Increase of high-risk tramadol use and harmful consequences in France from 2013 to 2018: Evidence from the triangulation of addictovigilance data.

AIMS: The aim of this paper is to assess recent developments in non-medical tramadol use, tramadol use disorder, illegal procurement and deaths. METHODS: This study used repeated cross-sectional analysis of data collected nationwide from 2013 to 2018. Analysis was conducted through multisource monitoring of the French Addictovigilance Network of: (1) validated reports of high-risk tramadol use, (2) record systems collecting information from toxicology experts investigating analgesic-related deaths (DTA) and deaths related to substance abuse (DRAMES), and pharmacists for forged prescriptions (OSIAP), and (3) survey of drug users, with investigation of patterns of use while visiting addiction-specialised institutions (OPPIDUM). RESULTS: Despite a plateauing level of tramadol exposure in the French population, the proportion of tramadol reports increased 1.7-fold (187 cases in 2018, 3.2% (95% confidence interval [CI]: 2.74-3.63%), versus 1.9% (95% CI: 1.49-2.42% in 2013). Trends were similar in OSIAP: 11.9% of forged prescriptions in 2018 (95% CI: 10.56-13.45%); 1.7-fold increase; in OPPIDUM: 0.76% (95% CI: 0.55-1.02); 2.2-fold increase; and DRAMES: 3.2% of drug abuse-related deaths in 2018 (95% CI: 1.89-5.16) versus 1.7% in 2013 (95% CI: 0.65-3.84). Tramadol was the primary opioid in analgesic-related deaths in DTA (45% in 2018). Two profiles of high-risk tramadol users were identified: (1) patients treated for pain or with tramadol persistence when pain disappeared (mainly women; mean age 44 years), and (2) individuals with non-medical use for psychoactive effects (mainly men; mean age 36 years). CONCLUSION: The triangulation of the data obtained through addictovigilance monitoring evidenced a recent increase in high-risk tramadol use. These findings have a practical impact on the limitation of the maximal duration of tramadol prescriptions.

Comment on: An Insight Into Z-Drug Abuse and Dependence: An Examination of Reports to the European Medicines Agency Database of Suspected Adverse Drug Reactions.

After the publication of an article discussing the methodological options to detect the diversion potential of prescription drugs, this letter presents the multidimensional functioning of the French Addictovigilance System. This system aims at monitoring all substances with abuse potential, relying on a network of experts specialized in clinical and fundamental pharmacology. For more than 25 years, we have created collaborations with partners at the interface with field data related to substance use and the potential related disorders. When relevant depending on the context, these data sources are explored and crossed to analyze the abuse potential of one given substance. This organizational approach is useful to detect early Addictovigilance warning signals and to take appropriate measures. Generalizing such a multidimensional approach outside France appears an appealing option to move towards more effective Addictovigilance systems at the international level.

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.

[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.

[Cyamemazine (Tercian®): Exploration of extrapyramidal syndrome cases contained in the French pharmacovigilance database]. / Cyamémazine (Tercian®) et syndromes extrapyramidaux : exploration des cas contenus dans la base nationale de pharmacovigilance.

PURPOSE: Cyamemazine (Tercian®) is currently the most widely prescribed neuroleptic in France. This widespread use is due to its anxiolytics properties and to a claimed good safety profile. Although, prescription of cyamemazine is not devoid of the risks associated with the use of neuroleptics: extrapyramidal syndromes. This study aims at describing extrapyramidal syndromes induced by cyamemazine registered in the French pharmacovigilance database. METHODS: All spontaneous reports of extrapyramidal syndromes in the French pharmacovigilance database between 1st January 1985 and 31th December 2015 were described and analyzed. RESULTS: During this period 132 cases following cyamemazine intake were reported in the French pharmacovigilance database. The extrapyramidal syndromes were considered as "serious" in 77% of cases. More than 80% of the cases were described with a dosage of cyamemazine under 100mg/day and no correlation between drug dose and seriousness of the cases were found. Thirty-six cases were described with a monotherapy of cyamemazine. CONCLUSION: We should keep in mind that despite its widespread use in various indications (e.g. anxiolytic) cyamemazine remains a neuroleptic and could induce extrapyramidal syndromes even with low dosage. Careful monitoring should be performed when introducing and with long-term use of cyamemazine, mostly in elderly patients or patient already being treated with neuroleptics.

[Twenty-five years of the French Addictovigilance Network (FAN)]. / Les 25ans des centres d'évaluation et d'information sur la pharmacodépendance-addictovigilance.

Based on recommendations from the World Health Organization (WHO), the French addictovigilance network was set up since 1990, in order to assess and to monitor the potential for abuse and dependence of psychoactive substances. This network composed of 13 addictovigilance centers implemented in medical pharmacology departments of French university hospitals has developed specific pharmacoepidemiological tools repeated each year so as to lead us to updated pharmacological indicators related to drug abuse. As a single source may not be informative enough, the French addictovigilance network consider simultaneously a range of indicators focusing on health insurance database, health professional sentinel networks, characteristics of psychotropic consumptions and analysed them from a medical and pharmacological point of view combined to pharmacodynamic and pharmacokinetic data. The task force and the original role of this addictovigilance network is to work with reactivity to all different levels (local, regional, national) linked to all heath professionals in order to detect more quickly a potential warning signal leading to information, public health decision at a regional and/or national level and contributing also to a European and an international overview.

Medical complications of psychoactive substances with abuse risks: Detection and assessment by the network of French addictovigilance centres.

The use of psychoactive substances, whether occasional or regular, can induce a large number of clinical and/or biological complications. These complications may be related to the effects of the active substance itself and/or adulterants, but also to the modalities for use (administrations route, contexts of use). The detection and evaluation of these potentially severe complications are a public health issue. Beyond the assessment of the potential for abuse of and dependence on psychoactive substances, the collection and evaluation of complications related to the use of the substances are one of the roles of addictovigilance centres. In this article, the expertise of the French addictovigilance centres in the detection and assessment of medical complications related to psychoactive substances, adulterants or route of administration of substances is advanced through a few recent examples.

[The congress of the French Society of Pharmacology and Therapeutics celebrate in Nancy, 20 April 2016, 40 years of French Regional Pharmacovigilance Centres!]. / Le congrès de la Société française de pharmacologie et de thérapeutique célèbre à Nancy, le 20 avril 2016, les 40ans des centres régionaux français de pharmacovigilance !

In 1976, the Regional Pharmacovigilance Centres were created in France to collect and analyze adverse drug reactions. Even if they have, to date, managed and transmitted more than 583,000 adverse drug reactions to the French and international health authorities, the missions of these university hospital structures supervised by clinical pharmacologists are not limited to this activity. They also provide a consulting and diagnostic aid for drug diseases. Their other main mission is information about drugs and their proper use for health professionals and patients on any matter relating to medicines. These queries are used to adjust and focus the training of health professionals in prevention of drug risks and improvement of drug use. Beside signal detection and identification of alerts, the 31 Regional Pharmacovigilance Centres collaborate with the French Drug Agency (Agence nationale de sécurité du medicament et des produits de santé [ANSM]) by achieving expertise on drugs and participation in various working groups and committees. Finally, Regional Pharmacovigilance Centres participate in scientific advancement through research and publication activities.

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).

Levamisole-adulterated cocaine: what about in European countries?

BACKGROUND: A wide variety of somatic complications is reported or expected among cocaine users because of the adulterant levamisole. Most of the reports come from North America. METHODS: To update the data on levamisole-adulterated cocaine in European countries, we present here a synthesis of data on samples seized by the police with the detection of levamisole, the amount of levamisole in cocaine samples, European drug information reports, and clinical cases. RESULTS: Although there is a variation in the percentage of levamisole in cocaine samples between European countries, the trend is an increase of these percentages. As in North America, levamisole is becoming the most common cocaine adulterant. First European cases of complications secondary to the use of adulterated cocaine with levamisole were skin necrosis, vasculitis, and agranulocytosis. Levamisole postmortem data concerned two cases of complications leading to death, possibly related to levamisole or its metabolite (acute coronary syndrome, pulmonary hypertension). CONCLUSION: Even if it is difficult to have a global European view with comparable data, levamisole is present in European cocaine specimens and can lead to severe adverse health effects. However data on the prevalence of toxicity related to levamisole-adulterated cocaine abuse are missing.

[Antidepressants and tamoxifen: an unrecognized interaction]. / Antidépresseurs et tamoxifène : une interaction méconnue.

The interaction between tamoxifen and antidepressants which are CYP2D6 inhibitors is unknown, as shown in our study in which these antidepressants are prescribed to 11% of women receiving tamoxifen.

[Hypersexuality associated with aripiprazole: a new case and review of the literature]. / Hypersexualité induite par l'aripiprazole: à propos d'un cas et revue de la littérature.

We report the case of a patient with hypersexuality while he was treated with aripiprazole since 6 months. Clinical manifestations were an increased libido, unusual frequent masturbation and sexual instincts. All have resolved upon discontinuation of aripiprazole, and recurred after it was restarted. The partial dopaminergic agonist effect of aripiprazole could probably explain the occurrence of this compulsive behaviour.

[Not Available]. / Dysthyroidie sous anti-VEGF, effet indésirable de classe ? À propos d'un cas.

Tyrosine-kinase inhibitors are recent therapy used in different neoplastic diseases. Dysthyroidism seems to be a class effect of these drugs with a potentially cross cumulative effect. We describe here the case of a man who first developed dysthyroidism with sunitinib, then a deep and permanent hypothyroidism when axitinib was introduced.

[Dysthyroidism with anti-VEGF treatment, a class effect? about one case report]. / Dysthyroidie sous anti-VEGF, effet indésirable de classe ? à propos d'un cas.

Tyrosine-kinase inhibitors are recent therapy used in different neoplastic diseases. Dysthyroidism seems to be a class effect of these drugs with a potentially cross cumulative effect. We describe here the case of a man who first developed dysthyroidism with sunitinib, then a deep and permanent hypothyroidism when axitinib was introduced.

Probable interaction between an oral vitamin K antagonist and turmeric (Curcuma longa).

We report a probable interaction between a vitamin K antagonist, fluindione, and the herbal medicine turmeric that resulted in the elevation of the international normalized ratio (INR). The case presented here underlines the importance of considering potential exposure to herbal medications when assessing adverse effects.