Observation of psychoactive substance consumption: methods and results of the French OPPIDUM programme.

This study presents a French programme designed to observe and evaluate psychoactive substance dependence and abuse. Annual surveys lasting 4 weeks are performed with drug users in drug centres. Its usefulness is discussed using examples from the study: potential for antidepressant dependence (amineptine), monitoring benzodiazepine use and consumption associated with maintenance treatments. Flunitrazepam is the most consumed benzodiazepine and often got by deal (29%). There are important differences between buprenorphine consumption in a maintenance treatment context (9/10) and beyond this context (1/10). The main methodology problems encountered are representativeness and validity of data. The limits of the programme and its role in the French health care system are discussed.

Recent evolution in opiate dependence in France during generalisation of maintenance treatments.

Two maintenance drugs had been used in France since 1996, methadone and high-dosage buprenorphine. This study aimed to examine changes in drug use from observations gathered between 1995 and 1997, within the framework of the French program for the monitoring of drug dependence (OPPIDUM). This annual survey studies psychoactive substances consumed by drug addicts attending specialised drug care centres. During the last three surveys, 16 centres collected a total of 1597 patient-files. This study shows an increase in the number of patients undergoing maintenance treatment (from 14 to 69%), a reduction in the number of intravenous drug users (from 55 to 22%) and a reduction in consumption of psychoactive substances. However, poly-drug addiction behaviour continues and high-dose buprenorphine subjects frequently use the substance intravenously and in association with benzodiazepines.

[Dependence on psychotropic drugs and substitution treatment: recent trends. The OPPIDUM study of the Centers for Evaluation and Information on Drug Dependence (CEIP), October 1997]. / Dépendance aux psychotropes et traitements de substitution: tendances récentes a propos de l'enquête OPPIDUM des Centres d'Evaluation et d'Information sur les Pharmacodépendances (CEIP) d'octobre 1997.

The aim of this study was to identify the latest trends in psychotropic drug use and the effect of the increase of maintenance treatments for serious opioid addiction. The results are based on data from OPPIDUM, an annual survey primarily concerned with the consumption of licit and illicit drugs. The study involved 1066 drug addicts recruited during the month of October 1997 from 38 French health centres connected with the Centres for Evaluation and Information on Drug Addiction (CEIP). The most frequently reported drugs were benzodiazepines (n = 323), some of which, especially flunitrazepam (Rohypnol, n = 123), are extremely addictive. The data showed a slight decrease in heroin consumption as well as a marked increase in the use of maintenance treatments. The association between benzodiazepines and buprenorphine (Subutex) should consequently be studied, whether buprenorphine is being used illicitly or prescribed as a maintenance treatment.

[Good practices of publication of clinical cases of pharmacovigilance: comments, Groupe de Travail sur les Bonnes Pratiques de Publication de Cliniques en Pharmacovigilance: commentary]. / Les bonnes pratiques de publication de cas cliniques de pharmacovigilance: commentaires. Groupe de Travail sur les Bonnes Pratiques de Publication de Cliniques en Pharmacovigilance: commentaires.

This paper introduces some comments on the complete text of Good Pharmacovigilance Publishing Practices, which forms appendix number 2 of the Good Pharmacovigilance Practices now published by the French Drug Agency, as was Good Clinical Practices. Each good practice is printed in italic and presented in a frame; the following comments are designed to facilitate its application. The technical terms that are used in this text are presented according to the glossary in Good Pharmacovigilance Practices.

[Observation of illicit or misused psychotropic drugs (O.P.P.I.D.U.M.): five years of surveillance of products consumed by drug addicts at Marseille]. / Observation des produits psychotropes illicites ou détournés de leur utilisation médicamenteuse (O.P.P.I.D.U.M.): cinq ans de surveillance des produits consommés par les toxicomanes à Marseille.

The aim of O.P.P.I.D.U.M. is the survey of products used by drug addicts. A five year survey, based on regular pools, has provided interesting results. 1,283 patients (80 per cent men, about 27 years old, 1/4 employed) used 2,241 drugs. The most frequent was heroin, followed by benzodiazepines, cannabis and cocaine. Flunitrazepam was the most commonly misused product, taken by users who started consumption earlier, with a higher rate of unemployment and imprisonment. Cocaine was as often taken intravenously as by sniffing, and most often used before imprisonment. Ecstasy (M.D.M.A.) has appeared recently. Codeine taken alone was used by subjects older than the heroin users, more frequently employed and virtually never prison inmates: this suggests the existence of an unofficial detoxication and substitution process. Confidence of clinicians needs anonymity of the records and return of information. Such a campaign is about to be launched.

[French pharmacovigilance database system: examples of utilisation]. / La banque de cas du système français de pharmacovigilance: quelques exemples d'exploitation.

UNLABELLED: The French drug surveillance (pharmacovigilance) system is based on a network of 31 regional centres which receive adverse drug reaction (ADR) reports from health professionals and are drug information centers. Cases are entered into a common database, with causality scores. This database contains large amounts of data, which may be used for pharmaco-epidemiological studies. As an example, all cases in which an antihypertensive drug, suspect or not, was cited were identified. ACE-inhibitor cough was also explored. RESULTS: Since 1985, > 70,000 case reports have been entered into the database. 63 per cent were reported by specialists, 20 per cent by GPs. 54 per cent came from University Hospitals, 21 per cent from private practice. The most numerous age group was 60 to 69. The overall sex ratio (F/M) was 1.28, the female preponderance being most marked at < 39 and > 70 years of age. 43 per cent took only one drug, 20 per cent two drugs, 13.4 per cent three, and 24 per cent > three drugs. The most frequently reported effects concerned the skin and appendages (15 per cent), general status and central nervous system (9.5 per cent each), platelets, liver, and GI systems (6 per cent each). Outcome was favourable in 74 per cent. Dechallenge was positive in 71 per cent, rechallence in 6 per cent. 3.4 per cent of the patients died; in 2.2 per cent death was related to a reaction. Causality assessment indicated close temporal relationship (C2 or C3) in 69 per cent of cases; in 51 per cent of cases, no other obvious cause was found. 66 per cent of the reactions were labelled when reported. The database could also be used to explore drug utilisation: as an example, we studied the age and sex distribution of reports containing antihypertensive drugs, irrespective of their possible causal role in the reaction. Antihypertensives were mentioned in 14 per cent of the reports. The age distribution was skewed towards greater age, with a maximum of 70 years. F/M was 1.57, with more M use < 20 and 30-59, whereas F were more common between 20-29 and 60 years. beta-blockers were more often associated with patients under 70, whereas above 70 diuretics and centrally acting antihypertensive drugs were more often reported. This could be related to greater use or worse tolerance of these drugs. As an example of the exploration of a specific drug-reaction relationship, we explored the relationship between the use of ACE inhibitors (ACEI) and cough. ACE inhibitors were present in 6 per cent of cases, but in 75 per cent of reports of cough. F/M was 1.29 (NS) for all reports concerning ACEI, 1.28 for cough unrelated to ACEI, 2.1 for cough with ACEI (P < 0.05). Cough was present in 12 per cent of all reports concerning ACEI. There was no clear difference between ACEI for cough or sex ratio; women cough more with ACEI. This does not seem related to greater ACEI use by women or to greater sensitivity of women to cough. The reason for this sex difference remains to be explained. There are large amounts of essentially underutilized data in drug surveillance databases. How they can or should be used remains to be validated.

Effects of some chelating agents on bismuth absorption in the rat.

Bismuth encephalopathies appeared in the mid-seventies in France and concerned about 1,000 people and led to a fatal outcome in 70 cases. Responsibility of Bi was clearly confirmed by the disappearance of the intoxication after prescription of drugs containing Bi had been more tightly regulated. Since the implication of a substance increasing the intestinal absorption of Bi has been suspected, we studied the concentrations of Bi in the tissues of rats who had been treated with bismuth nitrate basic 400 mg/kg per d for one month with and without an intake of a chelating agent added to the drinking water at a concentration of 10 mmol/l. The chelating agents tested were ethylenediaminetetraacetic acid (EDTA), nitriloacetic acid (NTA) and tripolyphosphate (TPP), cysteine and diethyldithiocarbamate (DEDTC). Cysteine and DEDTC gave the highest increase of Bi in tissues but with a wide dispersion of levels. However, even in the rats with the highest levels of Bi, there were no behavioral problems. EDTA induced an increase of Bi in kidney, brain and bone and NTA in kidney but there was no obvious sign of toxicity. We did not succeed in reproducing in rats the Bi toxicity observed in patients some years ago.

Steady-state population pharmacokinetics of sustained release theophylline in adult asthmatic patients.

The steady-state population pharmacokinetics of theophylline were studied in 52 asthmatic adult patients who received sustained-release theophylline as armophylline or euphylline. A total of 92 steady-state plasma theophylline concentration-dosage pairs were analyzed using a nonlinear mixed effects model. The pharmacokinetic model used was a one-compartment open model with single path Michaelis-Menten elimination. Dosage was adjusted to body weight. The effects of age, gender, alcohol consumption, cigarette smoking, dosage form, concurrent treatment with beta-agonists or steroids, outpatient dosing, and plasma caffeine concentration on maximum elimination rate (Vm) and Michaelis constant for theophylline metabolism (Km) were investigated. Hypothesis testing produced a final model in which Km = 0.42 (mg/l), and Vm (mg/kg per day) was based on cigarette smoking and dosage form, with Vm = 7.54 + 2.01 (smoking) + 1.08 (euphylline). Estimated coefficients of variation for interindividual variability in Km and Vm were 162.6% and 48.1%, respectively. Residual variability in dosage rates was estimated as 0.90 mg/kg per day. The identification of factors influencing theophylline disposition should prove useful for the a priori design of theophylline dosage regimens and monitoring of drug levels during therapy.

[Inventory of questions posed at a Regional Pharmacovigilance Center. Discussion about a possible coordination of informatics]. / Inventaire des questions posées à un centre régional de pharmacovigilance. Discussion d'une éventuelle harmonisation de leur informatisation.

All the requests (162) from the 1st to the 31th of december 1988 (a period of one month) are analysed by the Paris Fernand-Widal ADR Monitoring Centre. The requests are classified as following: 74 pharmacological consults (39 about pregnancy, 9 for breast-feeding, 3 neonates or children, 2 about G6PD deficiency, 3 guide-lines after a therapeutic error, 3 requests for treatment of ADR, and 15 miscellaneous). 5 ADRs notified and reported to an other nearest Centre to the caller and 3 diagnosed latter as an ADR 49 ADRs registered turn to a request because of lack of information (age: 15; sex: 18; name: 1; address: 31,) or faithfullness (4) or several reasons (18). 31 general information about drugs. Usually, physicians request the Monitoring Centre but recently patients request directly the Centre; specially during pregnancy. The progressive number of the questions makes computerization necessary. A single system appears to be essential for all the Regional Centres to improve the quality of the answer and for the new ADR's alert.

[Interstitial pneumopathies: criteria of drug side-effects. Results of consensus meetings]. / Pneumopathies interstitielles: critères d'imputation à un médicament. Résultats de réunions de consensus.

Since 1984, the use of the official method for determining the responsibility of drugs in side-effects has been compulsory in France. This method offers, but does not define, different qualificatives for chronological and semeiological criteria. Consensus workshops have been set up to define the undesirable side-effects themselves and the different qualificatives in each of the principal fields of pathology. As regards drug-induced interstitial pneumonia, chest specialists from university hospitals, members of the national system of pharmacovigilance and representatives of the Roussel-Uclaf central department of pharmaco-vigilance have determined: the limits of time elapsed between the beginning and end of drug administration and the occurrence of the adverse reaction; how to interpret various courses of the side-effect with and without temporary discontinuation of the drug, and how to interpret a possible readministration. A list of investigations aimed at excluding the main possible causes of interstitial pneumonia has been drawn up.

[Drug-induced cutaneous photosensitivity. Results of a consensus meeting]. / Photosensibilité cutanée médicamenteuse. Résultats d'une Réunion de Consensus.

In France, the use of an official drug adverse reaction assessment method is mandatory since 1984. The method proposes various qualifications for chronologic and semiologic criteria without clear limits. The definitions could vary with the nature of the side-effect. We report here the results of a consensus meeting on drug-induced photosensitivity. Dermatologists and experts in pharmacovigilance studied together how the "French method" could apply to the two variances of drug-induced photosensitivity: phototoxicity and photoallergy.

[Drug-induced renal insufficiency. Results of consensus meetings]. / Les insuffisances rénales d'origine médicamenteuse. Résultats de réunions de consensus.

We report the conclusions of consensus meetings organized by the "Direction de la Pharmacovigilance" of Roussel Uclaf, and attended by University Hospital Nephrologists, members of the National Network of Pharmacovigilance and representatives of Roussel Uclaf Drug Monitoring Department, in order to define more accurately, as regards drug-induced renal failure, the criteria and the terminology proposed by the French method of causality assessment of adverse drug reactions.