Identification of abuse and dependence cases through a hospital database.

UNLABELLED: Computerized hospital databases are used for clinical and economic research. In France, the hospital administrative database, Programme de médicalisation des systèmes d'information (PMSI), could be an interesting means for identifying cases of abuse and dependence in hospitals. PURPOSE: To assess the capability of PMSI to identify cases of abuse and dependence (medicines or illicit drugs; tobacco and alcohol not included). METHODS: Cross-sectional study, from October 1 to December 31, 2008, in teaching hospitals of Bordeaux. All hospitalizations with an ICD-10 code related to possible abuse or dependence were selected. Cases were validated by a committee composed of three pharmacologists using discharge summaries. RESULTS: Among the 34 816 patients registered in the PMSI during the study period, a total of 227 patients were pre-selected as potential cases; 21 patients, hospitalized for abuse or dependence, or complications of which, were included in the analysis. Mean age was 35 years. Substances implicated were buprenorphine (n = 8), benzodiazepines (n = 7), cannabis (n = 6), cocaine (n = 4), heroin (n = 3), amphetamine, ecstasy, morphine, codeine, and tramadol (n = 1, respectively); there was polydrug use in six cases. CONCLUSIONS: The PMSI database can be useful to identify certain cases of abuse and dependence. This pilot study has been conducted at a local level; as the PMSI is available in all hospital settings in France, further analysis could be done at the regional and national levels. Such data could be a valuable indicator to analyze trends and assess the medical consequences of substance abuse.

False discovery rate estimation for frequentist pharmacovigilance signal detection methods.

Pharmacovigilance systems aim at early detection of adverse effects of marketed drugs. They maintain large spontaneous reporting databases for which several automatic signaling methods have been developed. One limit of those methods is that the decision rules for the signal generation are based on arbitrary thresholds. In this article, we propose a new signal-generation procedure. The decision criterion is formulated in terms of a critical region for the P-values resulting from the reporting odds ratio method as well as from the Fisher's exact test. For the latter, we also study the use of mid-P-values. The critical region is defined by the false discovery rate, which can be estimated by adapting the P-values mixture model based procedures to one-sided tests. The methodology is mainly illustrated with the location-based estimator procedure. It is studied through a large simulation study and applied to the French pharmacovigilance database.

[Psychiatric adverse effects of fluoroquinolone: review of cases from the French pharmacologic surveillance database]. / Effets indésirables psychiatriques des fluoroquinolones: cas notifiés à la pharmacovigilance française.

INTRODUCTION: Psychiatric adverse effects of fluoroquinolones are known for long, but can sometimes be missed. We analyse cases spontaneously reported to the French pharmacovigilance. METHODS: Cases of psychiatric adverse effects with fluoroquinolones reported to the French pharmacovigilance system were analysed. The studied period was from January 1985 and June 2002. Data analysed included age, sex, adverse effect, fluoroquinolone, seriousness and evolution. RESULTS: Five hundred ninety cases have been reported concerning 273 males and 316 females (sex unknown in 1 case). Mean age was 66 years (median: 70, range: 12-102). The most frequently reported psychiatric adverse effects were confusion (51%), hallucinations (27%), agitation (13%), delusion (12%), insomnia (8%), somnolence (4%) (several adverse effects could be associated in a single patient). Serious cases represented 21.7% (resulting in hospitalisation in most cases). Evolution was favourable in most cases (88.5%), and was unknown in 9.5% of cases. CONCLUSION: The number of cases reported during this period is moderate, but under-reporting probably interferes. The eventuality of this kind of adverse effect with fluoroquinolones should be kept in mind. Dose should be adjusted to renal function, especially in older patients.

Acute Methiopropamine Intoxication After "Synthacaine" Consumption.

Use of methiopropamine (MPA), a synthetic metamfetamine analog, has been detected since 2011 in Europe, but there is limited information on its acute toxicity. A 30-year-old man was admitted to the emergency department in a confused state, with paranoid delusion, auditory and visual hallucinatory experiences, and incoherent speech following the use of "synthacaine" (a slang term derived from "synthetic" and "cocaine"). Toxicological screening for pharmaceuticals and drugs of abuse by liquid chromatography-diode-array detector, gas chromatography-mass spectrometry and liquid chromatography-tandem mass spectrometry (LC-MS-MS) detected MPA, which was subsequently quantified by a specific LC-MS-MS method. Of note, 13 h after presentation to the emergency department, the plasma concentration of MPA was 14 ng/mL. This case report confirms the toxicity of MPA and the need for toxicological analysis to confirm the substance actually ingested by users of new psychoactive substances.

Effectiveness and safety profile of leflunomide in rheumatoid arthritis: actual practice compared with clinical trials.

OBJECTIVE: Leflunomide, an immunosuppressant agent for treating rheumatoid arthritis, was first marketed in France in 2000. Three years after its launch, we sought to assess its prescription patterns in the real world of prescription and use, and to see if its efficacy and safety profiles observed during clinical trials were confirmed. METHODS: All patients treated with leflunomide from May 2000 to April 2003 in the Department of Rheumatology of the Bordeaux University Hospital were identified, and their treatment patterns and outcome ascertained. This was compared to data from clinical trials. RESULTS: 116 were included (mean age = 55 years, 70% women). Almost 21.7% stopped treatment for lack of efficacy (after a mean delay of 3.6 months), 16% for secondary loss of efficacy (median = 7 months), and 32% for the occurrence of an adverse event (half within 4 months). Over a similar time frame in clinical trials, in patients of about the same age and sex but with less severe disease, the corresponding figures were 7-17% for lack or loss of efficacy, and 14-22% for adverse effects. At one year of follow-up, the discontinuation rate was 70% in the cohort compared to 28-47% in clinical trials. DISCUSSION: The differences between the two populations confirm the need to conduct post-marketing studies in order to obtain better knowledge on the effectiveness and safety of a new drug. In many cases, a simple drug utilization study can provide relevant information on the degree of shift between populations included in clinical trials and those treated in real life.

Computerized comparison of six adverse drug reaction assessment procedures.

Several standardized assessment procedures are currently used in the evaluation of adverse drug reactions (ADRs). Disagreement in rating ADRs can result from between-raters variability and between-methods differences in weighting the evidence. We eliminated between-raters variability by computer simulation of 1134 ADRs (including all the possible combinations of criteria currently used) and by automatic rating using different algorithms adapted from six published methods. Percentage agreement (Po) and weighted kappa test (kappa w) between pairs of methods are always better than with randomized scores, but the strength of agreement is only moderate (0.26 less than Po less than 0.59; 0.14 less than kappa w less than 0.51). The weightings of criteria are evaluated in terms of sensitivity, specificity, and predictive values. Criteria are neither sensitive (0.41 less than Se less than 0.70) nor specific (0.18 less than Sp less than 0.63) and have poor predictive values. Disagreements on weightings are considerable for three major criteria: timing of event, dechallenge, and alternative etiologic candidates. We discuss some ways of improving reliability of ADR diagnosis.

Incidence of serious adverse drug reactions in general practice: a prospective study.

BACKGROUND: Many studies have been conducted to estimate the incidence and economic impact of adverse drug reactions. Most of these studies used historical data or were based on single hospital units. Little is known, however, about the frequency of serious adverse drug reactions in general practice. OBJECTIVE: To estimate the incidence of serious adverse drug reactions in the community. METHODS: A prospective study during 5 consecutive working days between March 1 and April 30, 1998, was conducted among a random representative sample of 254 general practitioners in Aquitaine, France. The main outcome measure was the number of serious adverse drug reactions (ie, resulting in death, life-threatening condition, hospitalization, incapacity, or sequel) observed by each general practitioner during the study period and validated by an expert panel. RESULTS: Thirteen validated serious adverse drug reactions, 2 of which were fatal (1 subarachnoidal hemorrhage with oral anticoagulant and 1 aplastic anemia with antineoplastics), were observed, resulting in an incidence density of 10.2 (95% confidence interval [CI], 5.4 to 17.5) per 1000 days of practice. Eleven case subjects (84.6%) were hospitalized. This represents an average of 2.6 cases per general practitioner per year, and 123,000 adverse drug reaction cases (95% CI, 65,400 to 210,000) for the 60,000 general practitioners in France. Antineoplastics and anticoagulants were the drugs most frequently involved, and blood dyscrasia and bleeding were the most frequent adverse drug reactions. CONCLUSION: This study, which is one of the few available that has prospectively measured the incidence of serious adverse drug reactions in general practice settings, confirms that serious adverse drug reactions are a major public health concern.

Power and weakness of spontaneous reporting: a probabilistic approach.

It has been clearly demonstrated that spontaneous reporting remains one of the best ways for picking up new adverse drug reactions (ADRs) once a drug is on the market. The probability of revealing a new ADR by spontaneous reporting was studied as a function of reporting rate, strength of drug-event association (relative risk), background incidence of the event and number of patients treated. The model included determination of (i) the probability of reporting at least one drug-event association case and (ii) the overall probability of concluding that the drug-event association is not coincidental. Both probabilities were generally low. The results suggest that the identification of a new risk by spontaneous reporting implies a strong association between the drug treatment and the occurrence of the event.

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.

[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.

[Analysis of generic drug supply in France]. / Analyse de l'offre de médicaments génériques.

BACKGROUND: The list of generic medicines (LGM), published since 1997 by the Agence Française de Sécurité Sanitaire des Produits de Santé (AFFSSaPS), the French Medicine Agency, concerns a special part of the medicines reimbursed by the National Health Insurance (Social Security). The objectives of the present study were: i) to describe the components of this list, based on pharmaceutical, economical and therapeutic characteristics, ii) to study differences between generic and reference products (formulations, excipients, prices, etc.), iii) to analyze information on excipients provided to health care professionals. METHODS: The 21st version of the LGM (April 2001) was used. Therapeutic value was retrieved from the 2001 AFSSaPS report on the therapeutic value of 4490 reimbursed medicines. Information on excipients in the LGM and the Vidal dictionary (reference prescription book in France) was compared. RESULTS: The products included in the LGM represent 20% of all reimbursed medicines. The mean price differences between generics and their reference products vary between 30 and 50% for more than two thirds of the generic groups. The therapeutic value of the products of the LGM was judged important in 71% of cases (vs 63% for the 4409 assessed medicines) and insufficient in 13% of cases (vs 19%). Information on excipients is often missing and sometimes erroneous. CONCLUSION: Although the LGM is regularly revised and thus the generic market in perpetual change, the 2001 cross description of this pharmaceutical market provides much informations and raises some concern.

[Official systems of pharmacovigilance in France and in Spain. Comparison of spontaneous reporting in two regional centers: Pays Basque and Bordeaux]. / Les systèmes officiels de pharmacovigilance en France et en Espagne. Comparaison de la notification spontanée dans deux centres regionaux Pays Basque et Bordeaux.

This report compares the drug surveillance systems in France and Spain. The Spanish causality assessment method is explained. The Spanish and French drug surveillance systems are rather similar, but with some variations in the data analysis and differences between causality algorithms used. Spontaneous reporting in two drug surveillance centres, Aquitaine (Bordeaux, France) and in the Spanish Basque Country (SBC) (type of reports, reporting form) is compared. Reports received by the two centres during the year 1992 are presented. The SBC Centre has received more reports and differences in the source and type of effects were observed.

[Users of a regional center of pharmacovigilance]. / Correspondants d'un centre régional de pharmacovigilance.

We analyzed the users of the Bordeaux Regional Centre--defined as any person calling the Centre for an inquiry--between 1986 and 1991. During this 6-year period, 3,046 different users called our Centre. Among them, 2,578 (85%) called the Centre for the first time during this period and among them, more than 700 became regular users. The Bordeaux Centre works in regular cooperation with approximately 1,200 health professionals. This corresponds to the surveillance of 500,000 inhabitants.

[Substitution treatment for opiate dependence: survey of community pharmacies in Aquitaine]. / Les traitements de substitution de la dépendance aux opiacés: enquête auprès de pharmaciens d'officine en aquitaine.

The prescription of maintenance treatment for opioid dependence has increased dramatically in France since the approval of high-dose buprenorphine in general practice. Community pharmacists are particularly involved since daily dispensing is recommended. A postal survey was conducted within a representative network of community pharmacies in Aquitaine, south-western France. The objective was to assess quantitative and qualitative data on these treatments in the region through pharmacists' opinions and experiences. Out of 61 responders, 62 per cent had already dispensed maintenance treatment. During the survey, 88 patients were under treatment at these pharmacies. Nearly 80 per cent of the pharmacists agreed with the dispensing of these treatments and more than 60 per cent had a positive opinion of them. Community pharmacists feel concerned by the treatment for opioid dependence.

[Benzodiazepine consumption: survey of community pharmacies in Aquitaine]. / Consommation de benzodiazépines: enquête auprès de pharmaciens d'officine en aquitaine.

For many years, the use of benzodiazepines has been particularly high in France. This use can be described through pharmacy delivery. A cross-sectional one-day survey was conducted in June 1999, within a randomly selected network of community pharmacies in Aquitaine. Pharmacists were asked to interview each patient presenting with a prescription form including at least one benzodiazepine. A total of 58 pharmacies participated in this study; 328 patients were included representing 356 benzodiazepines prescribed. Among the 20 different benzodiazepines concerned, bromazepam, lorazepam and alprazolam represented more than half (54 per cent) of the prescriptions. The mean age of the patients was 62 years (median: 64) and 70 per cent of them were women. Most patients (93 per cent) were known to the pharmacist and 86 per cent had benzodiazepines prescribed by a single physician. In most cases (77 per cent), the prescribed benzodiazepine had been used for more than one year and in one quarter for more than five years. For 81 per cent of chronic users, no dose increase was observed. This study confirmed that long-term use of benzodiazepines is frequent, particularly in the elderly. This use is commonly accepted by health professionals as well as by patients, although it clearly reflects the dependence potential of benzodiazepines.

[The French system of evaluation of dependence: establishment in a legal system]. / Le système français d'évaluation de la pharmacodépendance et de l'abus: consécration juridique.

The French system of evaluation of dependence has been defined in the French Public Health Code by decree 99-249 of 31 March 1999. It was created by health authorities 10 years earlier and concerns dependence and abuse, which were previously just submitted to control under the designation of non-conforming use and misuse. The consultative function of the narcotics and psychotropics commission has been reinforced and its mission extended to include evaluation. Cooperation with different actors has been organized. This is based on the complexity of the methods of evaluation and the impact of decisions concerning control and/or information. The same principles organize the cooperation of this system at the European and international levels.

[Cost of hospitalizations for adverse drug effects]. / Coût des hospitalisations pour effet indésirable médicamenteux.

The French network of Regional Pharmacovigilance Centres evaluated in 1997 the prevalence of adverse effects of drugs (AED). In 1998, and again with the support of the French Drug Agency, in collaboration with the company CEMKA for economic evaluations, the incidence of AED-related hospitalizations in the medical department of French public hospitals was studied. The evaluation was performed over 14 consecutive days in 62 hospital departments, which were selected randomly. The total number of 3137 patients were hospitalized for a mean duration of 9 days and they were using a mean number of six different drugs. Taking into account the number of about 4 million patients admitted per year in the hospitals represented, it was estimated that the total number of AED-related hospitalizations amounts to about 130,000 annually (CI95%: 100,916-156,620). Using established cost calculations for hospitalized days (AP-HP, results of 1996) the mean cost for an AED-related hospitalization was estimated to be about FF16,000.

[Iatrogenic medication: estimation of its prevalence in French public hospitals. Regional Centers of Pharmacovigilance]. / Iatrogénie médicamenteuse: estimation de sa prévalence dans les hôpitaux publics français. Centres régonaux de pharmacovigilance.

The French network of Regional Centres of Pharmacovigilance has made an estimation of the occurrence of adverse drug reactions in a representative sample of patients in French public hospitals (departments of medicine, of surgery and of geriatrics). The study looked at one specific day in the spring of 1997. Each observed case of adverse drug reaction was validated. The total sample comprised 2132 patients of whom 969 were in a university hospital and 1163 in a general hospital. The hospitals and units concerned are representative of the country as a whole. One adverse drug reaction at least was present for 221 patients on the day of the investigation. This means a prevalence rate of 10.3 per cent (95 per cent CI: 8.7 to 11.9 per cent). In 33 per cent of cases (95 per cent CI: 26 to 42 per cent), the observed effects were rated as serious. From an incidence rate of 1.8 per cent (95 per cent CI: 1.0 to 25 per cent) on one specified day it can be estimated that in France an adverse drug reaction will occur in about 1,300,000 patients per year during a stay in hospital.

[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.