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The inherent risk of agranulocytosis associated with clozapine requires the realization of weekly white blood cell monitoring (WBCM) during the 18 first weeks of treatment. The aim of this study was to assess the compliance with WBCM during clozapine initiation for schizophrenia and Parkinson's disease (PD) subjects.The analysis was conducted using SNDS data on a cohort of new users of clozapine in 2018. We analyzed all reimbursements for WBCM from 2 weeks before the index date to 18 weeks after (optimal monitoring during hospitalization was assumed). The primary outcome was the proportion of good realization of WBCM according to different thresholds of completion (70%; 80%; 90%). Descriptive and comparative analyses with chi-squared test or Student's t-test were performed.Two hundred and ninety-six subjects were included. Rates of patients with WBCM realization over 70%, 80%, and 90% of WBCM expected were, respectively, 78.1%, 70.0%, and 56.9% for subjects with schizophrenia and 71.3%, 63.2%, and 47.8% for PD subjects. Only hospitalization during the follow-up period for schizophrenia subjects was significantly associated with good WBCM realization.We observed rather good results for compliance with clozapine initial monitoring. Other studies are needed to confirm our results.

Depression as well as a treatment by antidepressant are factors that may interfere with sexuality. Due to this complex relationship between depression, antidepressant and sexuality, it is difficult to incontestably establish the exclusive accountability of a treatment or of a psychiatric disorder on sexual dysfunctions. The main purpose of the SADD (for Sexuality, Anti-Depressant and Depression) study is to evaluate sexual dysfunctions in depressed men treated with antidepressant or not.Participants of this transversal, observational study were men aged over 18 years old, suffering from unipolar major depressive disorder and treated by a psychiatrist, with or without antidepressant. Assessment of sexual functioning through three times: euthymia (before depression), untreated depression and treated depression if applicable was performed based on the ASEX scale.Seventy patients were included. Eight percent of euthymic patients presented a sexual dysfunction (average score on the ASEX=12.4) whereas 56% of untreated patients presented a sexual dysfunction (average total score on the ASEX=17.7) and 62% (34/55) of patients treated with antidepressant (average total score on ASEX=18.5) (P0.001). Sexual functioning of men receiving treatment is not significantly different to that among men not receiving any antidepressant, even if patients treated with antidepressant reported that they had a better mood than those untreated.Our results reveal a high prevalence of sexual dysfunction within the framework of major depressive disorder and its treatment and underlines the complex relationship between major depressive disorder, antidepressant and sexuality.

Background: One of the most important issues for opiate maintenance therapy efficacy is the involvement of primary care physicians (PCPs) in opiate use disorder treatment, especially after referral from specialized units. This study aimed to analyze the progress of subjects in a specialized center and after referral to PCPs. Methods: This study was an observational prospective study. Recruitment took place in a specialized addictive disorder center in western France. All patients were evaluated (sociodemographical data, severity of substance use disorders through the TMSP scale, the quality of life through the TEAQV scale) by physicians during the 5-year-follow up of the study. Analysis focused on four main times during follow-up: entry/last visit into specialized care and into primary care. Results: 113 patients were included in this study, 93% were receiving methadone and 7% buprenorphine. Ninety (90) were referred to primary care. In primary care follow-up, the probability of the lowest severity score for substance use disorders remained stable over time. Conclusions: In daily practice, a center specialized in addictive disorders referred OMT management to PCPs for a majority of patients, and benefits regarding substance use disorders severity and quality of life remained stable after referral. Our results need to be confirmed.

Benzodiazepines (BZDs) and related drugs (Z-drugs) are mainly taken chronically, and older people are much more likely to take them on a chronic basis despite recommendations. Withdrawal symptoms could be an obstacle to stopping BZD/Z-drug administration. The main objective of this study is to estimate the prevalence of withdrawal symptoms in patients aged 65 years and older who have experience a stop of BZD/Z-drug. The secondary objectives are to describe the withdrawal symptoms and identify factors associated. This ancillary study was based on a national observational study in patients with chronic BZD/Z-drug consumption. Patients who made at least one BZD/Z-drug stop experience were selected. Withdrawal symptoms are described, and a logistic regression was carried out to identify the variables most associated with withdrawal symptoms. In total, 697 patients were selected: 78% experienced at least one withdrawal symptom after a stop administering BZDs or Z-drugs; most of the withdrawal symptoms were psychological disorders. Our study identifies a specific population experiencing withdrawal symptoms and who cannot stop administering BZD/Z-drug. We assume that withdrawal symptoms in patients with chronic use play an essential role in the nonstop use of BZD/Z-drugs.

(1) Background: Opioid use disorder (OUD) is a complex condition that can require long-term treatment. Pharmacological therapy for OUD involves treatment with opioid agonists (OMT) tailored to individual profiles. The aim of our study in daily clinical practice was to compare the profiles of patients treated with methadone (MTD) and those using buprenorphine (BHD or BHD-naloxone-NX). (2) Methods: A cross-sectional multicentre study explored the psychological, somatic and social profiles of patients with Opioid Use Disorder (OUD) following Opioid Maintenance Treatment (BHD, BHD/NX, or MTD). Descriptive and comparative analyses were performed (3) Results: 257 patients were included, a majority were men using heroin. 68% (178) were on MTD, 32% (79) were on BHD. Patients with MTD were significantly more likely to report socio-affective damage, and more likely to be younger and not to report oral or sublingual use as the main route for heroin or non-medical opioids (4) Conclusions: In daily clinical practice, regarding OUD damage, only socio-affective damage was significantly more prevalent among patients on MTD than among those on BHD in the multivariate model. Age and route of administration also differed, and our results could raise the issue of the type of OMT prescribed in case of non-medical use of prescribed opioids. These hypothesis should be confirmed in larger studies.

International audience

Points essentiels Le syndrome d’hyperemese cannabinoide se caracterise par une triade diagnostique : usage chronique de cannabis, troubles digestifs (nausees, vomissements cycliques et douleurs abdominales) et comportement compulsif de prise de bains ou douches chaudes. Il n’existe aucune recommandation pour la prise en charge du syndrome d’hyperemese cannabinoide. Le traitement du syndrome d’hyperemese cannabinoide est essentiellement symptomatique. Seul l’arret total de l’usage de cannabis est un moyen efficace pour prevenir la recidive des symptomes. La physiopathologie du syndrome reste peu claire. L’identification precoce des patients souffrant du syndrome d’hyperemese cannabinoide est essentielle pour reduire les couts materiels lies aux prises en charge repetees et la morbidite associee aux explorations complementaires.

International audience; Background: Posterior reversible encephalopathy syndrome (PRES) is a rare clinical and radiological entity characterized by a typical brain edema. Although several case reports have described PRES in a context of poisoning, to our knowledge, a comprehensive assessment has not been performed. The aim of this systematic review was to raise awareness on poisoning-specific PRES features and to encourage consistent and detailed reporting of substance abuse-and drug overdose-associated PRES. Methods: Medline/PubMed, Web of Science, and PsycINFO were screened through May 31, 2019, to systematically identify case reports and case series describing PRES associated with poisoning (i.e., alcohol, drugs, illicit drugs, natural toxins, chemical substances) in accidental context, intentional overdose, and substance abuse. The methodological quality of eligible case reports/series was assessed. Patients and exposure characteristics were recorded; relevant toxicological, radiological, and clinical data were extracted. Results: Forty-one case reports and one case series reporting 42 unique cases were included. The median time to PRES onset from the start of exposure was 3 days (IQR 2-10). Acute high blood pressure, visual disturbance, and seizure were reported in 70, 55, and 50% of patients, respectively. The initial clinical presentation was alertness disorders in 64% of patients. Nine patients (21%) required mechanical ventilation. One-third of patients had at least one risk factor for PRES such as chronic hypertension (17%) or acute/chronic kidney failure (24%). The main imaging pattern (67%) was the combination of classical parieto-occipital edema with another anatomical region (e.g., frontal, basal ganglia, posterior fossa involvement). Vasogenic edema was found in 86% of patients. Intracranial hemorrhage occurred in 14% of patients. Both brain infarction and reversible cerebral vasoconstriction syndrome were diagnosed in 5% of patients. Three patients (12%, 3/25) had non-reversible lesions on follow-up magnetic resonance imaging. The median time required to hospital discharge was 14 days (IQR 7-18). Mortality and neurological recurrence rate were null. Conclusions: Comorbidities such as chronic hypertension and kidney failure were less frequent than in patients with other PRES etiologies. Imaging analysis did not highlight a specific pattern for poisoning-induced PRES. Although less described, PRES in the context of poisoning, which shares most of the clinical and radiological characteristics of other etiologies, is not to be ignored.

International audience; Hypersexuality is a well-known adverse side effect of dopamine replacement therapy (DRT), and anti-craving drugs could be an effective therapeutic option. Our aim was to update the knowledge on this issue, particularly on the influence of an Opioid Receptor Mu 1 (OPRM1) genetic polymorphism. A systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. We also analyzed a case of iatrogenic hypersexuality that occurred in a patient treated with DRT. An analysis of the OPRM1 gene was performed on said patient. Our search identified 597 publications, of which only 7 were included in the final data synthesis. All seven publications involved naltrexone use. Five of them were case reports. None of the publications mentioned DRT side effects, nor did they report genetic data. Regarding our case report, the introduction of naltrexone corresponded with the resolution of the patient's hypersexuality. Moreover, the patient carried the A/G genotype, which has been reported to be associated with a stronger response to naltrexone for patients with an alcohol use disorder. Although studies are inconclusive so far, naltrexone could be an interesting therapeutic option for resistant hypersexuality due to DRT. Carrying the A/G genotype could help explain a good response to treatment.

Many studies were conducted to assess the benefit/risk ratio of EMONO (Equimolar Mixture of Oxygen and Nitrous Oxide) in France before it was authorized for use outside the hospital setting in 2009. The main objective of this project is to evaluate the effects sought and felt by children when EMONO is used in paediatric dentistry. The secondary objectives are to (i) evaluate the appreciation of EMONO by the children, (ii) characterize children who experience both analgesia and anxiolysis, (iii) evaluate children’s appetite for EMONO and characterize children with a high appetite and (iv) evaluate the impact of the difference in practice among the French dental service university hospitals on anxiety. The maintenance of a framework for the safe use of this drug, whose place in dental care is fundamental, is essential. Twelve of the 16 French dental service university hospitals agreed to participate in this study. MEOPAeDent is an observational, descriptive, transversal study that aims to evaluate the effects sought and felt by children when EMONO is used in paediatric dentistry. Subjects requiring dental care under EMONO are recruited by 12 French dental service university hospitals. Patients aged from 3 to 15 years are recruited for the study when they visit a dental service of a French university hospital requiring dental care under EMONO. The investigator collects the necessary data from the child’s medical records, from his own observations and from questions posed to the child and his/her parents. A survey is completed at the first and final sessions of dental care under EMONO. This study will provide an evaluation of the effects of EMONO on the French paediatric population in need of dental care as well as evaluate the appetite for the use of this substance. The results will first be used to provide additional data that is essential to monitor the use of a product with an authorization to use it outside of hospitals from 2009 in France, confirm its safety for use and justify its framework of application. ClinicalTrials.gov ID: NCT03453411 registered 2 March 2018.

International audience; Geophagia is a feeding behavior involving the regular intake of soil, including clay-like kaolin. Frequent in Africa, kaolin consumption is associated with heavy metal intoxication, iron and other micronutrient deficiencies, geohelminth infection and inactivation of concomitantly taken drugs. It is expected that this practice would be imported into an asylum country during the immigration process. To confirm this hypothesis, a single center, cross-sectional study was conducted at the University Hospital of Nantes, France, whose main objective was to assess whether the prevalence of kaolin consumers was high in a migrant population living in a large French metropolitan area (the city of Nantes). Each woman consulting for the first time at the Medical and Psychosocial Gynecology Obstetric Unit during the inclusion period ranging from January 1, 2017, to July 1, 2017, was asked for consent to be included in the study. The main outcome was the proportion of positive answers regarding consumption of kaolin within the last twelve months, with its 95% confidence interval (CI). A logistic regression was performed to identify drivers of consumption, and a clustering approach was conducted to identify profiles of consumers. A total of 284 women were included in the study, of whom 110 (38.7%) were pregnant. Our main finding was a 14.1% (95% CI: 10.5-18.6) prevalence of clay consumers. Second, the characteristic most strongly associated with consumption was Central or West Africa origin (adjusted Odds Ratio (aOR) = 52.7; 95% CI: 13.7-202.2). Finally, 60% of consumers showed signs of addictive-like phenomena, and three profiles were identified, depicting a continuum of patients in regard to their control over their kaolin consumption. Our results suggest that kaolin consumption is frequent in particular subpopulations of migrants. This warrants further study of the clinical consequences of kaolin consumption and its associated addictive-like symptoms.

International audience; Background: Many studies were conducted to assess the benefit/risk of equimolar mixture of oxygen and nitrous oxide (EMONO), but evaluating the appetite associated to its use is now getting very little attention in the literature. The purpose of this study was to investigate the effects present, felt, and sought during care by the child related with the 50% nitrous oxide/oxygen (EMONO) sedation used in pediatric dentistry. Materials and methods: All patients in consultation with the Dental Service of Nantes hospital and in need of EMONO were included in the study. In this prospective single-center study, the effects present, felt, and sought during care by the child and the assessment of EMONO appreciation were recorded. The presence of clear signs that the child was trying to extend the duration of the EMONO use was also sought. Results: Only 62% of the patients were presented with an anxiolytic effect, and 40% relative analgesia. Both effects were associated in 33% of children. Over the 76 patients assessed, 12 attempted to extend the duration of the EMONO use (16%). After a bivariate statistical analysis, none of the variables appeared significantly associated with the extension of the EMONO use duration. Conclusion: The significant proportion of patients who have prolonged the EMONO use seems to indicate a real attraction for nitrous oxide. This is the first study to evaluate nitrous oxide appreciation on a child. How to cite this article: Prud'homme T, Allio A, Dajean-Trutaud S, et al. Assessment of an Equimolar Mixture of Oxygen and Nitrous Oxide: Effects in Pediatric Dentistry. Int J Clin Pediatr Dent 2019;12(5):429-436.

International audience; AIMS: Our study aimed to evaluate the impacts of the cytochrome P450 (CYP) 2B6-G516T and CYP2D6 genetic polymorphisms on pharmacokinetic and clinical parameters in patients receiving methadone maintenance treatment. METHODS: Opioid PhArmacoLogy (OPAL) was a clinical survey of the sociodemographic characteristics, history and consequences of pathology associated with methadone maintenance treatment response and current addictive comorbidities. A subgroup of 72 methadone patients was genotyped. RESULTS: When comparing the three CYP2B6 genotype groups, the methadone (R)- and (S)-methadone enantiomer concentrations/doses (concentrations relative to doses) were different (P = .029, P = .0019). The CYP2D6 phenotypes did not seem to be relevant with regard to methadone levels. On multivariate analysis, neither the CYP2B6 genotype nor the CYP2D6 phenotype explained the (R)-methadone concentration/dose values (P~= .92; P = .86); the (S)-methadone concentration/dose values (P = .052; P = .95 [although there was a difference between the TT group and GT and GG groups \P = .019\]); or opiate cessation (P = .12; P = .90). CONCLUSION: The genotyping of CYP2B6 G516T could be an interesting tool to explore methadone intervariability.

Background: Nitrous oxide (N2O) is used worldwide for analgesia and anesthesia. It is also used for recreational purposes by some people. N2O can have major side effects (myeloneuropathy, delusions, emphysema) when used to excess. In France, N2O is available as an equimolar mixture of oxygen and nitrous oxide (EMONO). Its substance use disorder potential is monitored by the French Monitoring Centre for Addiction (CEIP-A) network. Our objective is to provide an overview of the substance use disorder potential of N2O in general, and of EMONO in particular. Methods: This paper is based on a systematic review of the literature for case reports involving N2O use disorder and on CEIP-A network cases involving EMONO use disorder. We characterized use disorder in accordance with DSM-5 ( Diagnostic and Statistical Manual of Mental Disorders, 5th Edition) criteria. Furthermore, we considered data relating to medical history, age, gender, and N2O consumption habits. Results: We identified 59 cases of N2O use disorder in the literature and 17 cases of EMONO use disorder from the CEIP-A network. More than 90% of the cases used N2O in larger quantities and for longer than intended. Conversely, more negative as opposed to positive cases have been documented regarding tolerance and failed attempts to reduce usage. Conclusions: A specific profile of substance use disorder starts to emerge from all the cases studied here. Furthermore, we identified another way N2O use disorder can appear: through exposure for medical purposes.

International audience

The question of the association between isotretinoin and the development of psychiatric disorders has been debated for the past 20 years. Some authors have argued that similar psychiatric symptoms or disorders could also be induced by other systemic retinoids1. However, few reports have included a formal assessment of the causal link between systemic retinoids and psychiatric disorders. This article is protected by copyright. All rights reserved.

International audience; INTRODUCTION: Co-occurring pain impairs depression's prognosis. Selective serotonin reuptake inhibitors (SSRIs) or serotonin and norepinephrine reuptake inhibitors (SNRIs) are first-line pharmacotherapies for depression and inhibit many cytochrome 2D6 enzymes. Codeine is a first-line treatment for pain and needs to be metabolized into morphine by cytochrome 2D6 to exert its analgesic effect. Concomitant prescription of both pharmacotherapies leads to inadequate analgesia. Areas covered: We performed a systematic review of the literature to amalgamate the current knowledge regarding the clinical effect of this association and quantified its prevalence in clinical practice in the French Pays de la Loire area using a retrospective observational cohort study design. Expert opinion: The literature review highlighted that antidepressants with moderate-to-strong inhibition of CYP2D6 should be avoided in patients receiving codeine. However, 0.44% of the 12,296 sampled patients received concomitant codeine and CYP2D6 inhibitor between January 2015 and June 2015. Switching drugs in both painful and depressive patients depends on the pain and depression subtypes. Promising drugs that both show an effect on pain and depression are currently being studied but are not usable in clinical practice. Until then, tailored communication reinforcement toward health-care professionals is needed to prevent these problematic occurrences of concomitant prescription administration.

Background Cannabinoid hyperemesis syndrome is a variant of cyclical vomiting syndrome in a context of chronic cannabis usage. Our aim was to compare French cases to those identified in the international literature in order to further our knowledge of the clinical criteria, pathophysiology and treatments for cannabinoid hyperemesis syndrome. Methods We analysed cases reported in the international literature up to 30 June 2017, obtained from the MEDLINE, PsycINFO and The Cochrane Library databases; we selected relevant articles based on title and abstract. We also analysed cases of cannabinoid hyperemesis syndrome reported to the French addictovigilance network. Results A systematic search through the three databases enabled us to identify 137 articles. Finally, 55 articles were selected as they involved reported cases. In total, 113 cases were reported in these 55 articles. We were thus able to analyse 29 reported French cases of cannabinoid hyperemesis syndrome. Cannabinoid hyperemesis syndrome mainly affects young male subjects who have been smoking cannabis daily for several years. Taking hot baths or showers is the most effective means of relieving the symptoms, while antiemetics and dopamine antagonists do not appear to effective for relieving nausea and vomiting. Conclusions French cases display the same characteristics as the cases identified in the international literature. The pathophysiology of cannabinoid hyperemesis syndrome is unclear and several hypotheses have been put forward in the literature. We have only begun to characterise the syndrome, though there is an outbreak of cannabinoid hyperemesis syndrome in France.

International audience; Baclofen is often prescribed in high doses to fight cravings experienced by alcohol-dependent patients. Such an increase in the availability of baclofen is concerning. This study aimed to determine the change in number and profile of self-poisoning with baclofen over time, as baclofen has become increasingly popular, in order to describe the severity of self-poisoning with baclofen and to focus on co-existing alcohol use disorders, and psychiatric illnesses determine predictors of severity. This was a retrospective study of self-poisoning with baclofen as reported by the western France Poison Control Center (PCC), which represents a population of more than 12 million people from January 2008 to March 2014. One hundred and eleven cases of self-poisoning with baclofen were reported to the western France PCC (62 males and 49 females; average age 39 +/- 12). Poisoning severities were as follows: 'null' (nine cases), 'minor' (37 cases), 'moderate' (19 cases) and 'high' (46 cases, including four deaths). The most frequently reported symptoms were neurological (45%) and cardiovascular (27%). The severity was significantly associated with psychiatric disorders (OR = 2.9; p = 0.03). Baclofen, prescribed in high doses, may lead to severe poisoning, particularly in patients with psychiatric illnesses. Authorities should put forward a new policy for prescribing the drug as a treatment for alcohol dependence.

International audience; BACKGROUND: Gamma-hydroxybutyrate (GHB) is a synthetic drug increasingly used by consumers of psychoactive substances. The sought after psychoactive effects of GHB have resulted in an increase in recreational use in Europe. GHB is considered to have a high dependence potential, and abrupt discontinuation after long-term use can result in a severe withdrawal syndrome. Despite a large number of publications related to GHB withdrawal and detoxification, to date, no evidence-based protocol or consensual international therapeutic guidelines are available (over and above the administration of benzodiazepines). We hereby present a day-to-day description of inpatient GHB detoxification management, from admission to discharge. CASE SUMMARY: This case report pertains to a 47-year-old patient hospitalized for a severe GHB use disorder. The patient had independently made several unsuccessful attempts to stop GHB use. Following to these failures, the patient was oriented to our addiction department for inpatient detoxification. Withdrawal symptoms appeared 4 hours after the last dose of GHB, and consisted of diaphoresis, coenesthetic hallucinations, tremors, motor instability, tachycardia, and a hypertensive peak. Symptoms were successfully managed with diazepam titration and nonpharmacological treatment. The duration of hospitalization was 13 days. At discharge, detoxification was complete and the patient was engaged in relapse prevention therapy. Three months after discharge, the patient had maintained abstinence. CONCLUSIONS: GHB withdrawal, which can be severe, is better prevented or attenuated by daily medical monitoring and adjustment of treatment dosage. Failure of outpatient detoxification should be included in the indication criteria in the guidelines for inpatient detoxification.

International audience; The use of psychoactive substances, whether occasional or regular, can induce a large number of clinical and/or biological complications. These complications may be related to the effects of the active substance itself and/or adulterants, but also to the modalities for use (administrations route, contexts of use). The detection and evaluation of these potentially severe complications are a public health issue. Beyond the assessment of the potential for abuse of and dependence on psychoactive substances, the collection and evaluation of complications related to the use of the substances are one of the roles of addictovigilance centres. In this article, the expertise of the French addictovigilance centres in the detection and assessment of medical complications related to psychoactive substances, adulterants or route of administration of substances is advanced through a few recent examples.

International audience; The high consumption of psychotropic drugs is a public health prob- lem. Rigorous statistical methods are needed to identify consumption characteristics in post-marketing phase. Agglomerative hierarchical clustering (AHC) and latent class analysis (LCA) can both provide clusters of subjects with similar characteristics. The objective of this study was to compare these two methods in pharmacoepidemiology, on several criteria: number of clusters, concordance, interpretation and stability over time. From a data set on bromazepam consump- tion, the two methods present a good concordance. AHC is a very stable method and provides homogeneous classes. LCA is an inferen- tial approach and seems to allow identifying more accurately extreme deviant behaviour.

International audience; BACKGROUND: French general practitioners (GPs) were enrolled in a new payment system in January 2012. As part of a national agreement with the French National Ministry of Health, GPs were asked to decrease the proportion of patients who continued their benzodiazepine treatment 12 weeks after its initiation and to decrease the proportion of patients older than 65 who were prescribed long half-life benzodiazepines. In return, GPs could expect an extra payment of up to 490 euros per year. This study reports the evolution of the corresponding prescribing practices of French GPs during that period regarding patients who were prescribed a benzodiazepine for the first time. METHODS: The national healthcare system's administrative database was used to report the longitudinal follow-up of two historical cohorts of French patients from the Pays de la Loire area. STUDY PATIENTS: The "2011" and "2012" cohorts included all patients who initiated benzodiazepine regimens from April 1 to June 30 in 2011 and 2012, respectively.The primary outcomes were the proportion of those study patients who continued benzodiazepine treatment after 12 weeks and the proportion of study patients >65 years who were prescribed long half-life benzodiazepines.Analyses were performed using a multi-level regression. RESULTS: In total, 41,436 and 42,042 patients initiated benzodiazepine treatment in 2011 and 2012, respectively. A total of 18.97% of patients continued treatment for more than 12 weeks in 2012, compared with 18.18% in 2011. In all, 27.43% and 28.06% of patients >65 years continued treatment beyond 12 weeks in 2011 and 2012, respectively. The proportion of patients >65 years who were prescribed long half-life benzodiazepines decreased from 53.5% to 48.8% (p < 0.005) due to an increase in short half-life benzodiazepine prescriptions. Patients >65 years who were prescribed short half-life benzodiazepines were more likely to continue treatment after 12 weeks (p < 0.005). CONCLUSIONS: Despite the pay-for-performance strategy, the number of short half-life benzodiazepine prescriptions increased between 2011 and 2012, and the number of long half-life benzodiazepine initiations remained unchanged. Reducing the proportion of long half-life benzodiazepine prescriptions might be counterproductive because prescribing short half-life benzodiazepines was associated with higher rates of continuation beyond the recommended duration.

During clinical development, the risk to the patient is monitored. However, when a health product is placed on the market, knowledge of its benefit-risk balance is only fragmentary. The post-marketing surveillance system, which makes it possible to update this balance, is based essentially on spontaneous reporting of adverse effects. What is the need for phase IV studies, in addition to clinical trial data and pharmacovigilance evaluation? The objective of our research is to study the complementary approach of phase IV studies and their interest in relation to phase III studies and pharmacovigilance data, by focusing on an example of a population that is little studied in clinical trials, the elderly, and old drugs, benzodiazepines and an effect occurring during long-term use, drug dependence. Our work shows that post-marketing studies are essential to know the risk and dependence profile of a drug, which evolves throughout its "life". Predicting possible situations of dependence, detour, etc. requires a good evaluation of the benefit-risk balance not only for medical use in the MA, but also in all off-label use situations, including non-medical use. These data are essential to understand the obstacles to the application of recommendations or regulations on proper use., Durant le développement clinique, une surveillance du risque encouru par le patient, est réalisée. Cependant, lors de la mise sur le marché d’un produit de santé, la connaissance de sa balance bénéfice-risque n’est que parcellaire. Le système de surveillance post AMM, qui permet d’actualiser cette balance, est basé essentiellement sur la notification spontanée d'effets indésirables. Quelle est la nécessité d’études de phase IV, en complément des données d’essais cliniques et de l’évaluation de pharmacovigilance ? L’objectif de nos travaux de recherche est d’étudier l’approche complémentaire des études de phase IV et leur intérêt par rapport aux études de phase III et aux données de pharmacovigilance, en se focalisant sur un exemple de population peu étudiée des essais cliniques, les sujets âgés, et de médicaments anciens, les benzodiazépines et un effets survenant lors de l’utilisation au long cours, la pharmacodépendance. Notre travail montre que les études post AMM sont primordiales pour connaître le profil de risque et de pharmacodépendance d’un médicament, évolutif tout au long de la « vie ». Prédire au mieux les situations éventuelles de dépendance, détournement, etc. nécessite une bonne évaluation de la balance bénéfice-risque non seulement de l’utilisation médicale dans l’AMM, mais aussi dans toutes les situations de off label use y compris les utilisations non médicales. Ces données sont indispensables pour comprendre les freins à l’applications des recommandations ou réglementation de bon usage.