Repurposing drugs for treatment of alcohol use disorder.

Repurposing drugs for the treatment of alcohol dependence involves the use of drugs that were initially developed for other conditions, but have shown promise in reducing alcohol use or preventing relapse. This approach can offer a more cost-effective and time-efficient alternative to developing new drugs from scratch. Currently approved medications for alcohol use disorder (AUD) include acamprosate, disulfiram, naltrexone, nalmefene, baclofen, and sodium oxybate. Acamprosate was developed specifically for AUD, while disulfiram's alcohol-deterrent effects were discovered incidentally. Naltrexone and nalmefene were originally approved for opioids but found secondary applications in AUD. Baclofen and sodium oxybate were repurposed from neurological conditions. Other drugs show promise. Topiramate and zonisamide, anticonvulsants, demonstrate efficacy in reducing alcohol consumption. Another anticonvulsant, gabapentin has been disappointing overall, except in cases involving alcohol withdrawal symptoms. Varenicline, a nicotinic receptor agonist, benefits individuals with less severe AUD or concurrent nicotine use. Ondansetron, a 5-HT3 antagonist, has potential for early-onset AUD, especially when combined with naltrexone. Antipsychotic drugs like aripiprazole and quetiapine have limited efficacy. Further investigation is needed for potential repurposing of α1 adrenergic receptor antagonists prazosin and doxazosin, glucocorticoid receptor antagonist mifepristone, the phosphodiesterase inhibitor Ibudilast, the cysteine prodrug N-acetylcysteine, and the OX1R and OX2R blocker Suvorexant. This review supports repurposing drugs as an effective strategy for expanding treatment options for AUD.

Adolescent Hazardous Drinking and Socioeconomic Status in France: Insights Into the Alcohol Harm Paradox.

PURPOSE: The "alcohol harm paradox" has been evidenced among adults, but it is still largely unexplored among adolescents. We examined in a sample of French adolescents the relation between family socioeconomic status (SES), family living arrangement and parental substance use on 1 hand, and heavy episodic drinking (HED), lifetime alcohol-induced emergency room visits (A-ERV), and number of alcoholic drinks and solitary drinking during the last episode on the other hand. METHODS: A cross-sectional nationwide survey in March 2017 involved 13,314 French adolescents aged 17-18.5 years. They completed a pen and paper questionnaire about their own and their parents' alcohol and tobacco consumption. We used risk ratios (RRs) from modified Poisson regressions to assess the relationships. RESULTS: Adolescents from the lowest SES had reduced likelihood of reporting 1-2 or 3-5 episodes of heavy drinking compared to those from the highest SES (RR = 0.58, 95% confidence interval = [0.50; 0.66] and 0.35 [0.27; 0.45]), but no difference for six or more episodes (RR = 0.81 [0.59; 1.12]). A-ERV was more frequent among lowest SES adolescents (RR = 1.86 [1.05; 3.30]), possibly due to drinking larger quantities of alcohol and to more frequent solitary drinking in their last episode (p < .001). SES, parental substance use, and family living arrangement were independently associated with HED. DISCUSSION: Our findings reveal an "alcohol harm paradox" in late adolescence in France. Lower SES adolescents exhibit reduced HED but were more likely to consume large quantities alone and experience A-ERV. This emphasizes the significance of considering social determinants in alcohol-related research and interventions.

[Alcohol consumption and high blood pressure]. / Consommation d'alcool et hypertension artérielle.

ALCOHOL CONSUMPTION AND HIGH BLOOD PRESSURE. Cardiovascular disease is the second leading cause of alcohol-attributable mortality after cancer. The impact of alcohol consumption on blood pressure and the risk of cardiovascular pathologies are still largely underestimated by the general population and health professionals. However, numerous studies have demonstrated a dose-dependent increase in blood pressure, even at consumption levels close to the consumption guidelines (two drinks i.e. 20g per day). The alleged protective effects of low consumption levels are not confirmed, even in women. The binge drinking pattern has a particularly strong impact on blood pressure. The increase in blood pressure due to alcohol is reversible after reduction of consumption. Several pathophysiological mechanisms have been proposed to explain the hypertensive effects of alcohol. The screening of alcohol consumption by health professionals remains largely insufficient, especially in France, even in hypertensive subjects, although intervention is effective. It seems particularly important to reinforce the training of health professionals and the screening of alcohol consumption for primary prevention and also for secondary prevention when hypertension is already established. Scientific societies and federations should reinforce communication on the risks associated with alcohol consumption.

CONSOMMATION D'ALCOOL ET HYPERTENSION ARTÉRIELLE. Les pathologies cardiovasculaires sont la deuxième cause de mortalité attribuable à l'alcool, après les cancers. L'impact de la consommation d'alcool sur la pression artérielle et le risque de pathologies cardiovasculaires semble encore largement sous-estimé dans la population générale et par les professionnels de santé. Pourtant, de très nombreuses études ont démontré l'augmentation de la pression artérielle, dose-dépendante, même à des niveaux de consommation proches des repères de consommation (deux verres, soit 20 g/j). Les effets prétendument protecteurs des faibles niveaux de consommation ne sont pas confirmés, même chez les femmes. Le profil de consommation de type « binge drinking ¼ a un impact particulièrement important sur la pression artérielle. L'augmentation de la pression artérielle due à l'alcool est réversible après diminution de la consommation. Plusieurs mécanismes physiopathologiques ont été proposés pour expliquer les effets hypertenseurs de l'alcool. Le repérage de la consommation d'alcool par les professionnels de santé reste largement insuffisant, notamment en France, même chez les sujets hypertendus alors qu'une intervention est efficace. Il apparaît particulièrement important de renforcer la formation des professionnels de santé et le repérage de la consommation d'alcool à des fins de prévention primaire mais aussi secondaire lorsque l'hypertension est déjà installée. Les sociétés savantes et fédérations devraient renforcer la communication sur les risques liés à la consommation d'alcool.

Attitudes & behaviors toward the management of tobacco smoking patients: qualitative study with French primary care physicians.

BACKGROUND: Smoking cessation is a major public health issue. In France, primary care physicians (PCP) are the first contact points for tobacco management. The objective of this study was to understand how PCPs are involved in the management of smoking cessation: ownership, commitment, barriers. METHODS: A qualitative study was conducted using group and individual semi-structured techniques with PCPs. A thematic analysis of verbatim transcripts was performed to identify concepts and sub-concepts of interest. Saturation was evaluated retrospectively to ensure adequate sample size. RESULTS: A sample of 35 PCPs were interviewed, 31 in four focus groups and four in individual interviews. PCPs discussed their roles in the management of tobacco smoking cessation, including the different strategies they are using (e.g., Minimal Intervention Strategy, Motivational Interviewing), the multiple barriers encountered (e.g., lack of time, patients' resistance to medical advice), the support resources and the treatment and intervention they prescribed (e.g. nicotine replacement therapy, supporting therapist). CONCLUSIONS: This study provides a better understanding of the beliefs, attitudes, and behaviors of PCPs in managing smoking cessation. Guiding and encouraging patients toward smoking cessation remains a major objective of PCPs. While PCPs reported that progress has been made in recent years in terms of tools, technology and general awareness, they still face major barriers, some of which could be overcome by appropriate training.

The Efficacy of Primavera, a Prevention Programme on Alcohol and Tobacco Use among 10-12-Year-Old Schoolchildren: A Randomized Controlled Cluster Study.

Alcohol and tobacco use is a major health problem and one of the first causes of the burden of disease and mortality. School-based alcohol and tobacco use prevention programmes that have demonstrated efficacy are most often based on psychosocial skill development, individuals' experiential learning strategies, and community resources. Furthermore, early and prolonged interventions have been recommended. Primavera is a pluri-annual, generic, multimodal, experiential-oriented prevention program. It runs over a three-year period from the last year of primary school to the second year of secondary school. This randomized controlled cluster study aimed at assessing the effects of the Primavera programme compared to a control prevention intervention among schoolchildren from 10 to 12 years in eight secondary schools in a particular French geographical area. The primary outcomes were lifetime tobacco use and past-month alcohol use. Data were collected at baseline and over three follow-up time points. In all, 287 and 266 questionnaires, respectively, were collected at baseline from the Primavera group and from the control group. Attrition was 45% and 41%, respectively. The SARS-COV2 pandemic crisis made it impossible for questionnaires to be collected during the final year. After adjustment, children from the Primavera group were less likely to report current alcohol use at the end of the first year (odds ratio = 0.39, 95% CI: 0.18-0.78) and past-month alcohol use at the end of the second year (odds ratio = 0.07, 95% CI: 0.01-0.66) compared to those from the control group. The results for psychosocial skills and alcohol and tobacco use denormalization were contrasted. Primavera is shown to be effective in reducing alcohol use among schoolchildren.

Association of smoking reduction and mortality: protocol for a systematic review and meta-analysis of longitudinal observational studies.

INTRODUCTION: Strong evidence shows that smoking cessation decreases mortality. Much less is known regarding the association between reduction in cigarettes per day (CPD) and mortality. The primary aim of this systematic review is to compare the mortality risk between smokers achieving a sustained reduction of CPD and smokers maintaining their smoking rate. The secondary aims are to compare the mortality risk between smokers achieving complete, sustained smoking cessation and (1) smokers maintaining their smoking rate and (2) smokers who achieved a sustained reduction in smoking rate. METHODS AND ANALYSIS: MEDLINE, Web of Sciences and Embase will be searched using a prespecified search strategy, up to 23 November 2020, and will be limited to studies published in English and in French. Longitudinal observational studies using individual data including smokers with at least two distant CPD assessments and a follow-up period of systematic mortality data recording will be included. The main outcome will be the all-cause mortality. The secondary outcome will be specific mortality. The Newcastle-Ottawa Scale will be used to assess the risk of bias of individual studies. Outcomes will be analysed using HRs. All other outcomes' effect size reported in included studies will be converted in HRs using validated methods. ETHICS AND DISSEMINATION: We intend to publish the results of our review in a peer-reviewed journal and to present the findings at national and international meetings and conferences. PROSPERO REGISTRATION NUMBER: CRD42019138354.

Experimenting first with e-cigarettes versus first with cigarettes and transition to daily cigarette use among adolescents: the crucial effect of age at first experiment.

BACKGROUND AND AIMS: Most studies in English-speaking countries have found a positive association between e-cigarette experimentation and subsequent daily tobacco smoking among adolescents. However, this result may not be valid in other cultural contexts; in addition, few studies have assessed whether this association varies with the subject' age at the time of e-cigarette experimentation. This study aimed to estimate the association between experimenting first with e-cigarette (rather than tobacco) and subsequent daily smoking according to age at the time of experimentation. DESIGN: Secondary analysis; risk ratios (RRs) computed using modified Poisson regressions with inverse probability weighting. SETTING: A cross-sectional nation-wide representative survey performed in 2017 in France. PARTICIPANTS: French adolescents (n = 24 111), aged 17 to 18.5 years, who had previously experimented with either e-cigarettes or tobacco. MEASURES: Exposure was defined as the experimentation with e-cigarettes first (whether or not followed by experimentation with tobacco); the outcome as daily tobacco smoking at the time of data collection. Gender, age, literacy, socio-economic status, pre-exposure repeat school years and experimentation with drunkeness, 3 licit and 8 illicit drugs were adjusted for. Uncertainties about the sequence of events defining exposure were handled by the definition of three patterns of exposure, to avoid a misclassification bias. FINDINGS: Exposure reduced the risk of transition to daily smoking: RR = 0.58, 95% confidence interval (CI) = 0.54, 0.62. This effect increased in a linear manner with age at exposure (RR = 0.87, 95% CI = 0.78; 0.98 for 1 year, P < 0.001): from RR = 1.30, 95% CI = 1.09; 1.54 at age 9 to RR = 0.38, 95% CI = 0.32; 0.45 at age 17. CONCLUSIONS: Experimenting with e-cigarettes first (as opposed to tobacco first) appears to be associated with a reduction in the risk of daily tobacco smoking among French adolescents aged 17-18.5, but this risk varies negatively with age at experimentation, and early e-cigarette experimenters are at higher risk.

Passive smoking in childhood increases the risk of developing rheumatoid arthritis.

OBJECTIVES: To investigate the link between smoking status, including childhood and adult passive exposure, and the risk of incident RA. METHODS: The French E3N cohort includes 98 995 female volunteers prospectively followed since 1990. Self-administered questionnaires sent every 2-3 years collected medical events, general, lifestyle and environmental characteristics. RA diagnoses were collected in three successive questionnaires and confirmed if women received reimbursement for an RA-specific medication. The risk of incident RA was estimated using an age-adjusted Cox model that considers smoking status as a time-dependent variable. RESULTS: Among 71 248 women, 371 incident RA cases were confirmed. Ever-smokers not exposed to passive smoking had an increased risk of RA [1.38 (95% CI 1.10, 1.74)]. In never-smokers, passive smoking exposure during childhood was associated with a borderline increased risk of RA in the same range as active smoking in adults, with an hazard ratio (HR) of 1.43 (95% CI 0.97, 2.11). Ever-smokers who also had childhood passive smoking exposure had a higher risk of RA than smokers not exposed during childhood [HR 1.67 (95% CI 1.17, 2.39)], but without a significant difference (P = 0.30). RA began earlier in smokers exposed to childhood passive smoking. CONCLUSION: This study confirms that active smoking is associated with an increased risk of RA. It suggests for the first time that passive exposure to tobacco during childhood might also increase the risk of RA in future light smokers and probably non-smokers. Our results highlight the importance of avoiding any tobacco environment in children, especially in those with a family history of RA.

Pooled analysis of three randomized, double-blind, placebo controlled trials with rimonabant for smoking cessation.

Despite the withdrawal of CB1 antagonists, such as rimonabant, from the market and from active clinical development because of concerns about their side effect profiles, research suggests that the endocannabinoid system may play an important role in modulating nicotine's effects. We report the combined results, using a pooled analysis, of three previously unpublished trials assessing rimonabant as a smoking cessation pharmacotherapy conducted between 2002 and 2004. Smokers (n = 2097) motivated to quit were enrolled in three randomized, double-blind, placebo-controlled trials, STRATUS EU, US, and META, which consisted of a 10-week treatment period with either rimonabant 20 mg (n = 789), 5 mg (n = 518; used in only two of the three studies), or placebo (n = 790), in conjunction with brief counseling. The impact of drug on prolonged abstinence and adverse events was examined at 8 weeks (end-of-treatment) and at 48 weeks (available for STRATUS EU and US) after the targeted quit date. Rimonabant 20 mg resulted in significantly higher abstinence at end-of-treatment and at 48 weeks post-targeted quit date compared with placebo, while rimonabant 5 mg and placebo did not differ. Serious AEs did not differ by drug group. The 20 mg rimonabant dose, compared with placebo, produced increased nausea, diarrhea, anxiety symptoms, hyporexia, and vomiting, and decreased headache, constipation, and cough. These results support rimonabant 20 mg as a modestly effective aid for smoking cessation. Although work on CB1 antagonists such as rimonabant has mostly been stopped because of unacceptable adverse events, these results may inform and spur the development of other endocannabinoids for smoking cessation.

Tobacco use is associated with increased plasma BDNF levels in depressed patients.

Since serum Brain Derived Neurotrophic Factor (BDNF) levels are higher in tobacco smokers than in non-smokers and since Major Depressive Disorder (MDD) is associated with a 2-fold increased risk of smoking, we assessed the association of smoking and plasma BDNF levels in 359 depressed MDD patients. Plasma BDNF levels were positively correlated with the magnitude of tobacco consumption (current number of cigarettes/day and number of packs/year). Accordingly, current tobacco users had significantly higher plasma BDNF levels than non-users. In further studies of MDD, peripheral measures of BDNF should take into account tobacco use.

Pharmacotherapy for Alcohol Dependence: The 2015 Recommendations of the French Alcohol Society, Issued in Partnership with the European Federation of Addiction Societies.

BACKGROUND: The latest French good practice recommendations (GPRs) for the screening, prevention, and treatment of alcohol misuse were recently published in partnership with the European Federation of Addiction Societies (EUFAS). This article aims to synthesize the GPRs focused on the pharmacotherapy of alcohol dependence. METHODS: A four-member European steering committee defined the questions that were addressed to an 18-member multiprofessional working group (WG). The WG developed the GPRs based on a systematic, hierarchical, and structured literature search and submitted the document to two review processes involving 37 French members from multiple disciplines and 5 non-French EUFAS members. The final GPRs were graded A, B, or C, or expert consensus (EC) using a reference recommendation grading system. RESULTS: The treatment of alcohol dependence consists of either alcohol detoxification or abstinence maintenance programs or drinking reduction programs. The therapeutic objective is the result of a decision made jointly by the physician and the patient. For alcohol detoxification, benzodiazepines (BZDs) are recommended in first-line (grade A). BZD dosing should be guided by regular clinical monitoring (grade B). Residential detoxification is more appropriate for patients with a history of seizures, delirium tremens, unstable psychiatric comorbidity, or another associated substance use disorder (grade B). BZDs are only justified beyond a 1-week period in the case of persistent withdrawal symptoms, withdrawal events or associated BZD dependence (grade B). BZDs should not be continued for more than 4 weeks (grade C). The dosing and duration of thiamine (vitamin B1) during detoxification should be adapted to nutritional status (EC). For relapse prevention, acamprosate and naltrexone are recommended as first-line medications (grade A). Disulfiram can be proposed as second-line option in patients with sufficient information and supervision (EC). For reducing alcohol consumption, nalmefene is indicated in first line (grade A). The second-line prescription of baclofen, up to 300 mg/day, to prevent relapse or reduce drinking should be carried out according to the "temporary recommendation for use" measure issued by the French Health Agency (EC). During pregnancy, abstinence is recommended (EC). If alcohol detoxification is conducted during pregnancy, BZD use is recommended (grade B). No medication other than those for alcohol detoxification should be initiated in pregnant or breastfeeding women (EC). In a stabilized pregnant patient taking medication to support abstinence, the continuation of the drug should be considered on a case-by-case basis, weighing the benefit/risk ratio. Only disulfiram should be always stopped, given the unknown risks of the antabuse effect on the fetus (EC). First-line treatments to help maintain abstinence or reduce drinking are off-label for people under 18 years of age and should thus be considered on a case-by-case basis after the repeated failure of psychosocial measures alone (EC). Short half-life BZDs should be preferred for the detoxification of elderly patients (grade B). The initial doses of BZDs should be reduced by 30 to 50% in elderly patients (EC). In patients with chronic alcohol-related physical disorders, abstinence is recommended (EC). Any antidepressant or anxiolytic medication should be introduced after a psychiatric reassessment after 2-4 weeks of alcohol abstinence or low-risk use (grade B). A smoking cessation program should be offered to any smokers involved in an alcohol treatment program (grade B).

Smoker's identity scale: Measuring identity in tobacco dependence and its relationship with confidence in quitting.

BACKGROUND AND OBJECTIVES: Persistent smoking behaviours are associated with numerous motives, explaining the absence of a single treatment for quitting. One of these motives may include that of identification. The threat of losing their smoker's identity may represent a significant obstacle to lasting abstinence. The objective of this study is to design a specific identity questionnaire and examine correlations between the degree of smoking identity and persistent smoking. METHODS: Patients attending a smoking cessation seminar completed the Modified Reasons for Smoking Scale, Barriers to smoking cessation checklist and our 6-item Smoker's Identity Scale (SIS) (n = 170 questionnaires). RESULTS: SIS showed good internal consistency, calculated by a Chronbach test (α = .785) with no redundant questions. There was a correlation between strong tobacco dependence (measured by the Fagerström questionnaire) and strong smoking identity (p = .0001). Strong identity was associated with less confidence in quitting at both 1 and 6 months (p = .037 and p = .002, respectively). We showed that identity represents an obstacle to quitting in 32% of our patients and is associated with decreased confidence in quitting. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: Our study shows that measuring identity in smokers who wish to make a quit attempt may help to identify specific obstacles to abstinence. This may also help in elaborating improved quitting strategies and patient management. Further research is necessary to confirm these results.

Self-medication of achalasia with cannabis, complicated by a cannabis use disorder.

Achalasia is a rare esophagus motility disorder. Medical, endoscopic and surgical treatments are available, but all endorse high relapse rates. No data has been published to date reporting a therapeutic effect of cannabis use neither in achalasia nor on its influence on manometric measurements. We report the case of a patient diagnosed with achalasia. He could benefit from a large panel of therapeutic interventions, but none of them was effective over the time. He first used cannabis at age 20 and identified benefits regarding achalasia symptoms. He maintained regular moderate cannabis use for 9 years, with minimal digestive inconvenience. A manometry performed without cannabis premedication was realized at age 26 and still found a cardiospasm. Cannabis use could explain the gap between functional symptoms assessment and manometry measurement. Further investigations are warranted to explore a therapeutic effect of cannabis in achalasia and possible influence on outcome measurements.