/DAWN2k6ED.pdf (accessed on 2010 January 25).

58 Lavie E., Fatse´ as M., Denis C., Auriacombe M. Benzodiazepine use among opiate-dependent subjects in buprenorphine main- tenance treatment: correlates of use, abuse and dependence.

Drug Alcohol Depend. (2009)99338–344.

59 Informations sur le bon usage du RIVOTRIL [Information on good use of RIVOTRIL ]. AFSSaPS, Saint Denis; July 2008 http://www.afssaps.fr/content/download/12807/155809/ version/1/ le/ddl-rivotril-072008.pdf (accessed on 2010 January 25). Clonazepam abuse liability in France 641 ª2010 The Authors Fundamental and Clinical Pharmacologyª2010 Socie´ te´ Franc¸ aise de Pharmacologie et de The´ rapeutique Fundamental & Clinical Pharmacology25(2011) 633–641 Copyright of Fundamental & Clinical Pharmacology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.