Sex/gender differences in spontaneous reports to a French Addictovigilance centre.

To specify psychoactive substances and related complications observed in spontaneous reports (SRs) in women versus men, we assessed SRs on substance-linked acute toxicity sent to a French Addictovigilance centre. Over the period 2021-2022, 880 SRs were analysed (33.4% concerned women). Severe complications concerned more men than women (70.3% versus 59.5%; p = 0.0014). In women, the main implicated substances were psychoactive medications (opioids, benzodiazepines). The most frequently reported complication was suicidal behaviour (14.6% versus 7.8%, p = 0.002). In men, SRs concerned mainly illicit substances (cocaine, amphetamines) or misuse of opioid maintenance therapy or nitrous oxide. The main complications in men were infections (12.97% versus 5.4%, p = 0.0006) and neurological troubles (37.6% versus 23.5%, p < 0.0001).Our data highlight sex/gender disparities in substance use and complications, in agreement with recent literature and French national Addictovigilance data.

Isotonitazene, a synthetic opioid from an emerging family: The nitazenes.

From 2019, in the United States and Europe, the synthetic opioid market has diversified with the appearance of the 2-benzylbenzimidazole family, commonly named "nitazenes". In vitro studies show that these synthetic opioids have much higher affinities on µ-opioid receptors: 100 times more than morphine, and slightly higher than fentanyl for isotonitazene, increasing the risk of overdose. In south of France, isotonitazene (IZN) was identified for the first time in March 2023. In this context, there were 9 reports concerning the use of IZN in the south of France over a short period (March-April 2023), with identification of IZN in 4 cases and suspicion in others. They concerned 6 men and 3 women, with a mean age of 44.9±2 years. When available (2 cases), the product had been purchased from a dealer. IZN was identified on sample in 2 cases of overdose. Isotonitazene was also identified in biological samples in 2 cases: 1 case of overdose and coma requiring hospitalization with a favorable outcome (urinary analysis), and a death with post-mortem identification. This was the first identification of this product in France. The immediate broadcast of the alert limited the risks for users and made it possible to quickly inform regional and national health authorities. IZN is under intensive surveillance by the EMCDDA and classified as a narcotic in France since 2021. The analysis of the literature made it possible to identify cases of overdoses requiring very high doses of naloxone and deaths. The emergence of these synthetic opioids constitutes an important signal, due to their superior effects to heroin, their incomplete response to naloxone and the current difficulty in identifying them (devices for analyzing products in the reduction of risks, toxicology laboratories).

Cannabis use and dependence among festival attendees: results from the French OCTOPUS survey.

BACKGROUND: Chronic use of cannabis is associated with an increased risk of psychosocial, mental and physical health impairments. Sociohealth institutions reach a very limited proportion of cannabis users in need of treatment. Using data collected from festival attendees, this study aimed to estimate the prevalence of dependent cannabis users and to characterize cannabis dependence. METHODS: We used data from the cross-sectional OCTOPUS survey carried out at 13 music events in the French department of Loire-Atlantique between July 2017 and July 2018. 383 participants aged 18 or older underwent a face-to-face interview about their basic sociodemographics, tobacco use, alcohol use and past-year substance use. Using the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) criteria, we estimated the prevalence of dependent cannabis users and characterized their dependence. RESULTS: More than two-thirds of participants reported that they had used cannabis in the past 12 months. Among 194 regular cannabis users (at least monthly), 63.4% were dependent. At least 40% of regular users reported health and/or social consequences of cannabis use. Compared to nondependent cannabis users, dependent cannabis users were more likely to be stimulant users and hallucinogen users. CONCLUSIONS: Dependent cannabis use is common among festival attendees, especially among stimulant or hallucinogen users. Festival settings may be important arenas for i) implementing efficient harm reduction measures to prevent dependence and ii) providing information on care structures and promoting the use of care to dependent users. In addition, healthcare professionals should be aware of trends in polysubstance use among dependent cannabis users.

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.

Analgesic switching in chronic users of dextropropoxyphene in France.

BACKGROUND: The combination dextropropoxyphene/paracetamol (DXP/P) was the most prescribed opioid analgesic until its withdrawal in 2011. OBJECTIVES: This study investigated dispensations of analgesics in chronic users of DXP/P during the 18 months following its withdrawal. METHODS: A cross-sectional study repeated yearly was conducted by using the French reimbursement database from 2006 to 2015. Chronic DXP/P users were defined as patients who received at least 40 boxes of DXP/P in the year prior to withdrawal. Data on analgesic dispensing were analyzed at DXP/P withdrawal (T0) and then every 6 months for 18 months. RESULTS: A total of 63 671 subjects had a DXP/P reimbursement in the year prior to its discontinuation, of whom 7.1% were identified as chronic users (mean age: 71.5 years, women: 68.7%). Among the patients taking DXP/P alone at T0 (74.6%), one fourth switched to a peripheral analgesic, one fourth to a combination of peripheral analgesic/opioid, one fourth to another opioid, and the others mainly discontinued their treatment (14.1%) or died. During the following 12 months, most of the subjects taking only peripheral analgesics continued this treatment, while half of the subjects with a combination of opioid/peripheral analgesic or taking only an analgesic remained on this type of treatment. CONCLUSION: Eighteen months after DXP/P withdrawal, more than 10% of patients stopped taking an analgesic. Vigilance is required regarding any change in analgesics by regularly reassessing patients' pain and, in the case of opioid treatments, by monitoring the risk of use disorders.

Erratum: Nitrous oxide: a unique official French addictovigilance national survey.

[This corrects the article DOI: 10.3389/fpubh.2023.1167746.].

[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.

Nitrous oxide: a unique official French addictovigilance national survey.

Introduction: Nitrous oxide has become over the last few years a public health problem in many countries. France has a dedicated health monitoring system dedicated to the surveillance of the abuse, dependence and consequences associated with the use of psychoactive substances coordinated by the French National Agency for the Safety of Medicines and Health Products.We present the French national survey of nitrous oxide. Materials and methods: We analyzed all the cases with nitrous oxide from 2012 to 2021: number of notifications, characteristics of the subjects and consumption, consequences reported and their evolutions over time. In addition, we have made a special focus on the four main complications reported. Results: A total of 525 cases were received with an exponential increase since 2019. We observed changes in the characteristics of the notifications with an increase in the proportion of women [42.7% in 2021 vs. 30.8% in 2020 (p = 0.02)]; an increase in the quantities consumed (use of cylinders); a negative evolution of the contexts of use with a search for self-therapeutic effects and use in violent contexts; an increasing trend of the severity of cases [78.1% in 2021 vs. 70.0% in 2020 (p = 0.07)].The main effects were substance use disorders and/or associated criteria (82.5%), neurological disorders (75.4%), psychiatric symptoms (15.4%) and cardiovascular events (8.6%). In terms of evolution, we observed a significant increase in cases with a use disorder and an increase in neurological complications. Moreover, new serious effects, notably cardiovascular events were reported. Discussion: The combination of high availability, varied effects from euphoria to relief of discomfort in a stressful global pandemic context and the development of dependence could explain the rapid growth of consumption and the seriousness of the cases.It must now be taken into account that (i) Substance use disorders are associated with nitrous oxide consumption; (ii) clinicians must consider "nitrous oxide" in young subjects presenting different types of manifestations; and (iii) stopping consumption is imperative and is the first treatment. In this context, an addictological assessment must also be carried out.

Systematic assessment of non-medical use of prescription drugs using doctor-shopping indicators: A nation-wide, repeated cross-sectional study.

AIMS: The aim of this study was to present the first nation-wide, systematic, repeated assessment of doctor-shopping (i.e. visiting multiple physicians to be prescribed the same drug) during 10 years for more than 200 psychoactive prescription drugs in the 67 million inhabitants in France. DESIGN: This was a nation-wide, repeated cross-sectional study. SETTING AND PARTICIPANTS: Data are from the French National Health Data System in 2010, 2015 and 2019 for 214 psychoactive prescription drugs (i.e. anaesthetics, analgesics, antiepileptics, anti-Parkinson drugs, psycholeptics, psychoanaleptics, other nervous system drugs and antihistamines for systemic use). MEASUREMENTS: The detection and quantification of doctor-shopping relied upon an algorithm that detects overlapping prescriptions from repeated visits to different physicians. We used two doctor-shopping indicators aggregated at population level for each drug dispensed to more than 5000 patients: (i) the quantity doctor-shopped, expressed in defined daily doses (DDD), which measures the total quantity doctor-shopped by the study population for a given drug; and (ii) the proportion doctor-shopped, expressed as a percentage, which standardizes the quantity doctor-shopped according to the use level of the drug. FINDINGS: The analyses included approximately 200 million dispensings to approximately 30 million patients each year. Opioids (e.g. buprenorphine, methadone, morphine, oxycodone and fentanyl), benzodiazepines and non-benzodiazepine hypnotics (Z-drugs) (e.g. diazepam, oxazepam, zolpidem and clonazepam) had the highest proportions doctor-shopped during the study period. In most cases, the proportion and the quantity doctor-shopped increased for opioids and decreased for benzodiazepines and Z-drugs. Pregabalin had the sharpest increase in the proportion doctor-shopped (from 0.28 to 1.40%), in parallel with a sharp increase in the quantity doctor-shopped (+843%, from 0.7 to 6.6 DDD/100 000 inhabitants/day). Oxycodone had the sharpest increase in the quantity doctor-shopped (+1000%, from 0.1 to 1.1 DDD/100 000 inhabitants/day), in parallel with a sharp increase in the proportion doctor-shopped (from 0.71 to 1.41%). Detailed results for all drugs during the study period can be explored interactively at: https://soeiro.gitlab.io/megadose/. CONCLUSIONS: In France, doctor-shopping occurs for many drugs from many pharmacological classes, and mainly involves opioid maintenance drugs, some opioids analgesics, some benzodiazepines and Z-drugs and pregabalin.

[Opioid overdose prevention and naloxone diffusion (POP program): Results of an overview conducted among addiction specialized centres]. / Prévention des surdoses opioïdes et diffusion de naloxone (programme POP) : résultats d'un état des lieux réalisé auprès des structures d'addictologie.

INTRODUCTION: In France, opioids are responsible for the majority of overdose deaths in France. The antidote naloxone is available in France in take home formulations since 2016. Addiction specialized centres are in front-line for naloxone diffusion. The objective was to provide an overview of professional practices, difficulties and needs regarding overdose prevention and naloxone diffusion in these centres of the Provence-Alpes-Côte d'Azur (PACA) region. METHODS: The POP programme "Prevention and harm reduction of opioid overdoses in PACA region" aims to improve the care of patients at risk of overdose and facilitate naloxone diffusion. The 75 addiction specialized centres of the PACA region were invited to respond to a semi-structured interview or a telephone questionnaire. Data collected included 2020 centres' activity and professionals' perceptions of overdose risk in their active file, their practices, difficulties and needs. RESULTS: Overall, 33 centres answered. Among them, 22 were dispensing naloxone with a mean of 20 kits dispensed in 2020 (min-max: 1-100). Two strategies were pointed out: systematically offering of naloxone to all opioids users or targeting people considered at risk. Several difficulties limiting naloxone diffusion were expressed: a lack of knowledge from opioids users, refusal from people not feeling concerned or refusing the injectable formulation, a lack of training of some professionals to be comfortable with the tool or reglementary or time constraints. CONCLUSION: Naloxone diffusion is incrementally getting into common practices. However barriers are persisting. On the basis of expressed difficulties and needs, information and training materials were co-designed and diffused.

Alprazolam misuse: Analysis of French Addictovigilance Network data from 2011 to 2020.

OBJECTIVES: Alprazolam, a high-potency and short-acting anxiolytic benzodiazepine, is one of the most misused benzodiazepines in France. In the context of various reports on alprazolam misuse during the COVID-19 pandemic, the objective of this study was to assess alprazolam abuse potential by analyzing French addictovigilance and international data. METHODS: Data collected from 2011 to 2020 using the following epidemiological tools of the French Addictovigilance Network were analyzed: spontaneous reports (SRs), OPPIDUM (addiction care center data), OSIAP (falsified prescriptions), DRAMES (substance-related deaths), and chemical submission surveys. Moreover, the VigiBase™ database was analyzed to evaluate alprazolam abuse liability worldwide. RESULTS: During the study period, 675 SRs concerning alprazolam misuse were recorded (sex ratio: Ì´1; median age: 39 years). The desired effects were intensification of the therapeutic anxiolytic effect, euphoric effect, and management of substance withdrawal. Alprazolam was the third and first benzodiazepine listed in OPPIDUM and OSIAP surveys. Analysis of the SR and OPPIDUM data showed a recent increase in the alprazolam-opioid combination. In DRAMES data, alprazolam was directly linked to 11 deaths (associated with opioids in 10/11). VigiBase™ data analysis highlighted that France was the third country with the most cases of alprazolam misuse. The disproportionality analysis showed that in France, alprazolam was associated with higher risk of misuse and dependence compared with other benzodiazepines: reporting odds ratio=1.43, (95% CI: 1.04-1.95) and=1.97 (95% CI:1.50-2.59), respectively. CONCLUSIONS: This study highlighted an increase in various signals of alprazolam abuse in France, and an increased use of the alprazolam-opioid combination that was also linked to most of the recorded alprazolam-linked deaths. These signals have been reported also in the international literature, and should be thoroughly investigated.

Minors and young adult's hospitalizations after "chimique" consumption in Mayotte Island: Which substances are involved?

OBJECTIVES: Over the last 10 years, the use of an unknown drug called "chimique" has emerged, among adolescents and young adults in precarious situations in Mayotte Island. To date, the exact composition of "chimique" is still poorly documented, but seizures made on the Island at the same time indicated that it would be mainly composed of synthetic cannabinoids receptor agonists (SCRAs). The objective of this study was to identify which substances, among those consumed under the name of "chimique", leading to hospital admissions. METHODS: Between 1st march and 30th June 2019, all patients, over 14 years old, hospitalized in the emergency department of Mayotte hospital after use of "chimique" for which the physician required toxicological analysis were included. Blood samples and clinical data were recorded for each patient. Toxicological analyses were performed using high resolution mass spectrometry (UPLC-MS/QTOF). RESULTS: Twelve patients were included: 11 males and 1 female. The mean age was 26 years (median age: 22). There were 2 minors. Clinical presentations varied, mainly psychiatric and neurologic disorders were observed. No death was reported. Toxicological analysis identified psychoactive substances such as THC and/or its metabolites (n=3) and MDMB-4en-PINCA (n=2). The other substances identified were mainly part of the patients' treatment. CONCLUSION: This is the first study conducted in the Indian Ocean confirming the presence of SCRAs in the "chimique". For a while, the consumption of SCRAs in France seemed to be of limited importance. However, their use has become important in the Indian Ocean since the spread of "chimique" in Mayotte. It continues to spread especially in Reunion Island since 2017 under the name of "chamane".

More extreme duplication in FDA Adverse Event Reporting System detected by literature reference normalization and fuzzy string matching.

PURPOSE: Literature reports of adverse drug events can be replicated across multiple companies, resulting in extreme duplication (defined as a majority of reports being duplicates) in the FDA Adverse Event Reporting System (FAERS) database because they can escape legacy duplicate detection algorithms routinely deployed on that data source. Literature reference field, added to in 2014, could potentially be utilized to identify replicated reports. FAERS does not enforce adherence to the Vancouver referencing convention, thus the same article may be referenced differently leading to duplication. The objective of this analysis is to determine if variations of the same literature references observed in FAERS can be resolved with text normalization and fuzzy string matching. METHODS: We normalized the literature references recorded in the FAERS database through the first quarter of 2021 with a rule-based algorithm so that they better conform to the Vancouver convention. Levenshtein distance was then utilized to merge sufficiently similar normalized literature references together. RESULTS: Normalization of literature references increases the percentage that can be parsed into author, title, and journal from 61.74% to 93.93%. We observe that about 98% of pairs within groups do have a Levenshtein similarity of the title above the threshold. The extreme duplication ranged from 66% to 87% with a median of 72% of reports being duplicates and often involved addictovigilance scenarios. CONCLUSIONS: We have shown that these normalized references can be merged via fuzzy string matching to improve enumeration of all the individual case safety reports that refer to the same article. Inclusion of the PubMed ID and adherence to the Vancouver convention could facilitate identification of duplicates in the FAERS dataset. Awareness of this phenomenon may improve disproportionality analysis, especially in areas such as addictovigilance.

Addictovigilance in women, the hidden part of the iceberg?

Epidemiology of substance use disorders and their complications is driven by a male predominance, and women, even if they are more and more prevalent, are never specifically represented in studies in the field. Apart from the time of pregnancy, which in itself requires specific prevention, treatment and follow-up, the importance of the sex of women in the complications of substance abuse is neglected. To illustrate, we described some characteristics of women identified in the addictovigilance information system in France and Europe, related to drug use disorders (both for illicit substances and medications). Even if the exposure to some psychoactive substances remains more prevalent in men, women, and particularly young women, seem to be more vulnerable to the adverse effects of these substances, as observed for opioid analgesics, benzodiazepines, cannabis and even nitrous oxide. It is now imperative that the female sex/gender be taken into consideration in addictovigilance expertise and in drug safety in general, even for substances for which use is predominantly male. In addition, the adequate management of the women requires the development of specific prevention and care strategies.

Increase of cannabis and cocaine use by pregnant women in France from 2005 to 2018: Insights of the annual cross sectional OPPIDUM survey.

CONTEXT: Substance use disorders during pregnancy are associated with antenatal, neonatal and long-term adverse drug reactions in children. The aim of this study was to describe, using data from OPPIDUM survey, the evolution of illicit substance use or diverted prescription drug use among pregnant women visiting French addiction care centres from 2005 to 2018. MATERIAL AND METHOD: The current study focused on women of childbearing age (15-44years old) identified as pregnant, and included in the OPPIDUM survey from 2005 to 2018. OPPIDUM is a French nationwide survey repeated each year since 1995, which anonymously collects information on drug abuse and dependence observed in patients recruited in addiction care centres. Patterns of illicit substance use, psychoactive medications, and opioid maintenance treatment (OMT) were described over time (by period of 2 years) and changes between 2005-2006 and 2017-2018 were investigated. RESULTS: From 2005 to 2018, 784 pregnant women were included in the OPPIDUM survey (median age 28, interquartile range (IQR): 25-33). The proportion of women using exclusively cannabis (1.2% vs. 17.1%, P=0.0004) and cocaine (including crack) use (4.7% vs. 14.3%, P=0.0384) significantly increased over the period. Considering the first substance reported as leading to dependence, heroin significantly decreased (78.8% vs. 50.0%, P=0.0002) whereas cannabis significantly increased (5.9% vs. 25.7%, P=0.0005). CONCLUSION: This study highlighted an important change of patterns of drug use by French pregnant women over a 14-year-period. Health professionals must be aware of these changes to adapt prevention and care among women of childbearing age and pregnant women.

Ten-year trends in hospitalizations related to cocaine abuse in France.

In France, the abuse/misuse of psychoactive substances, including cocaine, is monitored via spontaneous notifications, and under-reporting is its main limitation. Therefore, the French national hospital discharge database (Programme de Médicalisation des Systèmes d'information [PMSI]) was used to identify all hospital stays possibly due to complications related to cocaine use. The objective was to determine the main trends in the rate of cocaine-related hospitalizations from 2010 to 2019 by age category and by areas. Relevant PMSI data were extracted using the International Classification of Diseases (10th edition). In France, hospitalizations for cocaine-related complications increased by fourfold (2461 in 2010, 9843 in 2019, +300%). This increase was similar in men and women and was observed in each age category. Patients were mainly men (75% in 2010 and in 2019), with a median age of 38.5 and 35.2 years for men and women, respectively, in 2019. Cocaine poisoning in pediatric patients (0-9 years) concerned less than 10 patients in 2010 and 21 patients in 2019. PMSI data analysis shows an overall increase of cocaine-related hospitalizations in France from 2010 to 2019 that can be linked in part to an increasing recreational use. The increase of pediatric cases of cocaine poisoning suggests a trivialization of cocaine consumption.