Pharmacoepidemiological characterisation of zolpidem and zopiclone usage.

PURPOSE: Zolpidem and zopiclone are two widely used non-benzodiazepine hypnotics whose usage seems to be associated to pharmacodependence. However, to our knowledge, there has as yet been no published epidemiological study which has compared their abuse or dependence potential. We used a pharmacoepidemiological approach to identify and characterise zolpidem and zopiclone users in real life situations. METHODS: Regular users of zolpidem or zopiclone were identified in the database of a French regional health insurance organisation. A latent class analysis (LCA) was used to identify different subgroups of users of these two hypnotics. RESULTS: The study cohort comprised 25,168 patients who regularly used zolpidem and 21,860 who regularly used zopiclone. The results of the latent class analysis, which enables subgroups with similar patterns of response to be identified, revealed four clinical subtypes of users of zolpidem: non-problematic users, users with associations with hypnotics/anxiolytics or with associated mental disorders, and problematic users. Only three subgroups were identified for zopiclone, and LCA did not discriminate a special class of problematic users for this drug. CONCLUSION: Our analysis indicates that there is a subclass of zolpidem user suggestive of abuse; this was not the case for zopiclone. This methodology is very interesting because it allows analysis of databases and determination of a specific signature of drugs potentially leading to abuse or dependence.

[Anticoagulant (AVK) and antibiotic drug interactions in community practice]. / Intéraction médicamenteuse anti-vitamines K/antibiotiques en médecine de ville.

AIM: Anticoagulants (AVK) are frequently responsible for iatrogenic accidents leading to hospitalisation. Antibiotics (ATB) are likely to interact with AVK. The aim of this study was to assess if Loire region practitioners complied with the French agency for the safety of health products (AFSSAPS) recommendations for AVK/ATB association. METHOD: Two strategies were implemented: a retrospective study of the 2007 Loire region general health insurance data on a population exposed to a single AVK split in two groups, exposed or not to antibiotics; a focus-group of practitioners from the Maine et Loire subdivision. RESULTS: Blood tests were not always performed. The proportion of blood tests per month was significantly more frequent in the AVK/ATB group than in the group "not exposed" to antibiotics. GPs did not implement this recommendation, which doesn't correspond to their behaviour, as analysed by a focus-group, and to the low incidence of hospitalisations due to AVK/ATB interaction. CONCLUSION: Loire region practitioners do not follow AFSSAPS recommendations. AVK/ATB interaction must be a GP's constant concern whether responsible or not for initiating AVK.

Benzodiazepines and hip fractures in elderly people: case-control study.

OBJECTIVE: To determine whether benzodiazepines are associated with an increased risk of hip fracture. DESIGN: Case-control study. PARTICIPANTS: All incident cases of hip fracture not related to traffic accidents or cancer in patients over 65 years of age. 245 cases were matched to 817 controls. SETTING: Emergency department of a university hospital. MAIN OUTCOME MEASURES: Exposure to benzodiazepines and other potential risk or protective factors or lifestyle items. RESULTS: The use of benzodiazepines as determined from questionnaires, medical records, or plasma samples at admission to hospital was not associated with an increased risk of hip fracture (odds ratio 0.9, 95% confidence interval 0.5 to 1.5). Hip fracture was, however, associated with the use of two or more benzodiazepines, as determined from questionnaires or medical records but not from plasma samples. Of the individual drugs, only lorazepam was significantly associated with an increased risk of hip fracture (1.8, 1.1 to 3.1). CONCLUSION: Except for lorazepam, the presence of benzodiazepines in plasma was not associated with an increased risk of hip fracture. The method used to ascertain exposure could influence the results of case-control studies.

Spontaneous reporting of adverse drug reactions: who reports and what?

A survey among Bordeaux pharmacovigilance centre 'users' and 'non-users' was conducted in Aquitaine, France. Two hundred physicians having reported to the centre at least one adverse drug reaction (ADR) during the past 3 years were matched to a randomly selected sample of 400 physicians who did not report. They were asked to anonymously fill out a postal questionnaire collecting data on their individual characteristics, including their practice mode, and on ADRs that they observed and reported during the past 12 months. The number of questionnaires returned was 151 (25%), of which 76 were from users (38%) and 75 from non-users (19%). The two groups had very close individual characteristics. All but three responders had observed at least one ADR during the past 12 months. For the different types of ADRs defined in terms of seriousness and labelling, more users had seen ADRs than non-users but among those who observed them, the numbers of ADRs seen were similar in both groups. In any case, the more recent the drug, the more prone to report were the physicians.

Comparing the toxicity of two drugs in the framework of spontaneous reporting: a confidence interval approach.

Spontaneous reporting remains the most frequently used technique in post-marketing surveillance. Decision-making usually depends on comparisons between the number of adverse drug reactions (ADRs) reported for two drugs on the basis of an equivalent number of prescriptions. The validity of such comparisons is expected to be jeopardized by probable underreporting ADR cases. This problem is accentuated when it cannot be assumed that the magnitude of underreporting is the same for the both drugs. Differences in reporting ratios can overemphasize, cancel, or reverse the conclusions of a statistical comparison based on the number of reports. We propose a single method for (1) calculating confidence intervals for relative risks estimated in the context of spontaneous reporting and (2) deriving the range of reporting ratios for which the conclusion of the statistical comparison remains statistically valid.

False-positives in spontaneous reporting: should we worry about them?

Spontaneous reporting remains the most used and, undoubtedly, the most cost-effective approach for the identification of adverse drug reactions (ADRs). Most of the limitations of this method are well recognised but the possibility of receiving false-positive reports of coincidental drug-event associations has received little attention. In this paper we propose a method based on the Poisson distribution for computing the maximum number of reports of an ADR that could be expected to be reported coincidentally. Three parameters are required: (i) the background risk of the event in the reference population, (ii) the total number of patients treated with the drug considered and, (iii) the proportion of cases that have been reported to the pharmacovigilance system. For most empirical situations occurring in the post-marketing surveillance setting, the expected number remains low and only a maximum of one to three cases could be accepted as possibly coincidental. For rare adverse events such as agranulocytosis or toxic epidermal necrolysis, coincidental associations are so unlikely that a number of reports greater than three constitutes a strong warning and requires further investigation. These findings suggest that for rare events, reports of coincidental drug-event associations are too unlikely to be considered as an important limitation of spontaneous reporting.

[Organization and results of drug vigilance in France]. / Organisation et résultats de la pharmacovigilance en France.

Pharmacovigilance represents all methods of detection, assessment, information and prevention of adverse drug reactions (ADRs). It mainly involves the post-marketing phase because of the low probability of detecting all possible adverse effects of a drug during pre-marketing development. The most widely used method for pharmacovigilance is spontaneous reporting which is an excellent signal generator but precludes satisfactory calculation of incidence rates. The French Pharmacovigilance System has been set up in 1973; reporting of ADRs has been made mandatory in 1984 for prescribers. This system consists in a network of 30 regional centres under supervision of a coordinating committee at the French Drug Agency. The number of ADR cases received, assessed and recorded by the regional centres is around 10,000 per year; a similar number of cases are reported to the Drug Agency by the pharmaceutical industry. Moreover, Regional Centres work as Drug Information Centres answering more than 23,000 inquiries per year.

[Mode of action of non-narcotic analgesics]. / Modes d'action des antalgiques non morphiniques.

According to Lim's experiments, non-narcotic analgesics are usually considered as "peripherally" acting drugs. Conversely, most of these compounds were shown to easily cross the blood-brain barrier, and hence partly produce their effects by a central mechanism. The relative contribution of each site of action may vary from one drug to another. Aspirin-like drugs may act by inhibiting arachidonate cyclooxygenase in both the damaged tissues and the central nervous system. Finally, these drugs appear to be either selective, or dose-dependent, or nonspecific inhibitors of prostaglandin-synthetases.

Health measures correlates in a French elderly community population: the PAQUID study.

PAQUID is an epidemiologic prospective study of mental and functional aging. A sample of 4,050 community-dwelling individuals, aged 65 and over, was randomly selected from electoral lists of 37 parishes of Gironde after stratification by age, sex, and size of urban unit; 68.9 percent agreed to participate. Baseline information was obtained from a one-hour home interview. Health measures included ADL, IADL, mobility, Rosow scale, and two subjective health assessments. Depressive symptomatology was assessed by the CES-D scale and cognitive functioning by Folstein's MMS. Dependence rates vary from 9.7 percent to 71.9 percent according to the indicator under consideration. Cross-sectional correlations with dependence are significant for age, sex, education, rural setting, joint pain, dyspnea, hearing and visual impairment, MMS score, and depression. In logistic regressions, only dyspnea, MMS score, and depression are always significantly correlated with dependence, whichever the indicator.

[Computerized data processing in the Pharmacovigilance Center of Bordeaux-Aquitaine. Analysis of clientele of the Center]. / Gestion informatisée des données du Centre de Pharmacovigilance de Bordeaux-Aquitaine. Analyse de la clientèle du centre.

Practitioners inquiries addressed to our Drug Information Centre are computerized since 1986. Their analysis allows to pinpoint special problems and needs for practitioners information, and to detect new adverse drug reactions. Time series analysis of calls (according to the practitioners specialities or geographic stay) allows to evaluate the effectiveness of the services provided by the Bordeaux Drug Information Centre.