Abuse and misuse of second-generation antipsychotics: An analysis using VigiBase, the World Health Organisation pharmacovigilance database.

The study aim was to assess the abuse/misuse potential of second-generation antipsychotics (SGAPs) using VigiBase data. We extracted individual case safety reports of "Drug abuse, dependence and withdrawal" involving SGAPs up to June 2018. We assessed disproportionate reporting by calculating the information component, considering the lower end of the 95% credibility interval for the information component (IC025 ), and the proportional reporting ratio. We identified 1683 individual case safety reports recorded as "abuse, dependence and withdrawal" involving SGAPs, mainly quetiapine (n = 1089) and olanzapine (n = 209). The disproportional reporting indicators highlighted an association between "Drug abuse and dependence", and quetiapine, olanzapine and ziprasidone, as indicated by the IC025 (2.263, 0.259 and 1.051, respectively) and proportional reporting ratio values (3.929, 1.020 and 1.334, respectively). The abuse/misuse potential is confirmed for quetiapine and olanzapine and highlighted for the first time for ziprasidone. Physicians should consider these risks when prescribing these antipsychotics, especially to patients with history of drug abuse.

Opioid misuse in community pharmacy patients with chronic non-cancer pain.

AIMS: Community pharmacists could contribute to identify people misusing prescription opioids, which may be associated with hospitalizations, substance use disorders and death. This study investigated prescription opioid misuse in community pharmacy patients and the factors potentially associated with high Prescription Opioid Misuse Index (POMI) scores. METHODS: In this cross-sectional study, pharmacy students asked patients with opioid prescriptions to fill in a questionnaire (including the POMI) in community pharmacies in a French region, in April 2019. Eligible patients were adults with chronic non-cancer pain who consented to participate. RESULTS: In total, 414 patients (62.4% women; mean age: 58.00 years ± 16.00) were included. The prescribed opioids were mainly weak opioids (73.2%; paracetamol/tramadol: 35%). Strong opioids (32.6%) included oxycodone (11.95%), fentanyl (9%) and morphine (9%). The median morphine milligram equivalent (MME) was 40 mg/day (IQR25-75 : 20-80). The POMI score (0 to 6) was ≥4 in 16% of patients who were younger (P < .01), more urban (P = .03), with higher pain visual analogue scale (VAS) score (P < .01) and MME (P < .01), and treated more frequently with strong opioids (P = .04). In multivariate analysis, age (ORfor 10y : 0.68 (95% CI: 0.56-0.82, P < .0001)), VAS (OR2units : 1.78 (95% CI: 1.26-2.40, P = .0008)), and MME (>100 mg, OR: 2.65 (95% CI: 1.14-4.41, P = .0194)) were significantly associated with POMI scores ≥4. CONCLUSIONS: The high proportion of patients with high POMI scores underlines the interest of prescription opioid misuse screening in community pharmacies, in order to help these patients and refer them to pain specialists, if needed.

Ten-year trend of opioid and nonopioid analgesic use in the French adult population.

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.

Risk assessment of using off-label morphine sulfate in a population-based retrospective cohort of opioid-dependent patients.

AIMS: Several addictovigilance studies have described the off-label use of morphine sulfate (MS) for nonchronic pain in opioid use disorder (OUD) patients as an alternative to conventional opioid substitution treatments (OSTs). This study primarily sought to compare the incidence of unintentional opioid-related overdose in the year following the prescription initiation in off-label MS users, compared to OST-maintained patients. METHODS: Sequential cohorts of OUD patients who were regularly dispensed MS, buprenorphine, or methadone, between 1 April 2012 and 31 December 2014, were retrospectively identified using the French nationwide healthcare data system. The incidence of overdoses, deaths, doctor shopping, and complications of a viral, bacterial or thrombotic nature, was compared using the Cox regression method. RESULTS: Overall, 1075, 20 834 and 9778 OUD patients without chronic-pain were included in the MS, buprenorphine, and methadone cohorts, respectively. Overdose incidence was 3.8 (P < .01 [95% confidence interval (CI): 2.1-6.8]) and 2.0 (P = .02 [95%CI: 1.1-3.6]) higher in the MS cohort vs buprenorphine and methadone, respectively. Death incidence was 9.1 (P < .01 [95%CI: 3.2-25.9]) and 3.9 (P < .01 [95%CI: 1.4-10.7]) higher in the MS cohort vs buprenorphine and methadone, respectively. The incidences of other associated risks were significantly higher in the MS group vs OSTs, except for hepatitis C viral infection and thrombotic complications. CONCLUSION: This first French comprehensive nationwide study reveals increasing overdose, death, bacterial infection, abuse and diversion risks when off-label MS is initiated as alternative to OST. These results question the relevance of prescribing MS as a safe opioid maintenance treatment, considering its health risk profile.

Doxycycline in the management of sexually transmitted infections.

Doxycycline is a second-generation tetracycline, available worldwide for half a century. It is an inexpensive broad-spectrum antimicrobial agent largely used in the management of several bacterial infections, particularly involving intracellular pathogens, as well as in the treatment of acne or for the prophylaxis of malaria. Physicochemical characteristics of doxycycline (liposolubility) allow a high diffusion in the tissues and organs. It has high bioavailability and a long elimination half-life allowing oral administration of one or two daily doses. Over the last decade, the prevalence of bacterial sexually transmitted infections (STIs) (syphilis, chlamydiosis, gonorrhoea and Mycoplasma genitalium infections) has increased in most countries, mainly in MSM, many of whom are infected with HIV. In light of increasing prevalence of resistance towards first-line regimens of some STI agents and recently updated recommendations for STI management, doxycycline appears to be an attractive option compared with other available antibiotics for the treatment of some STIs due to its efficacy, good tolerability and oral administration. More recently, indications for doxycycline in STI prophylaxis have been evaluated. Considering the renewed interest of doxycycline in STI management, this review aims to update the pharmacology of, efficacy of, safety of and resistance to doxycycline in this context of use.

[Involvement of addictovigilance in emergency department for the detection of abuse and dependence cases: 3 years of experience]. / Implication de l'addictovigilance dans un service d'urgence pour la détection et le recueil des cas d'abus et de dépendance : bilan de 3 ans d'expérience.

INTRODUCTION: Due to the increase of hospitalization at emergency department (ED) related to psychoactive substances use (PSU), the addictovigilance center of Montpellier has been integrated into the URGEIM program for the detection of iatrogenic events at the ED. The objective of the present work was to analyze spontaneous reports (SR) collected via the URGEIM program. METHODS: Analysis of spontaneous reports related to PSU at the ED of the Montpellier University Hospital, collected through the URGEIM program, between January 2014 and December 2016. RESULTS: During the study period, 160 SR were collected through the URGEIM program on 1118 SR collected by the Addictovigilance center over the period: 40SR/342 in 2014, 46 SR/303 in 2015 and 74 SR/473 in 2016. Most patients were male (70%) and the mean age at admission was 33 years old. A total of 240 psychoactive substances were identified with 160 illicit substances (66.6%) [cocaine 38.1%, cannabis 30.6%] and 80 medications (33.3%) [buprenorphine 22.5%, benzodiazepines 20% and methadone 18.8%]. Mental and behavioral disorders (20.0%), general health problems associated with substance use (17.5%), cardiovascular diseases (13.1%) and infectious diseases (12.5%) were the main reported effects. The duration of emergency stay was inferior to 12hours in 63.1% of cases and greater than 24hours in 12.5% of cases. In 69.4% of cases, the event was considered as serious. The outcome was unknown for 6.9% of patients. CONCLUSION: The number of SR from ED has increased over the study period, with the notification of serious and worrying cases, and the possibility of setting up actions. The deployment of addictovigilance within clinical services is a significant factor for notification and quality of care.

Prevalence of Antipsychotic-Treated Patients in a Cohort of Adult Addicted Patients.

PURPOSE: The objective of this cross-sectional study was to describe and estimate the prevalence of antipsychotics (AP) in a cohort of addicted patients, and to compare the profiles of addictive patients receiving AP or not. METHODS: We included all adult patients seen at the addiction care center of Montpellier University Hospital, between January 1, 2015, and March 31, 2015. Demographic, clinical, and therapeutic data were collected from the patients' medical records. RESULTS: During the study period, 415 patients were included, with a mean age of 38 ± 10 years. They were mostly men (73.3%), French (54.9%), and unemployed (61.8%). Among the study population, 93 patients (patients treated with AP [trAP], 22.4%) were treated by 111 different AP, mainly cyamemazine (29.0% of treated patients), aripiprazole (20.4%), olanzapine (17.2%), and quetiapine (16.1%), mostly in monotherapy (80.6%) and by oral route (93.2% of AP). Psychiatric history was more frequent in trAP than in those without AP (untrAP) (55.9% vs 35.4% respectively; P < 0.001). Professional activity tended to be less frequent in patients with AP (25.3% vs 38.9%, P = 0.08).When compared with untrAP, trAP consumed more amphetamine (10.8% vs 4.4%; P = 0.02) and tended to consume less opiates (7.5% vs 14.9%; P = 0.06); the consumptions of cannabis (43.0% vs 35.7%; P = 0.20) and cocaine (22.6% vs 16.8%; P = 0.20) were not statistically different.Opiate maintenance therapy was reported in 63.7% of trAP and 68.4% of untrAP (P = 0.41): it consisted of methadone (trAP, 60.3% vs untrAP, 56.5%) and buprenorphine (trAP, 39.7% vs untrAP, 43.5%). CONCLUSIONS: The concomitant management of psychiatric and substance use disorders in the same center may explain the high prevalence of trAP in this study. Cannabis and psychostimulants may have been used in these patients as self-medication for mental disease-related symptoms or adverse effects of APs.

Three Complementary Approaches to Characterize Buprenorphine Misuse.

BACKGROUND: In France, buprenorphine has been available for opioid maintenance therapy since 1996 and since then its misuse has been continuously evaluated by the French health authorities. OBJECTIVES: To characterize buprenorphine misuse in Languedoc-Roussillon (LR) region, using three different approaches. METHODS: Three different data sources were analyzed : (i) spontaneous reports (NotS) of buprenorphine misuse or dependence, (ii) a specific periodic survey from specialized care centers (OPPIDUM) over 11 years (2002-2012) and (iii) a drug reimbursement database (DRB). RESULTS: A total of 209 spontaneous reports were collected. The main type of buprenorphine misuse was use by an unintended route of administration. The main complications notified were directly related to the injection of buprenorphine. NotS enabled the collection of data about severe clinical complications or new diversion phenomenon. The OPPIDUM LR survey revealed a decrease in the buprenorphine misuse indicator through the study period. The DRB analysis identified one subgroup of patients with a buprenorphine deviant behavior, characterized by a significantly greater number of dispensing episodes, pharmacies, prescribers, daily dose and switch between buprenorphine forms (princeps and generic). The DRB analysis provides data on buprenorphine diversion in the context of outpatients care. CONCLUSION: The three complementary approaches allowed us to characterize buprenorphine misuse in LR area. The three approaches are complementary because each data source provides different types of information.

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

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

[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.

[Abuse Liability of Quetiapine (Xeroquel®)]. / Évaluation du potentiel d'abus et de dépendance de la quétiapine (Xeroquel®).

OBJECTIVE: In recent years, there have been several reports in the literature concerning the misuse and abuse of quetiapine. The aim of this study was to review the data reported to the French Network of the Addictovigilance Centers as well as the published data. METHODS: Epidemiological data from the studies of French network addictovigilance centers (spontaneous notifications, suspicious presciptions suggesting possible abuse [ ordonnances suspectes indicateur d'abus possibles, OSIAP], observatory of illegal psychotropic substances or delivered substances diverted from their medicinal use survey [observation des produits psychotropes illicites ou détournées de leur utilisation médicamenteuse, OPPIDUM], deaths related to medication and substance abuse survey [décès en relation avec l'abus de médicaments et de substances, DRAMES]) were analyzed between 2011 and 2014. All cases of abuse and dependence with quetiapine in PubMed were reviewed using the MeSH terms "quetiapine," "substances abuse," and "dependence", until October 2014. RESULTS: The analysis of the literature has identified 21 cases of abuse related to quetiapine, mainly in men (85.7%), with a history of substance abuse (76%). The main route of administration was oral but other routes were also reported (intravenous, intranasal). The main reason for abuse was sedation and anxiolytic. Other characteristics of quetiapine abuse include amplification or even simulation of psychotic symptoms to obtain quetiapine, an increased dose and the existence of street names. The French addictovigilance network reported few cases of abuse with quetiapine. DISCUSSION-CONCLUSION: The pharmacological mechanism of abuse of quetiapine is not fully understood. However, several arguments are in favor of the abuse liability of quetiapine. Despite the recent availability of quetiapine in France, there have been some isolated signals of abuse. Therefore, it seems important to inform prescribers on the risk of misuse of quetiapine and also of some other antipsychotics.

Role of Methadone in Induction and/or Exacerbation of Cluster Headache in Patients Treated for Opioid Addiction.

Methadone is a potent opioid agonist widely used in opioid maintenance therapy. In some countries, methadone is available for pain treatment. We report the cases of two patients with history of substance abuse (mainly heroin), who presented with cluster headache possibly related to high-dose methadone. One possible explanation for the severe pain described in these cases is hyperalgesia induced by high doses of methadone.

Levamisole-adulterated cocaine: what about in European countries?

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

[Necrotizing fasciitis related to injections of morphine (Skénan(®)) in a HIV-infected patient]. / Fasciites nécrosantes liées à des injections de morphine (Skénan(®)), chez un patient infecté par le VIH.

We report here a case of necrotizing fasciitis occurred because of intravenous misuse of morphine sulfate (Skénan (®)). Several factors are pertinent: the type of infection, rare but severe, the double localization of the necrotizing fasciitis, complicated by sepsis, the patient profile (HIV-infected) and the injected substance (opiate).

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).

Acute hepatitis and renal failure related to intranasal buprenorphine misuse: case report and analysis of cases reported to the French network for drug monitoring.

BACKGROUND: Rare cases of acute hepatitis have been reported following injection, overdose, and even during the use of buprenorphine (BPN) at therapeutic doses, especially in carriers of hepatitis C virus (HCV). OBJECTIVES: To report a case of acute hepatitis and renal failure related to intranasal BPN misuse in a HCV-negative patient and to analyze cases reported to the French postmarketing surveillance system (PMSS) of drugs and in the literature. METHODS: All cases of hepatitis related to BPN reported to PMSS between January 1996 and December 2012 were analyzed. RESULTS: A 42-year-old man with a history of intranasal BPN misuse (8 mg/d) for at least 10 years was admitted for flu-like symptoms and abdominal pain. At admission, the patient consumed alcohol, cannabis, and tobacco. Acute hepatitis and acute renal failure were diagnosed . Clinical signs and biological parameters resolved within 26 days. An objective causality assessment revealed that an adverse drug reaction (ADR) was possible. In the French PMSS database, 41 cases of suspected BPN-induced hepatitis are reported. In 36.6% of cases, BPN was misused by the intravenous route. In the literature, 16 cases of acute hepatitis related to BPN with or without renal failure are reported. In all cases, patients were HCV carriers. The primary mechanism of BPN-induced hepatitis is a mitochondrial dysfunction, exacerbated by cofactors (HCV, alcohol, and medications). CONCLUSION: Intranasal misuse of BPN is increasingly frequent. We report here the first documented case of acute hepatitis and renal failure related to intranasal BPN misuse in a patient negative for HCV infection.

Slow-release oral morphine sulfate abuse: results of the postmarketing surveillance systems for psychoactive prescription drug abuse in France.

BACKGROUND: Few data are available concerning the diversion and abuse of morphine sulfate. In France, morphine sulfate abuse is currently investigated by the health authorities. The aim of our study was to provide data on morphine sulfate abuse in France, collected during the period 1996-2011. METHODS: The French monitoring system for psychoactive medication abuse collected data from several sources: spontaneous reporting of cases of abuse or dependence (NotS; 'Notifications Spontanées'), specific periodic surveys from specialized care centers (OPPIDUM; 'Observation des Produits Psychotropes Illicites ou Détournés de leur Utilisation Médicamenteuse'), and community pharmacists (OSIAP; 'Ordonnances Suspectes Indicateur d'Abus Possible'). RESULTS: A total of 649 cases (75% men, median age: 34 years) were spontaneously reported: 578 cases of abuse and 71 cases of use as opiate maintenance treatment. The medication formulation was Skenan(®) (614 cases), and Moscontin(®) (35 cases). All surveys (NotS, OPPIDUM, and OSIAP) showed an overrepresentation of Skenan(®) (87.9-94.6% of cases) that was intravenously injected in 60.4-61.2% of the cases. Data analysis showed that patients abusing morphine sulfate have a long history of drug abuse and a history of polydrug use. CONCLUSION: All the data presented in this study highlight the level of morphine sulfate abuse, specify the modalities of use (intravenous route), and show the risks associated with abuse (infectious diseases). This study outlines the usefulness of our epidemiological tools, and provides evidence supporting intensive surveillance.

Necrosis of the intranasal structures and soft palate as a result of heroin snorting: a case series.

BACKGROUND: The link between nasal inhalation of cocaine and nasal and palatal necrosis is well documented. In contrast, few data are available concerning nasal mucosa necrosis related to heroin snorting. The authors report here the retrospective analysis of 24 cases of orofacial lesions in patients with nasal heroin usage, collected between 2006 and 2012. CASES: The cases concern 17 males and 7 females (median age 29.5 (range: 24-42)) with chronic consumption of intranasal heroin (from 2 months to more than 10 years). Six patients had a history of cocaine abuse. The median daily amount of heroin consumption was 5 g (range: 0.5-10). The complications were nasal perforation (11 cases), nasal ulceration or erythema (5 cases), nasal septum necrosis (5 cases), pharyngeal ulceration (3 cases), and palate damages (5 cases). The most common clinical signs and symptoms were nasal pain, purulent sputum, dysphagia, and rhinitis. Maintenance therapy with methadone (19 cases) or buprenorphine (3 cases) was initiated. In 8 cases, the injury improved. DISCUSSION: The potential of heroin to induce destructive orofacial lesions should be considered when nasal damages are observed in patients with drug abuse. A multidisciplinary approach seems to be the most effective means of managing such patients.