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Danièle Debruyne,1,2 Reynald Le Boisselier1 1Centre for Evaluation and Information on Pharmacodependence - Addictovigilance (CEIP-A), 2Toxicology and Pharmacology Laboratory, Department of Pharmacology, University Hospital Centre Côte de Nacre, Caen, France Abstract: New psychoactive drugs that have appeared over the last decade are typically dominated by cathinones and synthetic cannabinoids (SCs). SCs have been emerging as recreational drugs because they mimic the euphoria effect of cannabis while still being legal. Sprayed on natural herb mixtures, SCs have been primarily sold as “herbal smoking blends” or “herbal incense” under brand names like “Spice” or “K2”. Currently, SCs pure compounds are available from websites for the combination with herbal materials or for the use in e-cigarettes. For the past 5 years, an ever increasing number of compounds, representative of different chemical classes, have been promoted and now represent a large assortment of new popular drugs of abuse, which are difficult to properly identify. Their legal status varies by country with many government institutions currently pushing for their control. The in vitro binding to CB1/CB2 receptors is usually well-known and considerable differences have been found in the CB1 versus CB2 selectivity and potency within the different SCs, with several structure-activity relations being evident. Desired effects by CB1 agonist users are relaxation/recreative, however, cardiovascular, gastrointestinal, or psychiatric/neurological side effects are commonly reported. At present there is no specific antidote existing if an overdose of designer drugs was to occur, and no curative treatment has been approved by health authorities. Management of acute toxic effects is mainly symptomatic and extrapolated from experience with cannabis. Keywords: synthetic cannabinoids, chemistry, analysis, pharmacology, toxicology, dependence, medical care

Magalie Paillet-Loilier,1 Alexandre Cesbron,1 Reynald Le Boisselier,2 Joanna Bourgine,1 Danièle Debruyne1,2 1Toxicology and Pharmacology Laboratory, 2Centre d'Evaluation et d'Information sur la Pharmacodépendance – Addictovigilance (CEIP-A), Department of Pharmacology, University Hospital Centre, Caen, France Abstract: Substituted cathinones are synthetic analogs of cathinone that can be considered as derivatives of phenethylamines with a beta-keto group on the side chain. They appeared in the recreational drug market in the mid-2000s and now represent a large class of new popular drugs of abuse. Initially considered as legal highs, their legal status is variable by country and is rapidly changing, with government institutions encouraging their control. Some cathinones (such as diethylpropion or pyrovalerone) have been used in a medical setting and bupropion is actually indicated for smoking cessation. Substituted cathinones are widely available from internet websites, retail shops, and street dealers. They can be sold under chemical, evocative or generic names, making their identification difficult. Fortunately, analytical methods have been developed in recent years to solve this problem. Available as powders, substituted cathinones are self-administered by snorting, oral injestion, or intravenous injection. They act as central nervous system stimulants by causing the release of catecholamines (dopamine, noradrenaline, and serotonin) and blocking their reuptake in the central and peripheral nervous system. They may also decrease dopamine and serotonin transporter function as nonselective substrates or potent blockers and may inhibit monoamine oxidase effects. Nevertheless, considerable differences have been found in the potencies of the different substituted cathinones in vitro. Desired effects reported by users include increased energy, empathy, and improved libido. Cardiovascular (tachycardia, hypertension) and psychiatric/neurological signs/symptoms (agitation, seizures, paranoia, and hallucinations) are the most common adverse effects reported. Severe toxicity signs compatible with excessive serotonin activity, such as hyperthermia, metabolic acidosis, and prolonged rhabdomyolysis, have also been observed. Reinforcing potential observed in animals predicts a high potential for addiction and abuse in users. In case of overdose, no specific antidote exists and no curative treatment has been approved by health authorities. Therefore, management of acute toxic effects is mainly extrapolated from experience with cocaine/amphetamines. Keywords: substituted cathinones, chemistry, analysis, pharmacology, toxicology, dependence, medical care

Public health issues related to chronic pain management and the risks of opioid misuse and abuse remain a challenge for practitioners. Data on the prevalence of disorders related to the use of prescribed opioids in patients suffering from chronic pain remains rather patchy, in particular because of the absence of a gold standard for their clinical assessment. We estimated the prevalence of prescription opioid misuse (POM), using a specific and validated opioid misuse scale (POMI-5F scale), in adults with chronic non-cancer pain. Nine-hundred-fifty-one (951) patients with opioids prescription and followed-up in pain clinics and addictology centers for chronic non-cancer pain (CNCP) completed the survey interview. The results suggest that 44.4% of participants have POM, accompanied by overuse (42.5%), use of opioids for effects other than analgesia (30.9%), withdrawal syndrome (65.7%), and craving (6.9%). The motivations cited for POM, apart from pain relief, were to calm down, relax and improve mood. POM was shown to be related to male sex (OR 1.52), young age (OR 2.21) and the presence of nociplastic pain (OR 1.62) of severe intensity (OR 2.31), codeine use (OR 1.72) and co-prescription of benzodiazepines (OR 1.59). Finally, despite the presence of three subgroups of misusers, no factor was associated with the intensity of misuse, reinforcing the view that distinguishing between strong and weak opioids is not appropriate in the context of use disorder. Almost half of patients with CNCP misuse their prescribed opioid. Practitioners should be attentive of profiles of patients at risk of POM, such as young, male patients suffering from severe nociplastic pain, receiving prescription for codeine and a co-prescription for benzodiazepine. We encourage French-speaking practitioners to use the POMI-5F scale to assess the presence of POM in their patients receiving opioid-based therapy.Clinical Trial Registrationclinicaltrials.gov, identifier NCT03195374

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., (Copyright © 2023 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

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., (© 2024 The Authors. Fundamental & Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of Société Française de Pharmacologie et de Thérapeutique.)

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: ̴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., (Copyright © 2023 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

Aims: Analgesics are the most widely used medicines worldwide. In parallel, opioid abuse has increased and is of major concern. The accessibility of pharmacologically powerful medicines and the addictovigilance signals in France about the risk of opiates addiction call for an overview of analgesic use. The objective of this study was to investigate the use of analgesics reimbursed in France over a 10-year period through its prevalence., Methods: A cross-sectional study repeated yearly was conducted by using data from the French reimbursement database from 2006 to 2015. Analgesics were classified according to their pharmacological potency: prevalence of use for each category and sociodemographic characteristics of patients treated were analysed., Results: The annual prevalence of analgesic use was high and increased during the study period (59.8%, 253 976 users in 2015). In 2015, prevalence was always higher in women and increased with age, except for those older than 84 years. Peripheral analgesics were the most used (55.3%, 234 739 users). The prevalence of weak analgesic use decreased (21.3%, 90 257 users), mainly due to the definitive withdrawal of dextropropoxyphene in France in 2011, which was not offset by an increase in the consumption of other weak analgesics. For strong analgesics (1.2%, 5129 users), morphine was the most widely used, with a dramatic increase in oxycodone use, especially in the elderly., Conclusion: The prevalence of analgesic use is high: approximately 31 million adults had at least 1 analgesic reimbursed in 2015. The most widely used analgesics were peripheral analgesics, far ahead of opioid analgesics., (© 2020 The British Pharmacological Society.)

Objective : Drug-induced hypoglycaemia has been described with the use of tramadol and methadone. The authors aimed to determine if drug-induced hypoglycaemia could be a class effect for opioids. Methods : The authors performed a disproportionality analysis in VigiBase®, the WHO global individual case safety report database with nine opioids (codeine, fentanyl, hydromorphone, methadone, morphine, oxycodone, tramadol, buprenorphine and nalbuphine) using the broad Standardised MedDRA Query for hypoglycaemia. The authors also carried out a descriptive study of opioid-induced hypoglycaemia in the French PharmacoVigilance DataBase (FPVDB) using the MedDRA Preferred Term 'hypoglycaemia'. Results : The global adjusted Reporting Odds Ratio (aROR) value for the 9 opioids was 1.53 (95% CI 1.52-1.54). The aROR ranged from 1.09 to 1.97 depending on the opioid, but all were statistically significant. A sex ratio of 0.74 was found for the reports of opioid-induced hypoglycaemia in Vigibase®. The authors also found 133 reports of hypoglycaemia in the FPVDB related to opioids. Among the reports, 55 were glycaemic imbalances in diabetics occurring shortly after the start of opioid treatment. Conclusion : This work highlighted a significant association between all opioids and hypoglycaemia, thereby indicating that opioid-induced hypoglycaemia is probably a class effect. Women and/or diabetics seem to be more at risk for developing opioid-induced hypoglycaemia.

Ephenidine, diphenidine, and methoxphenidine belong to the family of diarylethylamines that are psychoactive substances derived from lefetamine (N, N-di-methyl-1,2-diphenylethylamine, also called L-SPA). These dissociative anesthetic compounds act as potent and selective N-methyl-d-aspartate receptor antagonists and were recently classified as narcotic drugs in France. The available data suggest a significant risk of psychic and somatic complications. To obtain more information, this retrospective study analyzed all spontaneous notifications of serious cases of ephenidine, diphenidine, and methoxphenidine abuse collected by the French Addictovigilance Network from 2012 to 2016 and classified them as proven, probable, and possible. For each case, age, sex, concomitantly ingested substances, pattern of abuse of psychoactive drugs, and related complications (scored using the poisoning severity score) were collected. Eighteen cases were identified (one in 2013, five in 2015, and 12 in 2016) in 16 men (median age: 31.5 years [IQR 25-75% 27-34]). Ephenidine, diphenidine, and methoxphenidine were involved in four, seven, and 11 cases, respectively. No case was considered proven, 16 cases were considered possible, and two probable due to polysubstance abuse (co-ingestion of other new psychoactive substances). The reported clinical complications were minor in five cases, moderate in six cases, and serious in four cases, and included psychiatric, neurologic, and cardiovascular problems. This analysis indicates that the number of reported cases progressively increased from 2012 to 2016 and mainly concerned methoxphenidine. The addictive potential of these substances seems highly probable; but further investigations are needed to limit their harmful effects., (© 2018 Société Française de Pharmacologie et de Thérapeutique.)

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., (Copyright © 2017 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

Methylenedioxymethamphetamine (MDMA), the active compound of ecstasy, has been used for several years, especially by young adults to benefit of psychostimulant properties. By raising the level of neuromodulators in the synapsis, MDMA can cause psychiatric and physical injuries. After reduced supplies in 2009 (number of ecstasy seizures equal to 10 percent of those recorded in 2002), judicial authorities now observed an increased availability (a half more part of seizures in 2012 than 2010). From its "Spontaneous Notifications" data base and "deaths in connection with the abuse of medicine and substances (DRAMES)", "observation of illegal drugs and misuse of psychotropic medications" (OPPIDUM), and "observation of drug dependencies in ambulatory medicine" (OPEMA) national inquiries, the French Addictovigilance network (CEIP-A) highlighted the increasing consumption of MDMA. The way of use appeared quite unchanged: users were mainly young men between 25 and 30 years; they favored an occasional use but mainly combined other products such as alcohol, cannabis and other stimulants. Severity of the clinical cases, based on hospital care and forensic data, could be consistent with the higher amounts of MDMA measured in pills., (Copyright © 2016 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

New substances, also known as "designer drugs" or "legal highs" are increasingly available to drug users. Two hundred and fifteen hitherto unlisted substances have been notified by European Union member states since 2005. These synthetic drugs, which have been developed to side-step the legislation on drugs, are analogues or derivatives of existing drugs and medications. The availability of these "legal highs", sold on Internet under various denominations such as bath salt, plant fertilizer, chemical not intended for human use, or spice, is unlimited. The effects felt by users vary, and the substances may be stimulant, entactogenic, hallucinogenic, psychedelic or dissociative. The pharmacological targets also vary, and may be either the increase of extracellular levels of neurotransmitters via different mechanisms (reuptake inhibition, stimulation of intracellular release) or else fixation on specific receptors. Several chemical classes, themselves divided into sub-classes, are involved: phenethylamines, tryptamines, piperazines, cathinones, cannabinoids etc. The toxicity of the main members of these categories is increasingly well known, the most deleterious being behavioural effects, physical manifestations, and cardiovascular consequences. However, small variations in their chemical structure can generate effects that are quantitatively different, thus enhancing their toxicity or addictive potential, and much remains to be achieved in terms of knowledge about these new drugs. These substances are indeed present on the French territory, as shown by data provided by the Observatoire Français des Drogues et Toxicomanies, and notifications by the French Addictovigilance network. Screening in clinical toxicology laboratories is not widespread, since these molecules are not detected by the standard screening tests, so that there is probably an under-estimation of the use of these new drugs. The legislation on these substances changes regularly, with more and more countries classifying them as "narcotics" or illegal psychotropic drugs so as to restrict their use, applying a generic classification when possible., (© 2015 Société Française de Pharmacologie et de Thérapeutique.)

It is important to assess drug abuse liability in 'real life' using different surveillance systems. Some are based on specific population surveys, such as individuals with drug abuse or dependence, or under opiate maintenance treatment, because this population is very familiar with drugs and is more likely to divert or abuse them. In France, an original surveillance system based on this specific population and called 'Observation of illegal drugs and misuse of psychotropic medications (OPPIDUM) survey' was set up in 1990 as the first of its kind. The aim of this article is to describe this precursor of French drug abuse surveillance using different examples, to demonstrate its ability to effectively give health authorities and physicians interesting data on drug abuse. OPPIDUM is an annual, cross-sectional survey that anonymously collects information on abuse and dependence observed in patients recruited in specialized care centers dedicated to drug dependence. From 1990 to 2010, a total of 50,734 patients were included with descriptions of 102,631 psychoactive substance consumptions. These data have outlined emergent behaviors such as the misuse of buprenorphine by intravenous or nasal administration. It has contributed to assess abuse liability of emergent drugs such as clonazepam or methylphenidate. This surveillance system was also able to detect the decrease of flunitrazepam abuse following implementation of regulatory measures. OPPIDUM's twenty years of experience clearly demonstrate that collection of valid and useful data on drug abuse is possible and can provide helpful information for physicians and health authorities., (© 2013 The Authors Fundamental and Clinical Pharmacology © 2013 Société Française de Pharmacologie et de Thérapeutique.)

Designer drugs are currently marketed as substitutes for stimulant drugs as cocaine, amphetamine, MDMA...Unlike compounds listed as narcotics, these new substances are deliberately synthesized to avoid anti-drug laws. Among them, mephedrone (4-methylmethcatinone) that belongs to cathinone family, has been recently introduced in France. Users report positive euphoric and entactogenic effects. They also describe negative effects such as increased dependence towards the drug itself and larger craving for tobacco and alcohol. The numerous and various described adverse effects include psychoactive, digestive, cardiovascular... effects. Some fatality cases have been reported in scientific literature or in press and attributed to mephedrone often in association with other substances. Mephedrone has been listed as narcotic in several European countries and more recently in France., (© 2010 Société Française de Pharmacologie et de Thérapeutique.)