Patterns of ketamine use among people with substance use disorder in France: Multisource analysis of the data from the French Addictovigilance Network.

BACKGROUND: Due to its psychoactive effects, ketamine has become a drug used for non-medical purpose. OBJECTIVES: To assess the latest trends in ketamine use among people with substance use disorder and to characterize its clinical complications using complementary health data sources of the French Addictovigilance Network. METHODS: First, we extracted all reports involving ketamine from 2012 to 2021 from the database of the OPPIDUM program (i.e., a multicentric program conducted in collaboration with hundreds of substance abuse treatment facilities that collects data on drugs used by subjects with substance use disorders). We described the reports globally and the changes from 2012 to 2021. Second, we extracted all cases involving ketamine from July 2020 to December 2022 from the French National Pharmacovigilance Database (BNPV). We identified the cases related to ketamine use among people with substance use disorder and described them. RESULTS: There was a 2.5-fold increase in the number of ketamine users with substance use disorder in the OPPIDUM program, from 35 (0.7%) subjects in 2012 to 89 (1.7%) subjects in 2021. There was an increase in the proportion of subjects who were daily users, had distress upon discontinuation, and presented addiction. There were 238 cases related to ketamine use among people with substance use disorder in the French National Pharmacovigilance Database from July 2020 to December 2022. Among them, 94 (39.5%) cases involved ketamine use disorder, 20 (8.4%) cases involved urinary tract and kidney symptoms, and 13 (5.5%) cases involved hepatobiliary symptoms. CONCLUSION: The trend observed over 10 years reflects the growth in ketamine use among people with substance use disorder, although it does not allow to estimate the rates of non-medical use of ketamine in the general population. Ketamine-induced uropathy and cholangiopathy are reported in ketamine users with substance use disorder, especially in case of repeated and/or prolonged use of high doses.

Antibiotic-induced neurological adverse drug reactions.

Antibiotics are drugs widely used all around the world. Central nervous system adverse drug reactions (CNS ADRs) are mostly under-suspected with antibiotics. Nevertheless, these ADRs could lead to severe complications such as encephalopathy. To illustrate the clinical patterns of these off-target ADRs, we here present data from pharmacovigilance system, through different populations and points of view (worldwide, French population, vulnerable population and individual). These data could help clinicians to better know about CNS ADRs with antibiotics, to better identify risk factors and vulnerable patients and to highlight the importance to set up the right diagnostic explorations in the best timing to avoid complications. Clinicians should request a pharmacological opinion from pharmacologist (biologists and pharmacovigilance clinicians) in front of vulnerable population before or during antibiotics. Pharmacovigilance advice could help clinicians in the diagnosis and the management of an ADR. Therapeutic drug monitoring is particularly contributive to adjust doses of antibiotics administered in vulnerable patients. Pharmacovigilance advice and TDM are essential to perform personalized medicine, and contribute to the proper use of drugs.

Cannabidiol and pharmacokinetics drug-drug interactions: Pharmacological toolbox.

Cannabidiol (CBD) is one of the most important components of the Cannabis sativa plant with delta9-tetrahydrocannabinol (THC). CBD is used both for medical and recreational purposes. It can be of pharmaceutical grade (Epidyolex®), and also self-service purchased in pharmacy, CBD shops and on the internet (non-pharmaceutical). CBD is almost as widespread as it is poorly understood from a pharmacological point of view and particularly in terms of drug interactions. Drug-drug interactions could lead to clinical complications, and we here gather data currently available on pharmacokinetics (PK) drug-drug interactions with CBD through a narrative review. This review shows that several PK drug-drug interactions exist with different class of medications and aims to help clinicians to better know about CBD for their practice as this product is increasingly used.

[Increase of overdose and deaths related to methadone during COVID-19 epidemic in 2020]. / Augmentation des surdoses et décès en lien avec la consommation de méthadone durant la crise sanitaire liée au COVID-19 en 2020.

INTRODUCTION: Due to the risk of overdoses increase especially with methadone, a reinforced monitoring has been set up by the French Addictovigilance Network following the first lockdown related to coronavirus disease 2019 (COVID-19). In this context, we managed a specific study to analyze overdoses related to methadone in 2020 compared to 2019. MATERIAL AND METHODS: We analyzed methadone-related overdoses which occurred in 2019 and 2020 from two sources: DRAMES program (deaths with toxicological analysis) and the French pharmacovigilance database (BNPV) (overdoses that did not lead to death). RESULTS: Data from DRAMES program in 2020 show methadone as the first drug involved in deaths as well as an increase in deaths: in number (n=230 versus n=178), in proportion (41% versus 35%) and number of deaths per 1000 exposed subjects (3.4 versus 2.8). According to BNPV, the number of overdose increased in 2020 compared to 2019 (98 versus 79; i.e., 1.2-fold increase) particularly during several target periods: first lockdown, end of lockdown/summer period and second lockdown. In 2020, a higher number of cases were observed in April (n=15) and May (n=15). Overdoses and deaths occurred in subjects enrolled in treatment programs or not (naïve subjects/occasional users who obtained methadone from street market or family/friends). Overdoses resulted from different factors: overconsumption, multiple drug use with depressants drugs or cocaine, injection, consumption for sedative, recreational purposes or voluntary drug poisoning. DISCUSSION/CONCLUSION: All these data show an increase of morbidity and mortality related to methadone during COVID-19 epidemic. This trend has been observed in other countries.

Sex differences in adverse drug reactions: Are women more impacted?

Pharmacovigilance and pharmacoepidemiology studies regarding the sex difference in adverse drug reactions are numerous, and it is now a challenge to take them into account in order to increase drug safety. Here, we present an overview of this topic through data on epidemiology, mechanisms, and methods used for assessing sex differences in drug safety. Because the literature is extensive, we choose to expose a few examples of studies for cardiovascular drugs, anti-infectious, psychotropics, antidiabetics, anticancer drugs and some specific drugs to illustrate our purpose. Many studies show a higher risk in women for most of drugs involving in sex differences. However, physiological, methodological and subjective points have to be taken into account to interpret these results. Clinical trials must also enroll more women to better evaluate sex differences both in efficacy and pharmacovigilance. Nevertheless, when there is a pharmacological rationale underlying the observed association between sex and drug safety profile, it is now unavoidable to think about its consideration for a personalized prescription.

What Do We Know About Medical Cannabis in Neurological Disorders and What Are the Next Steps?

Medical use of cannabis has been receiving growing attention over the last few decades in modern medicine. As we know that the endocannabinoid system is largely involved in neurological disorders, we focused on the scientific rationale of medical cannabis in three neurological disorders: amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease through pharmacological plausibility, clinical studies, and patients' view. Clinical studies (randomized controlled trials, open-label studies, cohorts, and case reports) exploring medical cannabis in these disorders show different results depending on the methods and outcomes. Some show benefits on motor symptoms and others on non-motor symptoms and quality of life. Concerning patients' view, several web surveys were collected, highlighting the real use of cannabis to relieve symptoms of neurological disorders, mostly outside a medical pathway. This anarchic use keeps questioning particularly in terms of risks: consumption of street cannabis, drug-drug interactions with usual medical treatment, consideration of medical history, and adverse reactions (psychiatric, respiratory, cardiovascular disorders, etc.), underlining the importance of a medical supervision. To date, most scientific data support the therapeutic potential of cannabis in neurological disorders. As far as patients and patients' associations are calling for it, there is an urgent need to manage clinical studies to provide stronger evidence and secure medical cannabis use.

[Increasing methylphenidate abuse: Tracking and profiles during 13-years]. / Augmentation de l'abus de méthylphénidate : repérage et profils sur 13 années.

BACKGROUND: Methylphenidate is indicated for attention deficit hyperactivity disorder (ADHD). Several studies have evaluated its abuse in specific populations (students, drug users) and few in the general population. This work describes the extent of its abuse in a region of more than 5 million inhabitants. METHOD: Based on regional health insurance data from 2005 to 2017, the clustering method identifies different methylphenidate use profiles according to several characteristics (number of different prescribers and pharmacies, number of dispensations, number of defined daily dose dispensed). The groups characterised by high values of these variables will be qualified as "deviant". RESULTS: In 13 years, the number of patients with at least one dispensation in the first quarter has been multiplied by 5.8 times. The proportion of adults has increased (20% in 2017) and their number has been multiplied by 10. Five groups are identified, three of them are characterised by "deviant" behaviour. Group 5 (n=11, 0.04%) has higher values than 4 (n=112, 0.4%) and 3 (n=407, 1.6%). These patients are older and more frequently use benzodiazepines and opiate substitution drugs. Groups 1 (n=13,132, 51%) and 2 (n=11,941, 46.7%) are more likely to be taken up by young subjects. The number of subjects with "deviant" behaviour increased until 2011 and after a decrease, the highest number of subjects concerned has been observed since 2015. CONCLUSION: In view of the increase of subjects with "deviant" behaviour, it is necessary to make the medical community and patients aware on the risk of abuse of methylphenidate. The recent extension of the indication for ADHD in adults and the broadening of the conditions of prescription require increased vigilance.

Comparative study of the adverse event profile of hydroxychloroquine before and during the Sars-CoV2 pandemic.

AIMS: At the beginning of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, there were no clinically-tested medications for the effective treatment of coronavirus disease. In this context, on 5 March 2020, the French Public Health Council issued several recommendations for the therapeutic management of this new disease, including the use of hydroxychloroquine (HCQ). An unexpected cardiovascular safety signal was quickly identified as being more frequent than expected thanks to the reports of adverse drug reactions (ADRs) submitted to French regional pharmacovigilance centres (RPVC). The objective of this study was to compare all ADRs reported with HCQ used in its usual indication, collected before the pandemic period (1985 to 31 December, 2019) with those reported with the coronavirus disease 2019 (COVID-19) indication (1 January to 21 July, 2020). METHODS: For this purpose, reports were extracted from the French pharmacovigilance database and analysed for these two periods. RESULTS: Our study showed a different safety profile in COVID-19 patients with more cardiac disorders (57% of ADRs versus 5% before the pandemic period), especially QT interval prolongation, resulting from an interaction with azithromycin in more than 20% of cases. Hepatobiliary disorders were also significantly more frequent. CONCLUSIONS: These observations could be associated with the effect of the virus itself on the various organs, the profile of the patients treated, and concomitant drug treatments.

Antidepressants abuse in subjects with opioid use disorders: A 10-year study in the French OPPIDUM program.

Accumulating evidence shows that some antidepressants are abused for their psychostimulant effects, but the extent of antidepressants abuse is unknown in subjects with opioid use disorders (OUD). The objective of this work is to assess the prevalence of antidepressant abuse and its correlates in subjects with OUD. Subjects ≥18 year-old in an opiate maintenance treatment (OMT) program who reported using an antidepressant were selected from the OPPIDUM program from 2011 to 2020. The outcome was antidepressant abuse. Antidepressant abusers were identified as subjects reporting at least one of the following behaviors: "drug abuse," "concomitant use of alcohol," "illegal obtaining," and "dose higher than recommended in the Summary of Product Characteristics." Among the 83 040 observations of subjects ≥18 year-old in an OMT program included in the OPPIDUM program from 2011 to 2020, 2708 (3.3%) subjects reported using an antidepressant in monotherapy. Among them, there were 385 (14.2%) abusers. The proportion of abusers was the highest for amitriptyline (n = 31, 25.0%). In multivariate analysis, antidepressant abuse was positively associated with amitriptyline (OR 2.07, 95% CI [1.16, 3.73]; p = 0.015), unemployment (OR 1.52, 95% CI [1.16, 2.01]; p = 0.003), the use of intravenous route of administration (OR 1.77, 95% CI [1.12, 2.80]; p = 0.014), and the use of benzodiazepines (OR 1.53, 95% CI [1.21, 1.94]; p < 0.001). Clinicians should be aware of the risk of antidepressant abuse when prescribing in subjects with OUD, accounting for their heterogeneous pharmacological properties that may account for their abuse potential.

Serious Neurological Adverse Events of Ceftriaxone.

We described ceftriaxone-induced CNS adverse events through the largest case series of Adverse Drug Reactions (ADRs) reports, from 1995 to 2017, using the French Pharmacovigilance Database. In total, 152 cases of serious CNS ADRs were analyzed; 112 patients were hospitalized or had a prolonged hospitalization (73.7%), 12 dead (7.9%) and 16 exhibited life-threatening ADRs (10.5%). The median age was 74.5 years, mainly women (55.3%), with a median creatinine clearance of 35 mL/min. Patients mainly exhibited convulsions, status epilepticus, myoclonia (n = 75, 49.3%), encephalopathy (n = 45, 29.6%), confused state (n = 34, 22.4%) and hallucinations (n = 16, 10.5%). The median time of onset was 4 days, and the median duration was 4.5 days. The mean daily dose was 1.7 g mainly through an intravenous route (n = 106, 69.7%), and three patients received doses above maximal dose of Summary of Product Characteristics. Ceftriaxone plasma concentrations were recorded for 19 patients (12.5%), and 8 were above the toxicity threshold. Electroencephalograms (EEG) performed for 32.9% of the patients (n = 50) were abnormal for 74% (n = 37). We described the world's biggest case series of ceftriaxone-induced serious CNS ADRs. Explorations (plasma concentrations, EEG) are contributive to confirm the ceftriaxone toxicity-induced. Clinicians may be cautious with the use of ceftriaxone, especially in the older age or renal impairment population.

French organization for the pharmacovigilance of COVID-19 vaccines: A major challenge.

In this special issue, we present the main highlights of the first weeks of pharmacovigilance monitoring of coronavirus disease 2019 (COVID-19) vaccines in this unprecedented situation in France: the deployment of a vaccination during an epidemic period with the aim of vaccinating the entire population and the intense pharmacovigilance and surveillance of these vaccines still under conditional marketing authorizations. In this unprecedented situation, the cross approach and interaction between the French pharmacovigilance network and French National Agency for the Safety of Medicines and Health Products (ANSM) has been optimized to provide a real-time safety related to COVID-19 vaccines. Every week, pair of regional pharmacovigilance centers gathered safety data from the French pharmacovigilance network, to acutely expertise all the adverse drug reactions (ADRs) reported with each COVID-19 vaccine within a direct circuit with ANSM. Results of this expertise are presented and discussed with ANSM in order to raise safety signals and take appropriate measures if necessary. These reports are then published online. At the 25th of March 2021, more than 9 815 000 doses were injected and 20,265 ADRs were reported, mostly non-serious (76%). Several potential or confirmed signals were raised at the european level for those vaccines and others ADRs are under special attentions. This underlines the adaptiveness of the French pharmacovigilance system to both the identification of new patient profiles experiencing ADRs and the evolution of the vaccine strategy. Such an efficiency is necessary to manage a careful and acute surveillance of these new COVID-19 vaccines for and to face the pandemic at the same time.

Early Detection of Prescription Drug Abuse Using Doctor Shopping Monitoring From Claims Databases: Illustration From the Experience of the French Addictovigilance Network.

Opioid analgesics and maintenance treatments, benzodiazepines and z-drugs, and other sedatives and stimulants are increasingly being abused to induce psychoactive effects or alter the effects of other drugs, eventually leading to dependence. Awareness of prescription drug abuse has been increasing in the last two decades, and organizations such as the International Narcotics Control Board has predicted that, worldwide, prescription drug abuse may exceed the use of illicit drugs. Assessment of prescription drug abuse tackles an issue that is hidden by nature, which therefore requires a specific monitoring. The current best practice is to use multiple detection systems to assess prescription drug abuse by various populations in a timely, sensitive, and specific manner. In the early 2000's, we designed a method to detect and quantify doctor shopping for prescription drugs from the French National Health Data System, which is one of the world's largest claims database, and a first-class data source for pharmacoepidemiological studies. Doctor shopping is a well-known behavior that involves overlapping prescriptions from multiple prescribers for the same drug, to obtain higher doses than those prescribed by each prescriber on an individual basis. In addition, doctor shopping may play an important role in supplying the black market. The paper aims to review how doctor shopping monitoring can improve the early detection of prescription drug abuse within a multidimensional monitoring. The paper provides an in-depth overview of two decades of development and validation of the method as a complementary component of the multidimensional monitoring conducted by the French Addictovigilance Network. The process accounted for the relevant determinants of prescription drug abuse, such as pharmacological data (e.g., formulations and doses), chronological and geographical data (e.g., impact of measures and comparison between regions), and epidemiological and outcome data (e.g., profiles of patients and trajectories of care) for several pharmacological classes (e.g., opioids, benzodiazepines, antidepressants, and methylphenidate).

Artificial Intelligence for Unstructured Healthcare Data: Application to Coding of Patient Reporting of Adverse Drug Reactions.

Adverse drug reaction (ADR) reporting is a major component of drug safety monitoring; its input will, however, only be optimized if systems can manage to deal with its tremendous flow of information, based primarily on unstructured text fields. The aim of this study was to develop an automated system allowing to code ADRs from patient reports. Our system was based on a knowledge base about drugs, enriched by supervised machine learning (ML) models trained on patients reporting data. To train our models, we selected all cases of ADRs reported by patients to a French Pharmacovigilance Centre through a national web-portal between March 2017 and March 2019 (n = 2,058 reports). We tested both conventional ML models and deep-learning models. We performed an external validation using a dataset constituted of a random sample of ADRs reported to the Marseille Pharmacovigilance Centre over the same period (n = 187). Here, we show that regarding area under the curve (AUC) and F-measure, the best model to identify ADRs was gradient boosting trees (LGBM), with an AUC of 0.93 (0.92-0.94) and F-measure of 0.72 (0.68-0.75). This model was run for external validation showing an AUC of 0.91 and a F-measure of 0.58. We evaluated an artificial intelligence pipeline that was found able to learn how to identify correctly ADRs from unstructured data. This result allowed us to start a new study using more data to further improve our performance and offer a tool that is useful in practice to efficiently manage drug safety information.

[Adverse drug reactions profiles for abiraterone and enzalutamide: A pharmacovigilance descriptive analysis]. / Profils d'effets indésirables sous abiratérone et enzalutamide : analyse descriptive des données de la base nationale de pharmacovigilance.

OBJECTIVE: The aim of this study was to describe the profile of adverse drug reactions (ADRs) observed with abiraterone and enzalutamide, based on cases registered in the French regional pharmacovigilance centres to identify potential pharmacovigilance signals. METHODS: We extracted from the French pharmacovigilance database all cases of ADRs or drug interactions involving abiraterone or enzalutamide from the time they market authorization date until December 31st, 2017. Signal detection results have been transmitted by the French Agency for Health Products (ANSM). The data were compared with those of the risk management plans for each drug and the literature. RESULTS: Among the 233 observations analyzed, nearly 62% involved abiraterone as a suspect drug and 38% involved enzalutamide; only 1 case involved both drugs. The ADRs profile is different between the drugs. Abiraterone is mostly associated with expected cardiac diseases (heart failure, and QT prolongation), expected with the drug. Also described, several cases of hepatotoxicity have been reported, however some cases with fatal outcome suggest that despite a follow-up of the liver function tests, it is difficult to anticipate this risk. Signals concerning acute renal failure and ischemic stroke have arisen. Enzalutamide is more particularly associated with various neurological disorders (convulsions, hallucinations, fatigue, and memory impairment) expected with the drug. While ischemic heart disease is also expected, signals of heart failure and atrial fibrillation have arisen. A potential hepatotoxicity of the molecule is discussed because of cases of cholestatic hepatitis. CONCLUSION: The analysis of the French pharmacovigilance database cases allows to confirm an expected and monitored risk profile in the risk management plan for both drugs. Several signals have arisen, some of which will be investigated through a pharmacoepidemiology study.

Innovative approaches in CNS clinical drug development: Quantitative systems pharmacology.

Clinical trials involving brain disorders are notoriously difficult to set up and run. Innovative ways to develop effective prevention and treatment strategies for central nervous system (CNS) diseases are urgently needed. New approaches that are likely to renew or at least modify the paradigms used so far have been recently proposed. Quantitative systems pharmacology (QSP) uses mathematical computerized models to characterize biological systems, disease processes and CNS drug pharmacology. Integrated experimental medicine should increase the probability and predictability of success while controlling clinical trials costs. Finally, the societal perspective and patient empowerment also offer additional approaches to demonstrate the benefit of a new drug in the CNS field.

Patients' organizations in rare diseases and involvement in drug information: Illustrations with LMC France, the French Association of Chronic Myeloid leukemia.

There are few areas in medicine in which patient-parent advocacy groups play such a central and prominent role as in the field of rare diseases. As illustrated by the French Association of Chronic Myeloid Leukemia (LMC France), its contribution is not only focused on its role as participants or key informant related to clinical studies but also on drug information and drug safety. The discovery of tyrosine kinase inhibitors against the BCR-ABL1 oncogenic fusion protein has revolutionized the management of CML, becoming a chronic illness rather than a life-threatening disease. Because ensuring ongoing well-being requires some knowledge, LMC France has built, in synergy with healthcare professionals from its scientific council, a CML-specific, patient-friendly knowledge base including resources and knowledge related to drug information (drug development, generics, pharmacovigilance) and drug safety using several educational tools such as videos, CML support, and CML drug sheets. To disseminate more largely, an e-university learning for regional key informants from LMC France and also CML patients and their caregivers was launched, including a large resources related to drug information and drug safety in synergy with hematologists and clinical pharmacologists.

Pharmacovigilance and drug-induced rare diseases: Strengths of the French Network of Regional Pharmacovigilance Centres.

The French-style organization in the field of rare diseases allows a close contact between reference centres and regional pharmacovigilance centres thanks to their implementation within the French university hospital. This collaboration leads to highlight more and more drug-induced rare diseases. Through several historical examples (eosinophilia-myalgia syndrome due to L-tryptophan, type 1 narcolepsy with H1N1 pandemic influenza vaccine, capillary leak syndrome, acquired von Willebrand syndrome), it remains clear that pharmacovigilance is the cornerstone of the alert system. Clinicians from the rare disease reference centres can easily report adverse drug reactions (ADRs) to pharmacologists from their regional pharmacovigilance centre. Through experience, collaboration between countries, large database, and sometimes pharmacoepidemiological studies, an alert can then be raised. This collaboration underlines also similarities between the two disciplines, through the frequency of ADRs and diseases, the difficulty of the diagnosis in front of scarce data, and through the unusual worsening symptoms. Patients and associations of patients play also a proactive role as research partners at different steps, to quantify and qualify symptoms and ADRs, and also to develop orphan drugs. These several collaborations are a precious tool to improve patients' outcomes. These close contacts between the different actors are important to make earlier diagnosis of rare diseases and severe ADRs. Rare disease does not have to mean overlooked diseases.

Non-targeted screening for novel psychoactive substances among agitated emergency department patients.

CONTEXT: Novel psychoactive substances (NPS) are being created and introduced at an unprecedented rate, causing frequent, large-scale epidemics. Current identification of NPS in clinical settings in the USA is limited to the retrospective case or small cluster analysis. OBJECTIVE: The purpose of this study was to assess the utility of non-targeted comprehensive drug screening in the agitated patients in an emergency department (ED) setting. MATERIALS AND METHODS: This is a prospective, observational case series that was conducted in the ED of an urban Level I Trauma Center with an annual census of approximately 65,000 patients per year. Since it is common clinical practice at this facility for haloperidol to be used as a second-line chemical restraint when initial dose(s) of benzodiazepines are deemed insufficient, we surmised that the subset of ED patients with psychomotor agitation severe enough to receive both these pharmaceuticals would be likely users of NPS. For 1 month, biweekly pharmacy medication audits identified 49 of these patients. There were sufficient, remaining blood samples from 23 of these patients for analysis. Serum from stored blood samples was analyzed using liquid chromatography-time-of-flight mass spectrometry (LC-TOF/MS; LC 1260, TOF/MS 6230, Agilent). Retrospective chart review was done to identify patient clinical information. RESULTS: Six patient samples yielded seven different NPS: JWH-073, JWH-081, JWH-200, methylenedioxybenzylpiperazine, mephedrone, methoxetamine, and herkinorin. CONCLUSION: This study demonstrates that prospective, non-targeted NPS screening in a selected ED patient population is feasible and effective in identifying NPS.