Use of proton pump inhibitors in adults in France: a nationwide drug utilization study.

PURPOSE: Proton pump inhibitor (PPI) drugs are approved for the management of gastric acid-related diseases, mainly treatment of gastroesophageal reflux disease, treatment of nonsteroidal anti-inflammatory drugs (NSAID)-related gastrointestinal complications and prevention in at-risk patients, Helicobacter pylori eradication, and treatment of ulcers. PPIs are one of the most commonly prescribed drug class worldwide, and off-label use is widespread. The aim of this study was to describe outpatient PPI use of the whole adult population in France, based on the French National Health Data System (SNDS). METHODS: All individuals aged 18 years or older, with at least one dispensing for PPI between January 1, 2015 and December 31, 2015, were identified as PPI users. PPI users were considered as new users if they received no dispensing for PPI in the prior year. New users were followed until treatment discontinuation or up to 1 year, whichever occurred first. Characteristics of new users and of their PPI treatment were described, overall and separately by treatment indication. RESULTS: In total, 15,388,419 PPI users were identified in 2015 (57.0% women; mean age 57.0 years), accounting for 29.8% of the French adult population. Of them, 7,399,303 were new PPI users; mean treatment duration was 40.9 days, and 4.1% received a continuous PPI therapy lasting more than 6 months (10.2% among new users > 65 years versus 2.4% among those 18-65 years). For 53.5% of new users, indication for PPI therapy was a co-prescription with NSAID; in this indication, the large majority of patients (79.7%) had no measurable risk factor supporting a systematic prophylactic co-prescription of PPI. A proportion of 32.4% of new users did not have any identified comedication or inpatient diagnosis supporting an indication for PPI therapy; among them, only a small proportion (7.3% overall, and 8.4% of patients aged > 65 years) underwent a procedure investigating the digestive tract at the time of PPI initiation. CONCLUSION: The results of this study suggest PPI overuse in France, not always in line with the French guidelines. In particular, inappropriate co-prescription with NSAID was frequent. Efforts should be made to limit PPI treatment to appropriate indications and durations.

Paradoxical pustular psoriasis induced by ustekinumab in a patient with Crohn's disease-associated spondyloarthropathy.

Palmoplantar pustular psoriasis (PPP) is a clinical form of psoriasis, for which tumor necrosis factor alpha inhibitors (TNFi) or interleukins 12/23 inhibitor (ustekinumab) can be a therapeutic option. Paradoxical psoriatic reactions induced by TNFi are now well known. We present the exceptional case of a paradoxical PPP appeared under ustekinumab in a patient with Crohn's disease-associated spondyloarthropathy. A 58-year-old woman presented with recent peripheral inflammatory arthralgias appeared in the context of a Crohn's disease diagnosed in 2008. Three weeks after the first injection of ustekinumab 390 mg for a refractory Crohn's disease, a slight pruritic erythematous and pustular dermatosis appeared on the right hand palm. The clinical aspect was strongly in favor of a PPP. Ustekinumab was discontinued and replaced by golimumab, leading to a complete healing of PPP after 15 days of discontinuation. Causality assessment calculated using the French method was plausible for ustekinumab in the induction of PPP. It was based on a compatible chronology according to time to onset associated with complete recovery 2 weeks after cessation of treatment, and on the negative assessment of an alternative etiology (nor bacterial or viral infection, nor other treatment taken by the patient, nor previous history of psoriasis). The worsening of underlying psoriasis under ustekinumab through the appearance of generalized or palmoplantar pustules has already been reported in five cases. We describe to our knowledge the first case of paradoxical PPP under ustekinumab in a patient with no known underlying psoriasis.

Antibiotic-induced neurological adverse drug reactions.

Antibiotics are drugs widely used all around the world. Central nervous system adverse drug reactions (CNS ADRs) are mostly under-suspected with antibiotics. Nevertheless, these ADRs could lead to severe complications such as encephalopathy. To illustrate the clinical patterns of these off-target ADRs, we here present data from pharmacovigilance system, through different populations and points of view (worldwide, French population, vulnerable population and individual). These data could help clinicians to better know about CNS ADRs with antibiotics, to better identify risk factors and vulnerable patients and to highlight the importance to set up the right diagnostic explorations in the best timing to avoid complications. Clinicians should request a pharmacological opinion from pharmacologist (biologists and pharmacovigilance clinicians) in front of vulnerable population before or during antibiotics. Pharmacovigilance advice could help clinicians in the diagnosis and the management of an ADR. Therapeutic drug monitoring is particularly contributive to adjust doses of antibiotics administered in vulnerable patients. Pharmacovigilance advice and TDM are essential to perform personalized medicine, and contribute to the proper use of drugs.

What Do We Know About Medical Cannabis in Neurological Disorders and What Are the Next Steps?

Medical use of cannabis has been receiving growing attention over the last few decades in modern medicine. As we know that the endocannabinoid system is largely involved in neurological disorders, we focused on the scientific rationale of medical cannabis in three neurological disorders: amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease through pharmacological plausibility, clinical studies, and patients' view. Clinical studies (randomized controlled trials, open-label studies, cohorts, and case reports) exploring medical cannabis in these disorders show different results depending on the methods and outcomes. Some show benefits on motor symptoms and others on non-motor symptoms and quality of life. Concerning patients' view, several web surveys were collected, highlighting the real use of cannabis to relieve symptoms of neurological disorders, mostly outside a medical pathway. This anarchic use keeps questioning particularly in terms of risks: consumption of street cannabis, drug-drug interactions with usual medical treatment, consideration of medical history, and adverse reactions (psychiatric, respiratory, cardiovascular disorders, etc.), underlining the importance of a medical supervision. To date, most scientific data support the therapeutic potential of cannabis in neurological disorders. As far as patients and patients' associations are calling for it, there is an urgent need to manage clinical studies to provide stronger evidence and secure medical cannabis use.

[Post-marketing surveillance systems for psychoactive prescription drug abuse]. / Les systèmes d'évaluation de l'abus et de la dépendance des médicaments psychoactifs.

Drugs affecting the central nervous system form a unique group of products for surveillance because they could be misused, abused or diverted. Considering the characteristics of this behaviour that is often concealed, specific post-marketing surveillance systems have been developed to monitor abuse of prescription drugs in some countries. The purpose of this review is to list and to describe post-marketing surveillance systems, according their methodology, in France and in foreign countries. These programs are based on adverse effect notifications, medical or legal consequences of abuse, general or specific population-based survey, professional networks or medication databases. Some programs use simultaneously several information sources. In conclusion, the multifaceted nature, the diversity and the inventiveness of post-marketing surveillance systems reflects the complexity of the abuse issue.

Antiparkinsonian drug-induced sleepiness: a double-blind placebo-controlled study of L-dopa, bromocriptine and pramipexole in healthy subjects.

AIMS: To assess the sleepiness induced by pramipexole, a D2/D3-dopamine receptor agonist commonly used in Parkinson's disease and restless legs syndrome, without the problem of the confounding factors related to the disease. METHODS: Placebo, bromocriptine (2.5 mg), L-dopa (100 mg) and pramipexole (0.5 mg) were administered in a single oral dose on four separate days, with at least a 2-week wash-out period in a randomized cross-over design. Induced somnolence was assessed using Multiple Sleep Latency Test (MSLT) and subjective scaling of vigilance. Twelve male subjects (26.3 +/- 5.5 years old) without anxiety, mood, sleep or sedation disorders were enrolled. RESULTS: Pramipexole significantly reduced mean sleep latency compared with placebo 3 h 30 min [-6.1 min (-9.8, -2.4), P = 0.002] and 5 h 30 min [-5.6 min (-7.7, -3.5), P = 0.003] after administration. In addition, the total duration of sleep during the tests was higher with pramipexole than with placebo [+6.0 min (2.3, 9.7), P < 0.001]. These differences were not observed with L-dopa and bromocriptine in comparison with placebo. The induced sleepiness was not associated with an increase in subjective somnolence scaling, indicating that this adverse event may occur without prior warning. CONCLUSIONS: These results show that a single oral dose of pramipexole induces sleepiness as assessed by MSLT in healthy young subjects, independent of disease-related sleep dysfunction.

Assessment of abuse of tianeptine from a reimbursement database using 'doctor-shopping' as an indicator.

Doctor-shopping is a patient behaviour characterized by simultaneous consultations of several physicians during the same period. Some case reports have described an abuse of tianeptine, an atypical antidepressant. Our objective was to assess the extent of abuse of this drug with a method quantifying doctor-shopping in comparison with other antidepressants and benzodiazepines (BZD). All dispensations of antidepressants and BZD during the year 2005 in a French area of 4.5 million inhabitants were extracted from a reimbursement database. For each patient, two quantities were computed: quantity dispensed and obtained by doctor-shopping. Tianeptine and other drugs were compared using their doctor-shopping indicator (DSI), defined as the percentage of drug obtained by doctor-shopping among dispensed quantity; 410 525 patients received at least one antidepressant dispensation during the year 2005. Tianeptine was the sixth most dispensed antidepressant. The DSI of tianeptine was 2.0%, ranking it first among antidepressant (the second being mianserine with a DSI of 1%). Flunitrazepam has the highest DSI (30.2%), the DSI of the five following BZD (clonazepam, zolpidem, oxazepam, diazepam, bromazepam) range from 3.0% to 2.0%. Tianeptine is associated with higher DSI, compared with other antidepressants, suggesting that it may be subject to abuse in the population. Moreover, its DSI as a measure of diversion is similar to the DSI of diazepam or bromazepam.

Evidence of clonazepam abuse liability: results of the tools developed by the French Centers for Evaluation and Information on Pharmacodependence (CEIP) network.

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 identifies drugs obtained by means of falsified 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 falsified prescriptions among all BZD falsified 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 flunitrazepam. 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 flunitrazepam. All these data provide some arguments in favour of clonazepam abuse liability in real life and the necessity to reinforce its monitoring.

Amygdala activity correlates with attentional bias in PTSD.

Post-traumatic stress disorder (PTSD) is an anxiety disorder arising in the aftermath of a traumatic event. The most prevalent hypothesis is that of an increased amygdala activity to threat cues. The amygdala has also shown an implication in orienting attention toward threat. The aim of the study was to explore the correlations between amygdala activity, symptom severity and attentional bias in PTSD. Patients and healthy controls were assayed on an fMRI emotional face matching task and an attentional detection of target (DOT) task. The amygdala showed enhanced activity in PTSD (vs. controls). It positively correlated with anxiety scores and PTSD symptomatology. It also positively correlated with the disengagement index. Mostly, these results provide preliminary support for an implication of the amygdala in attention orientation to threat in PTSD. These results are further discussed in light of recent theories concerned with cortico-limbic functioning.

Use of intravenous immunoglobulins in clinical practice: data from three French university hospitals.

Since several years, the use of intravenous immunoglobulins (IVIg) has increased. This growth has encouraged some countries to publish guidelines. In parallel, some countries have conducted audits to know how IVIg are used in clinical practice in the light of the available guidelines. The objective of this study was to assess IVIg use in three French university hospitals in 2006. All IVIg administrations were evaluated during 6 months (12 September 2005-12 March 2006) in French university hospitals of Marseille. Different data were recorded for each administration: patient characteristics, indication, formulation and quantity. During the study period, 2802 administrations of IVIg (corresponding to a total quantity of 76 780 g) have been recorded. Four hundred and thirty-five patients received at least one of these administrations. The five most reported indications were multifocal motor neuropathy (11.0% of total quantity), chronic inflammatory demyelinating polyradiculoneuropathy (10.2%), corticoresistant dermatomyositis (10.2%), immune thrombocytopaenia (9.9%) and primary immune deficiency (9.1%). According to available French recommendations, 70% of the IVIg use was for 'acknowledged indications', 9% for 'indications to be assessed' and 18% for 'unwarranted indications'. The 10 most reported indications were 'acknowledged indications' according to available recommendations of the French expert group. Nevertheless, the two most reported indications were not approved by the French Health Products Agency (AFSSAPS) at the time of the study and were approved since.

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

BACKGROUND: Benzodiazepines are widely used for different purposes because of their pharmacological properties, but their abuse potential may represent a limitation to their use. Data suggest that this abuse potential may vary between products and available dosages. Doctor shopping (the simultaneous use of several physicians by a patient) is one of the most important ways in which prescription drugs, in particular benzodiazepines, are diverted. OBJECTIVE: To assess the potential for abuse of several benzodiazepines using doctor shopping in a French administrative area as a proxy for abuse. METHODS: All prescriptions reimbursed during the year 2003 in Haute-Garonne, France (one million inhabitants) for benzodiazepines that were available in ambulatory care through community pharmacies as solid oral forms were extracted from a reimbursement database. The benzodiazepines were alprazolam (0.25 mg, 0.50 mg), bromazepam 6 mg, clonazepam 2 mg, clorazepate (5 mg, 10 mg, 50 mg), diazepam (1 mg, 5 mg, 10 mg), flunitrazepam 1 mg, lorazepam (1 mg, 2.5 mg) and tetrazepam 50 mg. For each patient, the quantities prescribed, dispensed and obtained by doctor shopping (i.e. overlap between prescriptions from different prescribers) were computed. Benzodiazepines were compared using their 'doctor shopping indicator' (DSI, the percentage of each drug obtained through doctor shopping among the total reimbursed quantity). RESULTS: About 128 000 patients received at least one benzodiazepine during the year. Four groups of benzodiazepines were identified according to their abuse potential: very high abuse potential (flunitrazepam, DSI = 42.8%); high abuse potential (diazepam 10 mg, DSI = 3.2%; clorazepate 50 mg, DSI = 2.7%); intermediate abuse potential (alprazolam 0.50 mg, bromazepam, clonazepam, DSI ranging from 1.8% to 1.9%); and low abuse potential (other benzodiazepines and dosages, DSI ranging from 0.3% to 1.1%). CONCLUSION: The DSI can be used to assess the relative abuse liability of benzodiazepines and to detect signals of new patterns of abuse in settings where centralized records of prescription or deliveries are available for the great majority of patients.

Estimation of clonazepam abuse liability: a new method using a reimbursed drug database.

Some observations suggest the existence of clonazepam abuse. The aim of this study was to assess its magnitude in real life by a new method, using a prescription database, and to assess its evolution between 2001 and 2006. Individuals from a region affiliated to the French health reimbursement system, who had a prescription of clonazepam reimbursed between 1 January and 15 February of two selected years were included. Their deliveries were monitored over a 9-month period. After a descriptive analysis, a clustering method illustrated by a factorial analysis was used to identify different subgroups of clonazepam consumers. An increase of 82% in participants who had a delivery of clonazepam between 2001 and 2006 was observed. Using the clustering method, this study identified some deviant participants. This group comprises a higher proportion of males, benzodiazepine users, and buprenorphine users. The number of deliveries by different prescribers and pharmacies are higher. The proportion of deviant participants increased between 2001 and 2006 (from 0.86 to 1.38%). Our method can be used to assess the magnitude of abuse liability of clonazepam and is also interesting for following its evolution, two important keys for assessing patterns of abuse.