Patterns and profiles of methylphenidate use both in children and adults.

AIM: The aim of the present study was to characterize patterns of use of methylphenidate (MPH), a prescription stimulant medication recommended in the treatment of attention deficit hyperactivity disorder (ADHD) and of narcolepsy, in France, both in children and adults, over a 3-year period. METHODS: Using the French General Health Insurance database, limited to two areas covering approximately 4 million individuals, we made up a cohort of incident MPH users between July 2010 and June 2013. Splitting them into distinct age groups (18-24, 25-49 and ≥50 years of age for adults and <6, 6-11 and 12-17 years of age for children), we established the characteristics of these populations at MPH initiation and during follow-up according to the duration of treatment, quantities dispensed and coprescription with central nervous system (CNS) drugs. RESULTS: We included a cohort of 3534 incident users, involving 30 238 dispensings of MPH, leading to an annual rate of 29 incident users per 100 000 in 2013. Children (66% of new users) were characterized by long-term use of MPH with few comedications. The group of 25-49-year-old patients were dispensed MPH more frequently than other groups, had the highest mean dose and were more often coprescribed other CNS drugs. The ≥50 year-old group was more often coprescribed antidepressants and antiparkinsonian drugs. CONCLUSIONS: Our pharmacoepidemiological study involving incident MPH users with a large number of characteristics showed different patterns of MPH use among children and adults. The results from the 25-49-year-old group suggested that MPH might be being used for medical conditions other than ADHD or narcolepsy in adults, and that it might be subject to misuse and/or abuse.

Proton pump inhibitors prescriptions in France: Main trends from 2006 to 2016 on French health insurance database.

Because national data on proton pump inbibitors (PPIs) consumption in France are scarce and because there is a growing literature on potential adverse drug reaction induced by this pharmacological class, we would like to more describe the main evolution of PPI use and the main characteristics of its users in France. We used a 1/97th representative sample of beneficiaries of the French health insurance called "échantillon généraliste des bénéficiaires" (EGB) to describe PPIs' use over time (duration of use by year) from 2006 to 2016. In 2016, 108,249 patients had at least 1 dispensing of PPI (i.e. 19.5% of EGB versus 16.5% in 2006). The part of patients with only 1 reimbursement of PPI by years decreased from 43.9% in 2006 to 39.0% in 2016. Among the patient with at least 2 PPI dispensing/years, the mean number of dispensing increased from 6.2±4.2 in 2006 to 6.9 in 2016. The over 75 year's old group is particularly concerned by the increase in both duration and dosage over the period of study, as mean DDD per year increased by 31% and mean number of dispensing per year by 17% from 2006 to 2016. Based on these results, PPI users could almost represent 11 million peoples in France (13 million on a whole population) in 2016. Initiatives to assess the appropriateness of use of these drugs might be warranted.

[Interest of take-home naloxone for opioid overdose]. / Intérêt de la mise à disposition de la naloxone auprès des usagers de drogues pour le traitement d'urgence de surdosage d'opioïdes.

Over the course of these last decades, we observed a change on opioid use with the marketing of opiate maintenance treatment, an increase of opioids used for pain management and recent concerns have arisen around the use of synthetic opioid. The World Health Organization (WHO) reports around 70,000 people opioid overdose death each year. In France, according to the DRAMES program (fatalities in relation with abuse of licit or illicit drugs) of the French addictovigilance network, most of deaths are related to opioids overdose (especially methadone, following by heroin, buprenorphine and opioid used for pain management). Opioid overdose is treatable with naloxone, an opioid antagonist which rapidly reverses the effects of opioids. In recent years, a number of programs around the world have shown that it is feasible to provide naloxone to people likely to witness an opioid overdose. In 2014, the WHO published recommendations for this provision and the need to train users and their entourage in the management of opioid overdose. In this context, in July 2016, French drug agency has granted a temporary authorization for use of a naloxone nasal spray Nalscue®. Because different opioids can be used and because each opioid has specific characteristics (pharmacodynamics, pharmacokinetics, galenic form…), the risk of overdose may differ from one opioid to another and it may be necessary, depending on the clinical context, to use larger and repeated doses of naloxone.

Chronic use of proton pump inhibitors, adverse events and potential biological mechanisms: A translational analysis.

Proton pump inhibitors (PPIs) are among the most frequently prescribed drugs. Even if PPI are usually considered as safe, there is a growing concern for a range of adverse effects of chronic PPI therapy often in the absence of appropriate indications. We propose, after a summary of renal, cardiovascular and neurological complications (dementia, chronic kidney disease, myocardial infarction and stroke), an integrative overview of the potential biological mechanisms involved. Eleven positive pharmacoepidemiological studies, mainly based on health insurance database linkage to hospital database, reported an increased risk of complications associated to PPI use and often a graded association suggesting also a possible dose-response relationship. Several mechanisms have been suggested through in vitro studies (endothelial dysfunction, endothelial senescence, hypomagnesemia, increase of chromogranin A levels, decrease of nitric oxide in endothelial cells) leading to the impairment of vascular homesostasis, paving the way to these complications. Evidence that PPIs may have off-targets and pleiotropic effects are mounting and may impose a cautious attitude in the prescription of PPI's, especially in elderly and/or in the context of chronic use.

Immeasurable time bias due to hospitalization in medico-administrative databases: which impact for pharmacoepidemiological studies?

PURPOSE: Drugs administered to hospitalized patients are not available within almost all health insurance databases. However, this unobservable exposure time bias is very rarely taken into account in pharmacoepidemiology. The objective was to model unobservable periods due to hospitalization and to assess their impact on risk estimates in the context of the association between benzodiazepines and mortality. METHODS: A cohort study was identified using the General Sample of Beneficiaries in France for the period 2006-2012. Benzodiazepines incident users were matched to incident users of antidepressants/non-benzodiazepine sedatives and to controls (non-users) according to age and gender. All-cause mortality at 1 year (Cox regression model) was studied using time-dependent variables (exposed/unexposed or under two hypotheses, inpatients are exposed or inpatients are unexposed), complemented with a multistate model based on observable/unobservable/death status. RESULTS: In each group, 57 242 patients were included. All-cause mortality was significantly higher among those exposed to benzodiazepines (adjusted hazard ratio (aHR) = 1.17, 95% confidence interval (CI) = 1.04, 1.32), as compared with controls. Use of benzodiazepines exposure as a time-dependent variable resulted in significant results after adjustment (aHR = 1.45, 95%CI = 1.16, 1.80). When inpatients were considered as unexposed, all-cause mortality was not significantly increased (aHR = 0.85, 95%CI = 0.76, 1.10), but was significantly augmented when inpatients were considered as exposed (aHR = 2.93, 95%CI = 2.46, 3.48). CONCLUSIONS: This study highlights the need to take account of the impact of unobservable exposure periods on risk estimates. Copyright © 2017 John Wiley & Sons, Ltd.

Methylphenidate: Gender trends in adult and pediatric populations over a 7year period.

OBJECTIVE: Methylphenidate (MPH) is a prescription-stimulant medication which is authorized in France for two indications: attention-deficit hyperactivity disorder in children (aged≥6years) and narcolepsy in cases where modafinil is ineffective (for children and adults). MPH use has increased worldwide in the past 2 decades in children and adults. Different pharmacoepidemiological Europeans studies have described MPH patterns of use. To our knowledge, few pharmacoepidemiological studies have described MPH patterns of use in France. METHODS: In this context, we have performed a study on regional reimbursement database (PACA-Corse area, covering approximately 4 millions inhabitants). The first part of the study analyzed the evolution of MPH users characteristic's yearly (grouped by age and gender) over a 7year period (2005-2011). In order to better characterize patterns of MPH use in adults, a specific analyze has been performed in the second part on MPH adult users in 2011 with a gender descriptive approach. RESULTS: During the 7year period, MPH dispensing grew from 0.28 to 0.68 patient per 1000. The proportion of adult patients rose from 14.8 to 25.7% (P<0.0001), with patients mainly aged 35-49years old. Gender differences in MPH users were noted between adults and children: the proportion of girls was less important in children than in adult (in 2011, 20.7% of girls among children vs 44.9% among adults). Moreover, the proportion of girls among children increased between 2005 to 2011 (15.1% of girls in 2005 versus 20.7% in 2011). Among adults, women were prescribed more antidepressants (41.5% versus 28.2%, P=0.003) and less opiate maintenance treatments (22.4% versus 31.9%, P=0.03) than men. Finally, 11% of men and 16.4% of women were over 50years old. CONCLUSION: MPH prescription greatly increased over7years, especially in adults. Moreover, in this population, patterns of MPH use differed with gender specificities. Such findings may increase clinical attention on monitoring MPH use in adults.

[Surveillance system on drug abuse: Interest of the French national OPPIDUM program of French addictovigilance network]. / Dispositif pharmacoépidémiologique de surveillance des substances psychoactives : intérêts du programme national OPPIDUM du Réseau français d'addictovigilance.

It is important to assess drug abuse liability in 'real life' using different surveillance systems. OPPIDUM ('Observation of illegal drugs and misuse of psychotropic medications') surveillance system anonymously collects information on drug abuse and dependence observed in patients recruited in specialized care centers dedicated to drug dependence. The aim of this article is to demonstrate the utility of OPPIDUM system using 2015 data. OPPIDUM is a cross-sectional survey repeated each year since 1995. In 2015, 5003 patients described the modality of use of 10,159 psychoactive drugs. Among them, 77% received an opiate maintenance treatment: 68% methadone (half of them consumed capsule form) and 27% buprenorphine (39% consumed generic form). Brand-name buprenorphine is more often injected than generic buprenorphine (10% vs. 2%) and among methadone consumers 7% of methadone capsule consumers have illegally obtained methadone (vs. 9% for syrup form). The proportion of medications among psychoactive drugs injected is important (42%), with morphine representing 21% of the total psychoactive drugs injected and buprenorphine, 16%. OPPIDUM highlighted emergent behaviors of abuse with some analgesic opioids (like tramadol, oxycodone or fentanyl), pregabalin, or quetiapine. OPPIDUM highlighted variations of drugs use regarding geographic approaches or by drug dependence care centers (like in harm reduction centers). OPPIDUM clearly demonstrated that collection of valid and useful data on drug abuse is possible, these data have an interest at regional, national and international levels.

Use of a multi-state model in a claims database: illustration with methadone.

PURPOSE: In pharmacoepidemiology, one of the main concerns is analysis of drug exposure time. However, in real-life settings, patient's behavior is complex and characterized by drug exposure dynamics. Multi-state models allow assessing the probabilities of various patterns, instead of just continuous use and/or discontinuation. The aim of this study was to illustrate with methadone, the use of multi-state model (MSM) in a large claims database. METHODS: This study is based on the French health insurance reimbursement database. Methadone exposure is defined using four states for each period of follow-up: syrup only, capsule only, syrup-capsule and no dispensing. The model considered 12 possible transitions (including reverse transitions) from one state to another. To describe these transitions a time-homogeneous Markov model was used. RESULTS: A total of 1265 methadone users were included. When patients belonged to the syrup-capsule state, they had a 61.8% chance of moving to capsules the following month and 20.9% of moving to syrup. The probability of moving from the syrup to the non-user state was 13.6% (11.7% from capsule state to non-user state). The average length of stay was 5.9 months (CI95%: [5.5-6.4]) in capsule state, 4.9 (CI95%: [4.6-5.2]) in syrup state and 5.9 (CI95%: [5.5-6.3]) in non user state. CONCLUSION: MSM provided a good description of methadone patterns of use. It outlined behaviors which have led to a rapid spread of capsule formulation among methadone users. Therefore, it illustrates the utility of MSM for modeling multiple sequences of drug use in a large claims database.

New methadone formulation in France: results from 5 years of utilization.

BACKGROUND: In France, methadone has historically been less accessible than buprenorphine. In 2008, a dry formulation (capsule) was introduced into the market, aimed in particular to improve methadone accessibility. OBJECTIVE: To describe the impact (prevalence of use, patient profiles and compliance with requirements) of the dry methadone formulation in France. METHOD: A retrospective cohort (from 2008 to 2012) was created from the data of the French General Health Insurance System which covers 80% of the French population. For each years, all subjects affiliated to this insurance system in southeast France (about 8.5 million inhabitants) with at least two reimbursements of methadone between 1st January and 31st December were selected. RESULTS: In 2012, the proportion of capsule users was almost the same as that of syrup users (40.0% versus 43.1%; p < 0.001). The rise in the number of methadone users has followed the rise in capsule users. Over the study period, the proportion of patients using benzodiazepines or antidepressants was 6-9% (p < 0.001) higher for capsule users than for syrup users. On average over the study period, 18% of subjects had at least one concurrent issue of the two forms. CONCLUSION: The study has shown the rapid spread of the capsule formulation among methadone users. This may suggest that the capsule is well accepted by patients and the medical community. However, the monitoring of methadone-related deaths should continue because of the pharmacodynamic properties of methadone and the context of relaxed regulations concerning access to methadone maintenance treatement (MMT).

Example of an investigation of an "emergent" phenomenon in addiction vigilance: the case of methylphenidate.

Abuse of and addiction to medication are a major public health issue which is evolving fast, in particular in countries like France, one of the largest consumers of medication in Europe. As a single source of information is not generally sufficient to measure a phenomenon as difficult to apprehend as medication-related addiction, as can be seen in the case of methylphenidate, it is essential to mobilise all the tools available, here surveillance programmes developed by the French CEIP Addiction vigilance network, such as suspicious prescriptions indicating possible abuse data (OSIAP) or observatory of illegal or misused psychoactive medications (OPPIDUM), as well as the health insurance databases, and health professional sentinel networks. The latest data available on methylphenidate abuse in France suggests a stabilisation of the phenomenon, which emerged in the Provence-Alpes-Côte-d'Azur (PACA) region in southern France. It also evidences its diffusion to other regions, so that the information needs to be widely relayed, and suggests that health professionals should exercise the greatest caution in the use of this substance, and should look for early signs of its misuse.

Doctor shopping of opioid analgesics relative to benzodiazepines: A pharmacoepidemiological study among 11.7 million inhabitants in the French countries.

BACKGROUND: The abuse of prescription opioids and its subsequent consequences is an important public concern particularly in the USA. The literature on opioid analgesic abuse is scarce. OBJECTIVE: We assess the extent and risk of opioid analgesics abuse relative to benzodiazepines (BZD) using the doctor shopping method, taken into account the pharmacological characteristics (dosage, route of administration, extended or immediate release). METHODS: We used SNIIRAM database covering 11.7 million inhabitants. All individuals with at least one reimbursement for non-injectable opioid analgesic or BZD in 2013 were included. Opioids for mild to moderate pain and for moderately severe to severe pain were studied. The Doctor Shopping Quantity (DSQ) is the quantity obtained by overlapping prescriptions from several prescribers. The Doctor Shopping Indicator (DSI) is the DSQ divided by the total dispensed quantity. RESULTS: The strong opioid analgesics have the highest DSI (2.79%) versus 2.06% for BZD hypnotics. Flunitrazepam ranked first according to its DSI (13.2%), followed by morphine (4%), and zolpidem (2.2%). The three-strong opioids having the highest DSI were morphine, oxycodone and fentanyl (respectively 4%, 1.7% and 1.5%). The highest DSI was observed for the highest dosages of morphine (DSI = 8.4% for 200 mg) and oxycodone (DSI = 2.8% for 80 mg). The highest DSI for fentanyl was described with nasal and transmucosal forms (4.1% and 3.3% respectively). The highest DSI for morphine was described for extended-release (4.1%). CONCLUSION: There is a need to reinforce surveillance systems to track opioid misuse and to increase awareness of healthcare professionals.

Long-term use of antipsychotics in community-dwelling dementia patients: prevalence and profile accounting for unobservable time bias because of hospitalization.

The aim of this study was to assess the prevalence of long-term antipsychotic (AP) use in community-dwelling patients with dementia considering hospitalization periods as AP exposure or not. A retrospective study was carried out from 2009 to 2012 on a PACA-Alzheimer cohort (which included 31 963 patients in 2009 and 36 442 in 2012 from 5 million inhabitants). Three groups of patients were identified according to the longest exposure to APs without interruption: nonusers, short-term users (≤3 successive months without discontinuation), and long-term users. Sensitivity analyses on hospitalization periods were carried out. The percentage of patients with at least one AP dispensing was stable over the study period (25.6% in 2009 vs. 26.5% in 2012). In 2012, 27.6% were AP long-term users. This increased to 46.7% when hospitalization periods were counted as AP exposure. In comparison with nonusers, AP users took more benzodiazepines and antidepressants. Short-term users were men [odds ratio (OR)=1.2, 95% confidence interval (CI) (1.1-1.3)] older than 85 years old [OR=1.2, 95% CI (1.1-1.2)]. Long-term users were more exposed to benzodiazepines [OR=1.2, 95% CI (1.1-1.4)]. This study showed that long-term use of AP remained frequent in community-dwelling patients with dementia. It also showed that the prevalence of long-term users almost doubled when hospitalization periods were counted as AP exposure. This underlines the need to consider hospitalization periods when assessing medication exposure in populations with frequent periods of hospitalization.

Antidepressant adherence patterns in older patients: use of a clustering method on a prescription database.

According to the World Health Organization, depression will become the second most important cause of disability worldwide by 2020. Our objective was to identify patterns of adherence to antidepressant treatments in older patients using several indicators of adherence and to characterize these patterns in terms of medication exposure. We conducted a retrospective cohort study using the French National Health Insurance reimbursement database. Incident antidepressant users aged more than 65 were included from July 1, 2010, to June 30, 2011, and followed up for 18 months. Antidepressant and other psychotropic drugs (opioids, benzodiazepines, antipsychotics, anti-epileptics) were recorded. Adherence to antidepressant treatment was assessed by several measures including proportion of days covered, discontinuation periods, persistence of treatment, and doses dispensed. Patients were classified according to their adherence patterns using a mixed clustering method. We identified five groups according to antidepressant adherence. One group (n = 7505, 26.9%) was fully adherent with regard to guidelines on antidepressant use. Two patterns of nonadherent users were identified: irregular but persistent users (n = 5131, 18.4%) and regular but nonpersistent users (n = 9037, 32.4%). Serotonin reuptake inhibitors were the most frequently dispensed antidepressant class (70.6%), followed by other antidepressants (43.3%, mainly serotonin-norepinephrine reuptake inhibitors and tianeptine) and tricyclic antidepressants (TCAs) (13.4%). Nonadherent users more frequently had a dispensing of TCA, opioid, and anti-epileptic medication than adherent users. Health policies to improve adherence to antidepressant treatment may require better training of physicians and pharmacists, insisting on the important role of the continuation period of antidepressant treatment.