Vincent Pradel

Impact of a prescription monitoring program on doctor-shopping for high dosage buprenorphine†

Doctor‐shopping (simultaneous use of several physicians by a patient) is one of the most frequent ways of diversion for prescription drugs. A specific method was used to assess the evolution of doctor‐shopping for High Dosage Buprenorphine (HDB) in a French region from 2000 to 2005 and the impact of a prescription monitoring program for HDB implemented in 2004.

Assessment of abuse potential of benzodiazepines from a prescription database using ‘doctor shopping’ as an indicator

AbstractBackground: 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 2mg, clorazepate (5mg, 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.

Patterns of methylphenidate use and assessment of its abuse and diversion in two French administrative areas using a proxy of deviant behaviour determined from a reimbursement database: main trends from 2005 to 2008.

AbstractBackground: Methylphenidate is a psychostimulant drug indicated for the treatment of attention-deficit hyperactivity disorder (ADHD). Its abuse and diversion have been previously described in specific populations, such as students; however, few studies investigating abuse and diversion among the overall population are available. Objectives: The aim of this study was to describe patterns of methylphenidate use and to explore the magnitude of its abuse and diversion in two French administrative areas using data from a reimbursement database. A proxy of ‘deviant behaviour’ was used for the abuse and diversion of methylphenidate, defined using the following parameters: total number of defined daily doses (DDDs) of methylphenidate dispensed; number of different pharmacies seen for dispensing of methylphenidate; number of prescribers consulted for a prescription of methylphenidate; and number of dispensings of methylphenidate. Data from the reimbursement database were analysed by clustering methods. These data were assessed from 2005 to 2008. Method: The French General Health Insurance System (GHIS) database was used to obtain data on methylphenidate use in two French administrative areas. Individuals affiliated to the GHIS who had a prescription for methylphenidate reimbursed between 1 January and 31 March of 4 selected years (2005, 2006, 2007 and 2008) were included. After the first dispensing of methylphenidate for these individuals, all their dispensings (including methylphenidate and other psychoactive drugs) were monitored over a 9-month period. Following a descriptive analysis, a clustering method was used to identify different subgroups of subjects according to the methylphenidate consumer profile characteristics. Results: With regard to the number of patients who had a dispensing for methylphenidate during the first quarter of the year, an 84% increase was observed between 2005 (n = 640) and 2008 (n= 1175). The clustering method identified two subgroups. One of them was characterized by a higher number of dispensings, different prescribers and pharmacies and a greater total dispensed quantity, suggesting a deviant behaviour and, thus, possible abuse and diversion of methylphenidate. These subjects were older (aged 35.4 ± 11.3 years) and were more frequently patients receiving benzodiazepines, antidepressants, antipsychotics and maintenance opioid treatment. The proportion of subjects with a deviant behaviour increased from 0.5% in 2005 to 2% in 2007 and then decreased to 1.2% in 2008. Conclusion: This method was able to assess the magnitude of methylphenidate abuse liability and to follow its evolution. The decrease in methylphenidate abuse and diversion seen between 2007 and 2008 can be explained by the enactment in April 2008 of specific regulations for prescription drugs (such as methylphenidate) that are deemed by the French government to have the potential for misuse; these regulations require the establishment of a ‘contract of care’ between the GHIS, prescriber and patient.

Hypoxia inducible factor 1α gene (HIF-1α) splice variants: potential prognostic biomarkers in breast cancer

BackgroundHypoxia-inducible factor 1 (HIF-1) is a master transcriptional regulator of genes regulating oxygen homeostasis. The HIF-1 protein is composed of two HIF-1α and HIF-1β/aryl hydrocarbon receptor nuclear translocator (ARNT) subunits. The prognostic relevance of HIF-1α protein overexpression has been shown in breast cancer. The impact of HIF-1α alternative splice variant expression on breast cancer prognosis in terms of metastasis risk is not well known.MethodsUsing real-time quantitative reverse transcription PCR assays, we measured mRNA concentrations of total HIF-1α and 4 variants in breast tissue specimens in a series of 29 normal tissues or benign lesions (normal/benign) and 53 primary carcinomas. In breast cancers HIF-1α splice variant levels were compared to clinicopathological parameters including tumour microvessel density and metastasis-free survival.ResultsHIF-1α isoforms containing a three base pairs TAG insertion between exon 1 and exon 2 (designated HIF-1αTAG) and HIF-1α736mRNAs were found expressed at higher levels in oestrogen receptor (OR)-negative carcinomas compared to normal/benign tissues (P = 0.009 and P = 0.004 respectively). In breast carcinoma specimens, lymph node status was significantly associated with HIF-1αTAGmRNA levels (P = 0.037). Significant statistical association was found between tumour grade and HIF-1αTAG(P = 0.048), and total HIF-1α (P = 0.048) mRNA levels. HIF-1αTAGmRNA levels were also inversely correlated with both oestrogen and progesterone receptor status (P = 0.005 and P = 0.033 respectively). Univariate analysis showed that high HIF-1αTAGmRNA levels correlated with shortened metastasis free survival (P = 0.01).ConclusionsOur results show for the first time that mRNA expression of a HIF-1αTAGsplice variant reflects a stage of breast cancer progression and is associated with a worse prognosis.See commentary: http://www.biomedcentral.com/1741-7015/8/45

Which psychoactive prescription drugs are illegally obtained and through which ways of acquisition? About OPPIDUM survey.

The objective of the study was to determine which psychoactive prescription drugs are illegally obtained and through which ways of acquisition. OPPIDUM is an annual national study. It is based on specialized care centers that included subjects presenting a drug dependency or under opiate maintenance treatment. All their psychoactive substances consumed are reported. This work focuses on the different ways of acquisition specially the illegal ways of acquisition (bought on the street, forged prescription, stolen, given, internet). For each medication illegally obtained, a ratio has been calculated (number of illegal acquisitions divided by the number of described acquisitions). In 2008, 5542 subjects have been included and have described the consumption of 11 027 substances including 63.8% of prescription drugs. Among them, 11% were illegally obtained. The different illegal acquisition ways were ‘street market’ (77.6%), ‘gift’ (16.6%), ‘theft’ (2.3%), ‘forged prescription’ (2.3%), and ‘internet’ (0.7%). The third first drugs illegally obtained were high dosage buprenorphine, methadone, and clonazepam. Some prescription drugs, less consumed, have an important ratio of illegal acquisition like ketamine, flunitrazepam, morphine, trihexyphenidyl, or methylphenidate. This study confirms that theft, forged prescription and internet are few used and permits to highlight diversion of prescription drugs. It is important to inform healthcare professionals on the different prescription drugs that are illegally obtained.

Estimated magnitude of diversion and abuse of opioids relative to benzodiazepines in France

INTRODUCTION Prescription drug abuse is a major concern in several countries. France appears to be particularly prone to the abuse of opiate maintenance treatment (OMT) opioids and benzodiazepines (BZD), whereas the abuse of opioid analgesics (OA) is less commonly reported. To estimate the extent of psychoactive drug abuse, the French drug agency relies on different methods measuring various diversion indicators used as proxies for the detection of abuse/misuse: suspicion of abuse/dependence, illegal acquisition by patients seen in specialized care centers, prescription forgery and doctor shopping. The main objectives of the present study are to analyse the abuse and diversion of opioids (both OA and OMT), in comparison with those of BZDs, through the concurrent use of three different data sources. METHODS Diversion and abuse of opioids were analysed using indicators of abuse and diversion derived from three data sources over the period 2006-2008. Then, opioids were compared to BZDs for the year 2008 using the same indicators. RESULTS The analysis suggests that BZDs are more commonly dispensed than OAs and OMTs but that abuse and diversion are related mainly to OMT (particularly to buprenorphine), morphine and BZDs and less to OAs (except for morphine). CONCLUSION This study presents an original approach, based on the use of multiple data sources, to evaluate and compare the estimated abuse and diversion of opioids and benzodiazepines. It provides health authorities with a global, comparative and summarized overall view of the importance of different patterns of diversion and abuse for different prescription drugs.

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.

Which indicators can public health authorities use to monitor prescription drug abuse and evaluate the impact of regulatory measures? Controlling High Dosage Buprenorphine abuse

BACKGROUND Two methods have been recently developed from a drug reimbursement database to provide useful indicators for public health authorities concerning the abuse potential of psychotropic drugs. The doctor-shopping indicator (DSI) measures the proportion of the drug obtained by doctor shopping among the overall quantity of the drug reimbursed and the clustering method reveals subgroups of deviant patients. OBJECTIVE The objective of the study was to analyze and compare indicators resulting from these two methods, applied to High Dosage Buprenorphine (HDB) (a product well-known to be diverted in France), in order to determine which public health authorities needs they answer. DATA ANALYSIS The patients with reimbursed HDB were grouped using the clustering method in terms of drug dispensations characteristics over a nine month period. The characteristics of the resulting subgroups, including their DSI, were then compared. RESULTS 4787 Patients (73.4%) had no measurable doctor-shopping behaviour. But the comparison of the two methods demonstrated that the more a patients profile was characterized by deviant behavior, the higher was the DSI: from 0.4% in a subgroup with a median profile to 72% in a subgroup with a deviant profile. CONCLUSION These two methods are useful surveillance tools for public health authorities: the clustering method may help devise pertinent intervention strategies to reduce prescription drug abuse while the DSI method provides quantitative information demonstrating whether these strategies are useful. We discuss the advantages and disadvantages of using these two methods as useful indicators for public health authorities.

Misuse of buprenorphine maintenance treatment since introduction of its generic forms: OPPIDUM survey

The purpose of the study was to compare, using data from Observation of Illicit Psychotropic Substances or Non‐medical Used Medications (OPPIDUM) surveys, first, the profile of buprenorphine users and their modalities of buprenorphine use from 2006 to 2008 and, second, two subgroups: brand‐name and generic buprenorphine users in 2008.

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.