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In clinical trials, long-term use of a specific chondroitin sulphate, Chondrosulf® 400 (CS400) has demonstrated symptomatic efficacy in osteoarthritis comparable to that of nonsteroidal anti-inflammatory drugs (NSAIDs) with significantly fewer side-effects. CS400 could therefore reduce the use of and risks associated with NSAIDs. A cross-sectional observational study was therefore devised in 199 randomly selected pharmacies in France to verify the concomitant use of analgesic and NSAIDs medication in patients prescribed CS400. Consecutive patients filling a prescription for CS400 were prospectively recruited and classified into recent users (3 months or less of continuous use) and long-term users (more than 3 months of continuous use) of CS400. The main outcome measure was current and long-term use of analgesics and NSAIDs. The 844 participating patients included 623 (73.8%) women and 221 (26.2%) men. Mean age was 65.9 years. Ninety eight (11.6%) patients did not use any analgesic or NSAIDs for osteoarthritis; 746 (88.4%) reported the use of at least one of these drugs. Compared to recent users, long-term users of CS400 had a significantly lower current (44.4 versus 52.5%, p < 0.05) and long-term use of NSAIDs (11.8% versus 18.5%, p < 0.05), and of analgesics (70.3 versus 79.3%, p < 0.01).

Background. A major public health issue is to determine whether long-term benzodiazepine use may induce cognitive deficits persisting after withdrawal. The aim of the present review was to examine findings from prospective studies carried out in general population samples exploring whether exposure to benzodiazepines is associated with an increased risk of incident cognitive decline.Method. Using a MEDLINE search and a hand-search of related references in selected papers, we retrieved original studies published in peer-reviewed journals that explored in general population samples the association between benzodiazepine exposure and change in cognitive performance between baseline and follow-up assessment.Results. Six papers met the inclusion criteria. Two studies reported a lower risk of cognitive decline in former or ever users, two found no association whatever the category of user, and three found an increased risk of cognitive decline in benzodiazepine users.Conclusions. The discrepant findings obtained by studies examining the link between benzodiazepine exposure and risk of cognitive decline may be due to methodological differences, especially regarding the definitions of exposure and cognitive outcome. As a large proportion of subjects are exposed to benzodiazepines, a small increase in the risk of cognitive decline may have marked deleterious consequences for the health of the general population. This issue needs to be explored further by pharmaco-epidemiological studies.

Our aim was to explore the agreement between clinically collected information on purported drug intake and plasma data in intentional drug overdose. We included all subjects with intentional drug overdose above 15 years of age consecutively admitted to the Emergency Department of the University Hospital during 4 months. Information about drugs used and sources of this information was collected and compared to presence of drug in plasma, concerning four drugs with high toxic potential (tricyclic antidepressants, meprobamate, paracetamol and ethanol). Sensitivity, specificity, predictive positive and negative values of all sources of information pooled were assessed for each drug. 413 intentional drug overdoses were included, 66% with more than one drug. According to clinical information, 8% took tricyclic antidepressants, 11% meprobamate, 9% paracetamol and 41% ethanol. Systematic plasma assays confirmed this in 59% of cases for tricyclic antidepressants, 76% for meprobamate and ethanol, and 77% for paracetamol. Plasma concentrations were considered toxic in 28% of cases for tricyclic antidepressants, 65% for meprobamate, 43% for ethanol and never for paracetamol. Tricyclic antidepressants and meprobamate were found unexpectedly in 3%, paracetamol in 7% and ethanol in 6%. Toxic concentrations were found only with meprobamate. The risk of erroneous, clinically collected information was greater by excess (25 to 40% false positives) than by lack (3 to 7% false negatives). Thus, the consequences of erroneous, clinically collected information were probably more excess cost for the institution than medical risk for the patients. However these results found at the population level may not be true at an individual level.

Background Benzodiazepines (BZD) are commonly prescribed in the elderly. Persons with dementia may be at a greater risk of adverse reactions of BZD such as cognitive impairment. Objective To assess the prevalence of BZD use in Alzheimer's disease patients and to examine patient and drug-characteristics associated with this use. Design Cross-sectional study. Participants Five thousand community-dwelling and institutionalized patients initiating a treatment with tacrine for a mild to moderate Alzheimer's disease and included in the tacrine-study (Paco cohort). Measurements Patient characteristics and BZD use recorded at the inclusion. Main outcome Use of BZD during the 3 months prior to inclusion. Results The 3-month prevalence of ever use of BZD was 20%. After controlling for age and gender, there was a non-significant inverse association between BZD use and a score of Mini-Mental Status Evaluation (MMSE) below 24 (OR: 0.88, 95%CI: 0.71–1.09), and significant inverse association with an increased number of chronic conditions (OR: 0.73, 95%CI: 0.58–0.91). Higher use of BZD was associated with higher level of overall drug consumption (OR: 2.3, 95%CI: 1.97–2.80). Conclusion Alzheimer's disease patients are frequently prescribed BZD. A low score of MMSE (

Background Automated measures of reporting disproportionality in databases of spontaneous reports of adverse drug reactions are an emerging tool to identify drug-related alerts. Sertindole, a new atypical neuroleptic known to prolong the QT interval, was suspended in November 1998 because the proportion of reports of fatal reactions suggesting arrhythmia among all reports with sertindole was almost ten times higher than that for other atypical neuroleptics in the UK. This excess risk was not predicted in preclinical data and had not been found in premarketing trials. Method Reporting patterns over time were analysed. Prescription Event Monitoring (PEM) studies and a large retrospective cohort allowed for the comparison of actual death rates with atypical neuroleptics, and to assess which proportion of the deaths that occurred were reported. Results There were indications of possible skewing of reporting related to notoriety, surveillance and market size effects. Death rates in PEM studies were essentially similar between sertindole and other neuroleptics. Cardiac deaths had been two to three times more often reported than other causes of death. Conclusion Proportional reporting ratios indicate differential reporting of possible reactions, not necessarily differential occurrence. There was no indication of an actual increase of risk of all causes or cardiac deaths during sertindole treatment, but only an increased risk of its being reported. The suspension of sertindole was rescinded by Committee on Proprietary Medicinal Products (CPMP) in October 2001. Copyright © 2003 John Wiley & Sons, Ltd.

The objective of this article was to examine the possible association between benzodiazepine use and the risk of dementia in the elderly. This was a nested case--control study set in community settings in Bordeaux area, France. The participants were a representative sample of 3,777 elderly persons (65 years of age and older) followed from 1989 to 1997. The main outcome measures were the use of benzodiazepines in incident cases of dementia versus nondemented controls. On the basis of medical and psychological data, 150 patients were diagnosed with dementia according to the criteria of the third revision of the Diagnostic and Statistical Manual of Mental Disorders. Information on benzodiazepine use was obtained by face-to-face interview and visual assessment of patient's medicine chest by a trained neuropsychologist. After controlling for age, gender, education level, living alone, wine consumption, psychiatric history, and depressive symptomatology, ever use of benzodiazepines was associated with a significantly increased risk of dementia [adjusted odds ratio (OR), 1.7; 95% confidence interval, 1.2-2.4]. Former use was associated with a significantly increased risk of dementia (adjusted OR, 2.3; 95% CI,1.2-4.5). No association was found between dementia and the current use of benzodiazepines (adjusted OR, 1.0; 95% CI, 0.6-1.6). Our finding suggest that former use of benzodiazepines could be a risk factor for dementia, but more detailed investigation are needed.

Purpose Misuse and overuse of benzodiazepines (BZD) are common. Several studies have shown that benzodiazepines are frequently used in hospitalized patients, but fewer studies have been conducted to investigate whether BZD use increases during the hospital stay or whether patients have already taken BZD before admission. Objective to assess the prevalence of benzodiazepine use in hospitalized patients and to determine characteristics associated with this use. Methods Prospective study over a 4-month period based on all admissions to a department of internal medicine. The main outcome was the prevalence of benzodiazepine use at admission, during hospital stay and at discharge. Results Of 444 patients admitted, 147 (33%) used at least one benzodiazepine which was in 75% of the cases, short-elimination half-life BZD used as hypnotic. Of 105 (23.6%) patients using BZD at admission, 23 (5.2%) stopped BZD during hospital stay or when leaving hospital. The in-hospital prevalence of BZD use was 30% (133 patients). In 28 (6.3%) patients without BZD at baseline, BZD was introduced during the hospital stay then stopped at discharge in 18 (4%) patients. The prevalence of BZD use at discharge was 23.9% (106 patients). In multivariate analyses, BZD use was significantly associated with number of drugs taken during hospitalization (OR:1.13; 95% CI: 1.03–1.24), and current neuropsychiatric diseases (OR:2.12; 95% CI: 0.86–5.23), but not with gender, age or length of stay. Conclusion Prevalence of BZD use appeared to be fairly high among hospitalized patients. There were very few new BZD users during hospital stay, most of whom were stopped at discharge. Most treatments were started before hospital, and continued during and after hospital stay without clear reevaluation. Copyright © 2001 John Wiley & Sons, Ltd.

Objective Exposure in pharmacoepidemiologic studies can rely on various sources such as medical records, patient questionnaires, or plasma samples, which do not always concur. This study endeavored to compare sources of information on current exposure to benzodiazepines in elderly subjects. Methods In a study in a hospital admissions department, 1136 elderly subjects included in a case-control study each completed a structured questionnaire. In addition, an inspection of the medical records of each subject was performed, as well as screening of a plasma sample (high-pressure liquid chromatography–diode array detector) for current exposure to benzodiazepines. Results Benzodiazepines were found in the plasma of 33% of 1013 patients, in the records of 31% of patients, and in the questionnaires of 36% of 797 respondents. With use of the plasma results as a standard, questionnaires had 11% false positives and 28% false negatives; medical records had 14% false positives and 23% false negatives. The κ for concordance between questionnaires and records was 0.63. Most of the errors were related to the unexpected presence in plasma of clorazepate, commonly used as a hypnotic agent. Conclusions Patient recall and medical records are not reliable measures of current exposure to benzodiazepines in elderly persons, although this unreliability may be more marked with certain drugs used as hypnotic agents. Clinical Pharmacology & Therapeutics (2001) 69, 445–450; doi: 10.1067/mcp.2001.116147

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.

Objective: Adverse drug reactions (ADRs) are a major cause of hospital admission and in-hospital morbidity. Departments of internal medicine are at the forefront of this problem. To increase the knowledge base, we did a study of the frequency, hazard function, avoidability, and cost of ADRs as a cause for admission in internal medicine, or when occurring after admission. Methods: This prospective cohort study was based on all admissions to an internal medicine unit over a 4-month period. Patients were intensively followed in order to assess any ADR occurring during the hospital stay. Causality, direct costs, and preventability were assessed. Results: Of 444 admissions (2569 patient-days), 156 ADRs occurred in 116 patients (26.1% of all admissions); 95 (21.4%) of these had ADRs at admission, which were the reason for admission in 32 (7.2%). Twenty-one patients (4.7%) presented with 26 ADRs during hospitalization. The in-hospital ADR incidence rate was 10.1 per 1000 patient-days. The cost of ADRs leading to hospitalization was estimated at Euro 11,357 per hospital bed per year. Eighty percent of ADRs could be considered preventable. Conclusion: ADRs in hospitalized patients are common and often preventable. Since most ADRs occurred before admission, prevention strategies should preferentially target primary health care providers.

A retrospective, observational, cohort study in primary care. To determine the total direct medical and non-medical cost of chronic low back pain (LBP) in France and its associated factors. Chronic LBP affects 5-10% of the population its burden in France is unknown. Ninety-eight randomly selected general practitioners included 796 adult patients with chronic LBP between October 2001 and December 2002. Direct costs due to physician visits, investigations, medications, hospitalizations, and other medical and non-medical resource use were collected for the 6 months prior to study visit. Costs both reimbursed and not by the French health insurance system were considered. Quality of life (QoL) and disease severity were measured using Short Form (SF)-8 and Roland-Morris disability questionnaire (RMDQ), respectively. Costs were updated to represent 2007 prices. Men represented 50.6% of the 796 patients, mean age was 53 +/- 11.3 years, and the duration of LBP was more than 1 year in 80.9% of patients. The total mean cost per patient over six months was 715.6 euro (95% CI: 644.2-797.8). Of these costs, 22.9% related to care provided by physiotherapists and allied specialists, 19.5% to medications, 17.4% to hospitalizations, 9.6% to investigations, and 12.5% to physician fees. In multivariate analysis, the factors associated with the cost of chronic LBP were disease severity (RMDQ score) and age of the patients. LBP is a disease that is both common and costly.

Objective To assess how norepinephrine (NE), an emergency treatment of cardiovascular collapse, is used in intensive care. Methods Nurses and physicians of 14 intensive care units of the Bordeaux University Hospital were given questionnaires on the way they say they use NE and on actual NE treatment of patients. Results The clinical monitoring parameters cited were blood pressure, heart rate and hourly urine flow. Only 25% of the prescribers indicated the systematic use of hemodynamic monitoring. All the prescribers indicated they adapted the treatment to clinical objectives and blood pressure, and 77.5% to hourly urine flow. Initial NE concentrations ranged from 0.5 to 2 mg/ml, diluted in saline or dextrose. Initial prescribed dose ranged from 0.1 to 1 μg/kg/min. Large differences were observed between services and even within units. Conclusion These data clearly show the need for recommendations regarding the use of norepinephrine.

To investigate the prevalence of current use of benzodiazepines (BZDs) and related drugs in the French general population and factors associated with this use. National cross-sectional telephone survey conducted between 25 April 2001 and 8 May 2001 in a representative sample of non-institutionalized adults of BZD use and duration, prescriber specialty, socio-demographic data and mood and anxiety disorders, using a structured diagnostic interview. The prevalence of current use of BZD was 7.5%. It was higher among women (9.7%) than men (5.2%). It increased with age and was higher in the jobless (10.9). Duration of BZD use was more than 6 months in 75.9% of users and increased with age. Of the 711 (17.7%) subjects with at least one mood or anxiety disorder, 122 (17%) used BZD compared with180 (5.5%) of the 3296 subjects without mood or anxiety disorders. In multivariate analysis, factors associated with BZD use were age [odds ratio (OR): 3.6; 95% confidence interval (CI) 2.0–5.6], 6.5 (4.1–10.3) and 10.9 (6.9–17.1), respectively, for ages 35–44 years, 45–59 years and over 60 years compared with below 34 years, female gender (OR: 1.7; 95% CI 1.3–2.1), anxiety only (OR: 2.2; 95% CI 1.5–3.2), mood disorder only (OR: 4.4; 95% CI 2.7–7.1) or both mood and anxiety disorders (OR: 8.8; 95% CI 5.9–12.6). Despite precautions, warnings and attempts to limit use, there remains a high proportion of long-term BZD users in the general French population, especially in the elderly. Our findings add to the weight of opinion that messages concerning proper use of BZDs certainly need to be clarified and amplified.

Our aim was to explore the agreement between clinically collected information on purported drug intake and plasma data in intentional drug overdose. We included all subjects with intentional drug overdose above 15 years of age consecutively admitted to the Emergency Department of the University Hospital during 4 months. Information about drugs used and sources of this information was collected and compared to presence of drug in plasma, concerning four drugs with high toxic potential (tricyclic antidepressants, meprobamate, paracetamol and ethanol). Sensitivity, specificity, predictive positive and negative values of all sources of information pooled were assessed for each drug. 413 intentional drug overdoses were included, 66% with more than one drug. According to clinical information, 8% took tricyclic antidepressants, 11% meprobamate, 9% paracetamol and 41% ethanol. Systematic plasma assays confirmed this in 59% of cases for tricyclic antidepressants, 76% for meprobamate and ethanol, and 77% for paracetamol. Plasma concentrations were considered toxic in 28% of cases for tricyclic antidepressants, 65% for meprobamate, 43% for ethanol and never for paracetamol. Tricyclic antidepressants and meprobamate were found unexpectedly in 3%, paracetamol in 7% and ethanol in 6%. Toxic concentrations were found only with meprobamate. The risk of erroneous, clinically collected information was greater by excess (25 to 40% false positives) than by lack (3 to 7% false negatives). Thus, the consequences of erroneous, clinically collected information were probably more excess cost for the institution than medical risk for the patients. However these results found at the population level may not be true at an individual level.

Benzodiazepines (BZD) are commonly prescribed in the elderly. Persons with dementia may be at a greater risk of adverse reactions of BZD such as cognitive impairment.To assess the prevalence of BZD use in Alzheimer's disease patients and to examine patient and drug-characteristics associated with this use.Cross-sectional study.Five thousand community-dwelling and institutionalized patients initiating a treatment with tacrine for a mild to moderate Alzheimer's disease and included in the tacrine-study (Paco cohort).Patient characteristics and BZD use recorded at the inclusion.Use of BZD during the 3 months prior to inclusion.The 3-month prevalence of ever use of BZD was 20%. After controlling for age and gender, there was a non-significant inverse association between BZD use and a score of Mini-Mental Status Evaluation (MMSE) below 24 (OR: 0.88, 95% CI: 0.71-1.09), and significant inverse association with an increased number of chronic conditions (OR: 0.73, 95% CI: 0.58-0.91). Higher use of BZD was associated with higher level of overall drug consumption (OR: 2.3, 95% CI: 1.97-2.80).Alzheimer's disease patients are frequently prescribed BZD. A low score of MMSE (24) is associated with a decreased use of BZD. These results suggest important differences in BZD use patterns among persons with Alzheimer's disease.

Objective : The putative role of neuroleptics in the known excess mortality of subjects with schizophrenia remains disputed. The aim of this study was to assess the link between mortality and the class of neuroleptic. Method : Causes of death (suicide, cardiovascular, etc.) and exposure to neuroleptics were studied in a cohort of 3474 patients with schizophrenia followed from 1993 to 1997. Results : From 1993 to 1997, 178 patients died. The risk of all-cause death (OR=1.59; 95% CI 1.02–2.50; p =0.04), and suicide (OR=2.22; 95% CI 1.24–3.97; p =0.006) were increased in users of thioxanthenes (alone or associated with other drugs), and increased risk of “other causes” of death was associated with use of atypical neuroleptics (OR=2.06; 95% CI 1.15–3.70; p =0.0016). Conclusion : Our findings suggest the existence of association between certain classes of neuroleptics and death, all cause or specific. This could be related to the drug itself or to patient selection.

Aims Uncertainty as to relative under-reporting plagues the comparisons of spontaneous reporting rates as a tool for decision-making in pharmacovigilance. However, it is generally accepted that under-reporting should be reasonably similar for similar drugs sharing the same indication, country and period of marketing. To test this, we compared the adverse drug reaction reporting rates to the French regional pharmacovigilance centres for six pairs of identical drug marketed at the same time by different companies under different brand names (co-marketing). Methods All reaction reports were related to sales, to compute reporting rate; within each pair, the reporting rate ratio and its confidence interval were calculated. Results The rate ratios were all between 0.76 and 1.33. Two of them were significantly different from 1 (1.28; 95% C.I. [1.01; 1.60] and 1.33; 95% C.I. [1.06; 1.74]). Conclusions These small differences in reporting rates would not warrant regulatory action and support the usual assumption of similar reporting for similar drugs.

Alcohol, especially wine, may be the most commonly used anxiolytic. France is a country which has among the highest per capita use of wine and of benzodiazepines [1, 2]. It is not known whether these are used as a complement to one other, or as substitutes. To explore this, we examined the relationship of current wine intake to benzodiazepine (BZD) use in a cohort of community residents, 65 years and older living in the area of Bordeaux, France, included in the Paquid program in 1989 (n = 3777) [3]. Usual daily intake of wine was estimated from a questionnaire on food habits. Daily wine consumption was divided into: (i) none, (ii) moderate: up to 0.25 l day−1 and (iii) heavy: more than 0.25 l day−1. Benzodiazepine use was recorded on adhoc questionnaires including visual control of patient pharmacies. Multivariate unconditional logistic regression was used to calculate the odds ratios (ORs) and 95% confidence intervals (95% CIs) for BZD use and wine consumption, after adjustment for potential confounding variables (age, gender, living alone, depressive symptomatology evaluated by the Center for Epidemiological Studies-Depression (CES-D) scale, global cognitive decline defined as a Mini-Mental State Examination (MMSE) score lower than 24, education level and subjective health assessment). Table 1 shows the baseline characteristics of the 3767 persons (99.7%) for whom wine consumption was available. Current use of benzodiazepines was inversely correlated to drinking patterns: 37.4% of non-drinkers used BZD, compared with 31.3% of moderate drinkers (unadjusted OR 0.76; 95% CI 0.66, 0.88; adjusted OR 0.99; 95% CI 0.85, 1.16), and 19.3% of heavy drinkers (unadjusted OR 0.40; 95% CI 0.32, 0.50; adjusted OR 0.70; 95% CI 0.52, 0.94) (Table 2). This relationship was essentially unchanged during subsequent follow-up of the same population. Table 1 Baseline characteristics of the cohort. Table 2 Unadjusted and adjusted odds ratios (ORs) for benzodiazepine use dependent on wine consumption. Heavy wine consumption (> 0.25 l day−1) is associated, in the 65 years old and above population, with a lower use of benzodiazepines, contrary to the finding of Finnish doctors [4]. The direction of a possible causality is uncertain, and the relative health benefits between wine and benzodiazepines to treat anxiety could be a matter of debate [5].