Substance use disorder of equimolar oxygen-nitrous oxide mixture in French sickle-cell patients: results of the PHEDRE study.

BACKGROUND: In many countries, nitrous oxide is used in a gas mixture (EMONO) for short-term analgesia. Cases of addiction, with significant misuse, have been reported in hospitalized patients. Patients suffering from sickle cell disease (SCD) could represent a high-risk population for substance use disorder (SUD) due to their significant pain crisis and repeated use of EMONO. The objective of the PHEDRE study was to assess the prevalence of SUD for EMONO in French SCD patients. RESULTS: A total of 993 patients were included. Among 339 EMONO consumers, only 38 (11%) had a SUD, with very few criteria, corresponding mainly to a mild SUD due to a use higher than expected (in quantity or duration) and relational tensions with the care teams. Almost all patients (99.7%) were looking for an analgesic effect, but 68% of patients were also looking for other effects. The independent risks factors associated with at least one SUD criterion were: the feeling of effects different from the expected therapeutic effects of EMONO, at least one hospitalization for vaso occlusive crisis in the past 12 months and the presence of a SUD for at least one other analgesic drug. CONCLUSIONS: The use of EMONO was not problematic for the majority of patients. Manifestations of SUD that led to tensions with healthcare teams should alert and lead to an evaluation, to distinguish a true addiction from a pseudoaddiction which may be linked to an insufficient analgesic treatment related to an underestimation of pain in SCD patients. TRIAL REGISTRATION: Clinical Trials, NCT02580565. Registered 16 October 2015, https://clinicaltrials.gov/.

Assessment of 19 years of a prospective national survey on drug-facilitated crimes in France.

Drug facilitated-crime or chemical submission (DFC/CS) is defined as the concealed or forced administration of psychoactive substances to a victim for criminal purposes. This is a national program set up in the early 2000 s in the form of a prospective multicenter survey, the results of which this manuscript presents. Over this 19-year period, 5487 cases were collected, analyzed and classified into 54 % of suspected cases, 29 % of chemical vulnerability (CV) cases and 17 % of proven DFC/CS cases. In the overall data, the most prevalent victims were female (81 %), with an average age of 27 years. Sexual assault was the most frequent aggression (77 %), followed by theft (14 %). Victims of proven DFC/CS cases were from of all ages including children and elderly. In 934 victims of DFC/CS, 100 various psychoactive substances were detected mostly represented by benzodiazepines and z-drugs (55 %), various sedatives including antihistamines (16 %) and non-therapeutic substances (16 %). Gamma-hydroxybutyric acid (GHB) was found in 4 % cases. In CV cases, alcohol (90 %) and cannabis (32 %) intake were mainly involved. In France, despite prevention messages, DFC/CS has been an epidemic for many years and has been proven by our national study. This national program has the aim to identifying the substances used but unfortunately not the goal to fight against this phenomenon. Since 2009, we observed a new modus operandi of the aggressors who pose as taxi drivers facilitating the reception of the victims leaving nightclubs. We can emphasize that GHB is not the "date rape drug" but rather the benzodiazepine class is.

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.

Chemsex practice in France: An update in Addictovigilance data.

BACKGROUND: Complications related to Chemsex practice (consumption of psychoactive substances in sexual context) were first assessed by the French Addictovigilance Network in 2014. In response to the deaths reported in 2016, a new expert report was commissioned to update the complications and evolution of Chemsex-related practices in France. METHODS: Between January 2008 and August 2017, all Chemsex cases collected through the French Addictovigilance Network's epidemiological tools were analyzed. Comparison of data between two periods (before and after 2014) was performed to assess the evolution of practices. RESULTS: Over the entire survey period, 235 Chemsex cases were identified, all of them in men, with a mean ± SD age of 39 ± 11 years, including 24 deaths (10.2%). An increase in the number of reported cases was observed from one in 2008 to 50 in the first 8 months of 2017. The main medical histories include human immunodeficiency virus (HIV; 45%) and hepatitis C (20%) infections, and substance use disorders (36%). In those 235 cases, 345 psychoactive substances were identified, mainly cathinones. Polydrug use was reported in 75% of cases. The main complications were substance use disorders (63%), acute neurological or cardiovascular intoxications (50%), various psychiatric disorders (39%), and viral and bacterial infections (18%). γ-Butyrolactone (GBL) was present in 95% of comas. An increase in the number of deaths was observed during the survey period. CONCLUSION: The French Addictovigilance Network, via this pharmacoepidemiological surveillance, warns public health authorities in order to support harm reduction programs and the management of Chemsexers.

Descriptive analysis of sickle cell patients living in France: The PHEDRE cross-sectional study.

BACKGROUND: Sickle cell disease (SCD) induces chronic haemolytic anaemia and intermittent vaso-occlusion that results in tissue ischaemia causing acute, severe pain episodes that can lead to frequent hospitalizations. These consequences can have repercussions on family, social, school and/or professional life. Here, we present some of the results of the PHEDRE study (Pharmacodépendance Et DREpanocytose-drug dependence and sickle-cell disease), which is the largest study of patients with SCD in France. This paper intends to describe characteristics of the French SCD population. We also aimed to assess the impact of the disease on the lives of patients using objective and subjective variables. METHODS: The PHEDRE study was a national multicentric observational study. Adults, adolescents and children with a confirmed SCD diagnosis were included in the study by their referring doctor. Then, they were interviewed by phone about their socioeconomic status, about the impact of the disease on their lives and about their analgesic and psychoactive drug use. RESULTS: The study population consisted of 872 patients (28% were minors). Seventy-two percent of adults were active, and all minors were in school. Many patients presented criteria of severe SCD. Seventy-five percent were homozygous SS, 15% were double heterozygotes SC and 8% were heterozygotes Sßthal, 87% received specific treatment, 58% were hospitalized at least once for vaso-occlusive crisis in the past 12 months, and the number of analgesic drugs taken averaged 3.8. Seventy-five percent of patients reported academic or professional consequences related to their SCD, and 52% reported social consequences. CONCLUSIONS: The impact of SCD on patients' lives can be significant, nevertheless their social integration seems to be maintained. We highlighted respect of recommendations regarding analgesic treatments and only a few patients used tobacco, alcohol or cannabis. TRIAL REGISTRATION: Clinical Trials, NCT02580565; https://clinicaltrials.gov/ Registered 16 October 2015.

[Thirty years of nefopam abuse in France]. / Trente ans d'abus de néfopam en France.

AIM OF THE STUDY: The use of nefopam is constantly increasing in France. The objectives of this study were to quantify the intensity of the drug dependence signal, to identify the populations at risk and the risk factors of dependence. METHODS: All serious and non-serious cases of misuse, abuse, drug dependence, overdose and withdrawal syndrome reported to the French Addictovigilance Network since 1988 were reviewed. An analysis of nefopam reimbursement data from the French national EGB (échantillon généraliste des bénéficiaires) database for the period 2006-2017 was also performed. RESULTS: The drug dependence profile of nefopam is close to that of a psychostimulant. Our literature review and the analysis of spontaneous reports confirm the risk of abuse and dependence of nefopam. In addition to a frequent psychiatric history (depression, psychosis, anxiety), nearly half of the patients also present addictive disorders, including more than one-third with opioid-dependence. In almost half of the 120 reported cases, the main adverse reaction was dependence and the frequency of serious effects was greater than 40%. In nearly 70% of the reported cases, the use was associated with chronic pain, which might explain the prolonged use. Moreover, the analysis of data on the reimbursement of nefopam in the general population showed that one French person out of two, having a prescription for nefopam, presented chronic pain. However, nefopam is only indicated in the treatment of acute painful conditions. Although it does not seem to be associated with a greater risk of abuse or dependence, taking the drug orally is another very frequent off-label use that needs to be regulated. CONCLUSION: In France, the prescription of nefopam outside of its marketing authorization is regrettable, because it contributes to the development of abuse and drug dependence.

Use of new psychoactive substances to mimic prescription drugs: The trend in France.

Among the expanding world of New Psychoactive Substances (NPS), Designer Medicines (DM) are designed to mimic psychoactive drugs and might lead to adverse events of various severity. The DM category includes designer benzodiazepines (DB), phenmetrazine, modafinil, methylphenidate analogs, and novel synthetic opioids (NSO). To investigate DM-related complications in France, all data on NPS collected in the French Addictovigilance network database through spontaneous reports (SRs) and the annual survey on deaths related to the abuse of licit and illicit psychoactive substances (DRAMES survey) between 2009 and 2017 were analyzed. From 2009-2017, about 800 cases of NPS-related abuse or somatic complications were reported to the French Addictovigilance Network, including 71 fatal cases (9%). DM use progressively increased over the years, particularly after 2013 (4% of all SRs on NPS in 2011 versus 14 % in 2017). Moreover, DM were implicated in 17 % of NPS-related deaths in France, just after cathinones (43 %) and dissociative drugs (22 %). NSO, DB and phenidate analogs were identified in 42 %, 25 % and 25 % of all DM-related death reports, respectively. DM seem to interest a new target group of users that includes mainly patients and healthy people rather than substance users. The availability on the Internet of compounds mimicking therapeutic drugs is a worrying phenomenon that could lead to their uncontrolled use.

[Clinical complications of new synthetic drugs]. / Complications cliniques des nouvelles drogues de synthèse.

Clinical complications of new synthetic drugs. Synthetic drug intoxication alerts have been at the forefront in recent years in France and abroad. We are thus witnessing an infinite production of derivatives of ancient psychoactive molecules belonging to various pharmacological classes, thus creating the name of new of synthetic products or "new psychoactive substances". Faced with evocative clinical symptoms, the clinician remains puzzled by the negativity of routine toxicological analyzes.

Complications cliniques des nouvelles drogues de synthèse. Les alertes d'intoxication aux drogues de synthèse occupent le devant de la scène ces dernières années en France et à l'étranger. On assiste à une production infinie de dérivés de molécules psychoactives anciennes appartenant à des classes pharmacologiques diverses et créant ainsi la dénomination de nouveaux produits de synthèse ou new psychoactive substances. Face à un tableau clinique évocateur, le clinicien reste perplexe devant la négativité des analyses toxicologiques de routine.

[Use of psychostimulants in a sexual context: Analysis of cases reported to the French network of Addictovigilance Centers]. / Usage de psychostimulants dans un contexte sexuel : analyse des cas rapportés au Réseau français des centres d'addictovigilance. Évaluation des risques liés à la pratique du SLAM.

The "SLAM" phenomenon is an increasingly popular practice, in Paris and London gay scene, defined by 3 characteristics: injection, sexual party and psychostimulant drugs. The French Medical Agency requested a risk assessment of "SLAM" and more broadly of the use of psychostimulants in a sexual context, by the analysis of complications related to this practice notified to the French Network of Addictovigilance Centers. All cases of complications related to "SLAM" practice, including cases of abuse or dependence, and somatic and psychiatric complications, were analysed. Between January 2008 to December 2013, 51 cases were collected. Users were exclusively men, with a mean age of 40 years, having psychostimulants exposure in a sexual context, mainly in men who have sex with men (MSM) context (100%, n=35). The prevalence of human immunodeficiency virus (HIV) infection was 82% (n=32) with a high level of HIV/hepatitis C virus (HCV) co-infection (50%, n=16). The main psychostimulants reported are synthetic cathinones (89.5%). Cathinones users tended to be polydrug users: 62% also reported use other than psychoactive substances (gamma-butyrolactone [GBL], ketamine, methylenedioxyméthamphetamine [MDMA], lysergic acid diethylamide [LSD]…). The main complications were psychiatric disorders in 50% (psychotic symptoms, agitation, anxiety, suicidal ideas or attempt and forensic problems), acute intoxication in 25% (including 3 deaths), dependence and abuse in 17% and infectious complications in 8% (viral seroconversion). Health professionals as well as users should be aware of the physical (cardiovascular) and behavioural (psychic, fast dependence syndrome) toxicity of cathinones. Risk reduction policy must be targeted to the population of MSM with specific interventions both on risky sexual behavior and substance use.

Patterns of Methylphenidate Use and Assessment of Its Abuse among the General Population and Individuals with Drug Dependence.

PURPOSE: The aim of this study was to describe the extent of methylphenidate (MPH) abuse and characterize its patterns by following several cases involving intravenous administration of crushed MPH tablets. METHODS: First, a drug reimbursement database (covering 4 million inhabitants) was explored to assess the magnitude of MPH abuse among the general population, and second, a specific study based on individuals with drug dependence was performed to describe abusers' characteristics (n = 64), patterns of abuse and clinical implications. RESULTS: From 2005 to 2011, the number of patients who were dispensed MPH at least once increased by 166%. The patients with 'deviant' patterns of MPH consumption were mainly male adults with opiate maintenance treatment reimbursements. MPH abusers had precarious living conditions. Half of them consumed MPH daily by intravenous route and reported amphetamine-like effects (cardiovascular events, weight loss, psychiatric adverse events). CONCLUSION: Given the increase of MPH use, it is important to warn the scientific community about possible MPH abuse, especially in individuals with drug dependence. This study has facilitated public health intervention and dissemination of information related to MPH abuse among health care professionals at local and national levels.

[Mephedrone: a designer drug of recent use in France]. / La méphédrone : une designer drug d'usage récent en France.

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.

Adverse effects of voriconazole: analysis of the French Pharmacovigilance Database.

BACKGROUND: The most common adverse effects of voriconazole reported during clinical trials were disturbances of vision (30% of pts.), skin rashes (17.3%), and elevations in hepatic enzymes level (approximately 10% of pts.; varying with enzymes). However, postmarketing data concerning safety of voriconazole are limited. OBJECTIVE: To describe voriconazole adverse drug effects (ADEs) after 4 years of the drug's availability in France and determine their occurrence. METHODS: All cases of ADEs including voriconazole reported to the French Pharmacovigilance Database between 2002 and 2005 were analyzed. For each case, the following data were recorded: age, sex, indication, concomitant disease, concomitant medications, and ADE description. Causality link between voriconazole and ADEs was performed using the Naranjo probability scale. RESULTS: A total of 227 ADE cases were reported in 178 adults and 9 children (<12 y), with 66% occurring in males. The patients' median age was 49.6 (2-80) years. ADEs included liver function test abnormalities (23%), visual disturbances (18%), skin rashes (17%), neurologic disturbances (14%), cardiovascular events (10%), hematologic disorders (8%), and renal disturbances (4%). Other less commonly identified ADEs included headache, nausea, vomiting, and diarrhea. Drug-drug interactions were observed in 7 cases. According to the Naranjo criteria, 84% of ADEs were classified as possible, 7% as probable, 5% as highly probable, and 4% as doubtful. CONCLUSIONS: Most ADEs found in this study are well documented in the literature, except for cardiac complications, which are rarely reported. Few ADEs related to drug interactions were observed; however, due to the extensive metabolism of voriconazole by cytochrome P450 isoenzymes, clinicians should be aware of potential interactions between voriconazole and other drugs metabolized through this pathway.