Reductions in World Health Organization risk drinking level are associated with improvements in sleep problems among individuals with alcohol use disorder.

AIMS: Among individuals with alcohol use disorder (AUD), sleep disturbances are pervasive and contribute to the etiology and maintenance of AUD. However, despite increased attention toward the relationship between alcohol use and sleep, limited empirical research has systematically examined whether reductions in drinking during treatment for AUD are associated with improvements in sleep problems. METHODS: We used data from a multisite, randomized, controlled trial that compared 6 months of treatment with gabapentin enacarbil extended-release with placebo for adults with moderate-to-severe AUD (N = 346). The Timeline Follow-back was used to assess WHO risk drinking level reductions and the Pittsburgh Sleep Quality Index was used to assess sleep quality over the prior month at baseline and the end of treatment. RESULTS: Sleep problem scores in the active medication and placebo groups improved equally. Fewer sleep problems were noted among individuals who achieved at least a 1-level reduction (B = -0.99, 95% confidence interval (CI) [-1.77, -0.20], P = .014) or at least a 2-level reduction (B = -0.80, 95% CI [-1.47, -0.14], P = .018) in WHO risk drinking levels at the end of treatment. Reductions in drinking, with abstainers excluded from the analysis, also predicted fewer sleep problems at the end of treatment (1-level: B = -1.01, 95% CI [-1.83, -0.20], P = .015; 2-level: B = -0.90, 95% CI [-1.59, -0.22], P = .010). CONCLUSIONS: Drinking reductions, including those short of abstinence, are associated with improvements in sleep problems during treatment for AUD. Additional assessment of the causal relationships between harm-reduction approaches to AUD and improvements in sleep is warranted.

Prazosin and cyproheptadine in combination in the treatment of alcohol use disorder: A randomized, double-blind, placebo-controlled trial.

BACKGROUND AND AIMS: Pre-clinical studies suggest that the simultaneous blockade of the α1b and 5HT2A receptors may be effective in reducing alcohol consumption. This study aimed to assess the efficacy and safety of prazosin (α1b blocker) and cyproheptadine (5HT2A blocker) combination in decreasing total alcohol consumption (TAC) in alcohol use disorder (AUD). DESIGN, SETTING AND PARTICIPANTS: This was a double-blind, parallel group, placebo-controlled, Phase 2, randomized clinical trial conducted in 32 addiction treatment centres in France. A total of 108 men and 46 women with severe AUD took part. INTERVENTION: Participants were randomly assigned to one of the following 3-month treatments: (1) low-dose group (LDG) receiving 8 mg cyproheptadine and 5 mg prazosin extended-release (ER) formulation daily; (2) high-dose group (HDG) receiving 12 mg cyproheptadine and 10 mg prazosin ER daily; and (3) placebo group (PG) receiving placebo of cyproheptadine and prazosin ER. A total of 154 patients were randomized: 54 in the PG, 54 in the LDG and 46 in the HDG. MEASUREMENTS: The primary outcome was TAC change from baseline to month 3. FINDINGS: A significant main treatment effect in the change in TAC was found in the intent-to-treat population (P = 0.039). The HDG and LDG showed a benefit in the change in TAC from baseline to month 3 compared with PG: -23.6 g/day, P = 0.016, Cohen's d = -0.44; -18.4 g/day, P = 0.048 (Bonferroni correction P < 0.025), Cohen's d = -0.36. In a subgroup of very high-risk drinking-level participants (> 100 g/day of pure alcohol for men and > 60 g/day for women), the difference between the HDG and the PG in the primary outcome was -29.8 g/day (P = 0.031, Cohen's d = -0.51). The high and low doses were well-tolerated with a similar safety profile. CONCLUSIONS: A randomized controlled trial of treatment of severe alcohol use disorder with a cyproheptadine-prazosin combination for 3 months reduced drinking by more than 23 g per day compared with placebo. A higher dose combination was associated with a larger magnitude of drinking reduction than a lower dose combination while showing similar safety profile.

Reductions in World Health Organization Risk Drinking Level Are Associated With Reductions in Alcohol Use Disorder Diagnosis and Criteria: Evidence From an Alcohol Pharmacotherapy Trial.

OBJECTIVES: This study aimed to evaluate the validity of World Health Organization (WHO) risk drinking level reductions as meaningful endpoints for clinical practice and research. This study examined whether such reductions were associated with a lower likelihood of a current alcohol use disorder (AUD) diagnosis and fewer AUD criteria. METHODS: We conducted a secondary data analysis to address these objectives using data from a multisite randomized controlled trial of gabapentin enacarbil extended release in treating moderate to severe AUD among adults (N = 346). Participants received gabapentin enacarbil extended release or placebo for 6 months. The timeline follow-back was used to assess WHO risk drinking level reductions, and the Mini-International Neuropsychiatric Interview was used to assess Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) AUD diagnosis and criteria at baseline (past year) and end of treatment (past month). RESULTS: Most participants (80.1%) achieved at least a 1-level reduction in the WHO risk drinking levels from baseline to end of treatment, and nearly half of participants (49.8%) achieved at least a 2-level reduction. At least a 1-level reduction or at least a 2-level reduction in WHO risk drinking level predicted lower odds of an active AUD diagnosis (1-level: odds ratio, 0.74 [95% confidence interval (CI), 0.66-0.84]; 2-level: odds ratio, 0.71 [95% CI, 0.64-0.79]) and fewer AUD criteria (1-level: B, -1.66 [95% CI, -2.35 to -0.98]; 2-level: B, -1.76 [95% CI, -2.31 to -1.21]) at end of treatment. CONCLUSIONS: World Health Organization risk drinking level reductions correlate with Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) AUD diagnosis and criteria, providing further evidence for their use as endpoints in alcohol intervention trials, which has potential implications for broadening the base of AUD treatment.

AUD in perspective.

Alcohol is a major cause of pre-mature death and individual suffering worldwide, and the importance of diagnosing and treating AUD cannot be overstated. Given the global burden and the high attributable factor of alcohol in a vast number of diseases, the need for additional interventions and the development of new medicines is considered a priority by the World Health Organization (WHO). As of today, AUD is severely under-treated with a treatment gap nearing 90%, strikingly higher than that for other psychiatric disorders. Patients often seek treatment late in the progress of the disease and even among those who seek treatment only a minority receive medication, mirroring the still-prevailing stigma of the disease, and a lack of access to effective treatments, as well as a reluctance to total abstinence. To increase adherence, treatment goals should focus not only on maintaining abstinence, but also on harm reduction and psychosocial functioning. A personalised approach to AUD treatment, with a holistic view, and tailored therapy has the potential to improve AUD treatment outcomes by targeting the heterogeneity in genetics and pathophysiology, as well as reason for, and reaction to drinking. Also, the psychiatric co-morbidity rates are high in AUD and dual diagnosis can worsen symptoms and influence treatment response and should be considered in the treatment strategies.

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.

Reductions in WHO risk drinking levels correlate with alcohol craving among individuals with alcohol use disorder.

BACKGROUND: Abstinence has historically been considered the preferred goal of alcohol use disorder (AUD) treatment. However, most individuals with AUD do not want to abstain and many are able to reduce their drinking successfully. Craving is often a target of pharmacological and behavioral interventions for AUD, and reductions in craving may signal recovery. Whether reductions in drinking during AUD treatment are associated with reductions in craving has not been well examined. METHODS: We conducted secondary analyses of data from three AUD clinical trials (N's= 1327, 346, and 200). Drinking reductions from baseline to the end of treatment were measured as changes in World Health Organization (WHO) risk drinking levels; alcohol craving was measured using validated self-report measures. Regression analyses tested whether drinking reductions were associated with end-of-treatment craving reductions; moderation analyses tested whether associations between drinking reduction and end-of-treatment craving differed across AUD severity. RESULTS: Reductions of at least 1 or at least 2 WHO risk drinking levels were associated with lower craving (all p's < 0.05). Results were substantively similar after removing abstainers at the end-of-treatment. Associations between drinking reductions and craving were generally not moderated by AUD severity. CONCLUSIONS: Individuals with WHO risk drinking level reductions reported significantly lower craving, as compared to those who did not achieve meaningful reductions in drinking. The results demonstrate the utility of WHO risk drinking levels as AUD clinical trial endpoints and provide evidence that drinking reductions mitigate craving.

[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.

Caudate gray matter volumes and risk of relapse in Type A alcohol-dependent patients: A 7-year MRI follow-up study.

Background: Whether alteration in regional brain volumes can be detected in Type A alcoholics both at baseline and after a long follow-up remains to be confirmed. Therefore, we examined volume alterations at baseline, and longitudinal changes in a small follow-up subsample. Methods: In total of 26 patients and 24 healthy controls were assessed at baseline using magnetic resonance imaging and voxel-based morphometry, among which 17 patients and 6 controls were re-evaluated 7 years later. At baseline, regional cerebral volumes of patients were compared to controls. At follow-up, three groups were compared: abstainers (n = 11, more than 2 years of abstinence), relapsers (n = 6, <2 years of abstinence), and controls (n = 6). Results: The cross-sectional analyses detected, at both times, higher caudate nuclei volumes bilaterally in relapsers compared to abstainers. In abstainers, the longitudinal analysis indicated recovery of normal gray matter volumes in the middle and inferior frontal gyrus, and in the middle cingulate, while white matter volumes recovery was detected in the corpus callosum and in anterior and superior white matter specific regions. Conclusions: Overall, the present investigation revealed larger caudate nuclei in the relapser AUD patient group both at baseline and at follow-up in the cross-sectional analyses. This finding suggest that a higher caudate volume could be a candidate risk factor of relapse. In patients with specific type A alcohol-dependence, we showed that long-term recovery in fronto-striato-limbic GM and WM volumes occurs during long-term abstinence. These results support the crucial role of frontal circuitry in AUD.

Sodium Oxybate for Alcohol Dependence: A Network Meta-Regression Analysis Considering Population Severity at Baseline and Treatment Duration.

AIMS: The estimated effect of sodium oxybate (SMO) in the treatment of alcohol dependence is heterogeneous. Population severity and treatment duration have been identified as potential effect modifiers. Population severity distinguishes heavy drinking patients with <14 days of abstinence before treatment initiation (high-severity population) from other patients (mild-severity population). Treatment duration reflects the planned treatment duration. This study aimed to systematically investigate the effect of these potential effect moderators on SMO efficacy in alcohol-dependent patients. METHODS: Network meta-regression allows for testing potential effect modifiers. It was selected to investigate the effect of the above factors on SMO efficacy defined as continuous abstinence (abstinence rate) and the percentage of days abstinent (PDA). Randomized controlled trials for alcohol dependence with at least one SMO group conducted in high-severity and mild-severity populations were assigned to a high-severity and mild-severity group of studies, respectively. RESULTS: Eight studies (1082 patients) were retained: four in the high-severity group and four in the mild-severity group. The high-severity group was associated with larger SMO effect sizes than the mild-severity group: abstinence rate risk ratio (RR) 3.16, P = 0.004; PDA +26.9%, P < 0.001. For PDA, longer treatment duration was associated with larger SMO effect size: +11.3% per extra month, P < 0.001. In the high-severity group, SMO showed benefit: abstinence rate RR 2.91, P = 0.03; PDA +16.9%, P < 0.001. In the mild-severity group, SMO showed benefit only in PDA for longer treatment duration: +23.9%, P < 0.001. CONCLUSIONS: In the retained studies with alcohol-dependent patients, high-severity population and longer treatment duration were associated with larger SMO effect sizes.

Development and Psychometric Properties of a New Patient-Reported Outcome Instrument of Health-Related Quality of Life Specific to Patients with Gambling Disorder: The Gambling Quality of Life Scale (GQoLS).

BACKGROUND: Impairment or distress caused by gambling disorder can be subjectively assessed via quality of life. The aim of this study was to develop a new patient-reported outcome instrument to explore the health-related quality of life (HRQoL) in gambling disorders, the Gambling quality-of-life scale (GQoLS), and to document its psychometric properties. METHODS: A previous qualitative study had been conducted using focus groups of problem gamblers to identify areas of HRQoL impacted by gambling. The seven domains identified served as the basis for the hypothetical structure of GQoLS. Draft items were generated from the patient's speeches to illustrate each of these domains. Cognitive debriefing interviews were realized to obtain a final hypothetical GQoLS. A validation study was then carried out to determine the final version of GQoLS and its psychometric properties (structural validity, construct validity, internal consistency). RESULTS: The final GQoLS was composed of 21 items, with a total mean score of 38.3 (±13.6). Structural validity found a major dimension and four other minor dimensions. The five dimensions were: "emotion", "lifestyle", "loneliness", "taboo" and "preoccupation". GQoLS was moderately to strongly correlated with PGSI and EQ-5D visual analogic scale. Cronbach's alpha coefficient was 0.92. CONCLUSION: GQoLS is the first HRQoL instrument specific to patients with a gambling disorder and developed from the patient's perspective. GQoLS presents good psychometric properties. GQoLS can be used in clinical research to demonstrate the effectiveness of an intervention on outcomes that are relevant from the patient's perspective.

Sodium oxybate for the maintenance of abstinence in alcohol-dependent patients: An international, multicenter, randomized, double-blind, placebo-controlled trial.

BACKGROUND: Sodium oxybate (SMO) has been shown to be effective in the maintenance of abstinence (MoA) in alcohol-dependent patients in a series of small randomized controlled trials (RCTs). These results needed to be confirmed by a large trial investigating the treatment effect and its sustainability after medication discontinuation. AIMS: To confirm the SMO effect on (sustained) MoA in detoxified alcohol-dependent patients. METHODS: Large double-blind, randomized, placebo-controlled trial in detoxified adult alcohol-dependent outpatients (80% men) from 11 sites in four European countries. Patients were randomized to 6 months SMO (3.3-3.9 g/day) or placebo followed by a 6-month medication-free period. Primary outcome was the cumulative abstinence duration (CAD) during the 6-month treatment period defined as the number of days with no alcohol use. Secondary outcomes included CAD during the 12-month study period. RESULTS: Of the 314 alcohol-dependent patients randomized, 154 received SMO and 160 received placebo. Based on the pre-specified fixed-effect two-way analysis of variance including the treatment-by-site interaction, SMO showed efficacy in CAD during the 6-month treatment period: mean difference +43.1 days, 95% confidence interval (17.6-68.5; p = 0.001). Since significant heterogeneity of effect across sites and unequal sample sizes among sites (n = 3-66) were identified, a site-level random meta-analysis was performed with results supporting the pre-specified analysis: mean difference +32.4 days, p = 0.014. The SMO effect was sustained during the medication-free follow-up period. SMO was well-tolerated. CONCLUSIONS: Results of this large RCT in alcohol-dependent patients demonstrated a significant and clinically relevant sustained effect of SMO on CAD. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04648423.

Management of alcohol-related liver disease: the French Association for the Study of the Liver and the French Alcohol Society clinical guidelines.

Excessive alcohol consumption is the leading cause of liver diseases in Western countries, especially in France. Alcohol-related liver disease (ARLD) is an extremely broad context and there remains much to accomplish in terms of identifying patients, improving prognosis and treatment, and standardising practices. The French Association for the Study of the Liver wished to organise guidelines together with the French Alcohol Society in order to summarise the best evidence available about several key clinical points in ARLD. These guidelines have been elaborated based on the level of evidence available in the literature and each recommendation has been analysed, discussed and voted by the panel of experts. They describe how patients with ARLD should be managed nowadays and discuss the main unsettled issues in the field.

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.

Baseline severity and the prediction of placebo response in clinical trials for alcohol dependence: A meta-regression analysis to develop an enrichment strategy.

BACKGROUND: There is considerable unexplained variability in alcohol abstinence rates (AR) in the placebo groups of randomized controlled trials (RCTs) for alcohol dependence (AD). This is of particular interest because placebo responses correlate negatively with treatment effect size. Recent evidence suggests that the placebo response is lower in very heavy drinkers who show no "spontaneous improvement" prior to treatment initiation (high-severity population) than in a mild-severity population and in studies with longer treatment duration. We systematically investigated the relationship between population severity, treatment duration, and the placebo response in AR to inform a strategy aimed at reducing the placebo response and thereby increasing assay sensitivity in RCTs for AD. METHODS: We conducted a systematic literature review on placebo-controlled RCTs for AD.We assigned retained RCTs to high- or mild-severity groups of studies based on baseline drinking risk levels and abstinence duration before treatment initiation. We tested the effects of population severity and treatment duration on the placebo response in AR using meta-regression analysis. RESULTS: Among the 19 retained RCTs (comprising 1996 placebo-treated patients), 11 trials were high-severity and 8 were mild-severity RCTs. The between-study variability in AR was lower in the high-severity than in the mild-severity studies (interquartile range: 7.4% vs. 20.9%). The AR in placebo groups was dependent on population severity (p = 0.004) and treatment duration (p = 0.017) and was lower in the high-severity studies (16.8% at 3 months) than the mild-severity studies (36.7% at 3 months). CONCLUSIONS: Pharmacological RCTs for AD should select high-severity patients to decrease the magnitude and variability in the placebo effect and and improve the efficiency of drug development efforts for AD.

Treating alcohol dependence with an abuse and misuse deterrent formulation of sodium oxybate: Results of a randomised, double-blind, placebo-controlled study.

Sodium oxybate (SMO) has been approved in Italy and Austria for the maintenance of abstinence in alcohol dependent (AD) patients. Although SMO is well tolerated in AD patients, cases of abuse and misuse have been reported outside the therapeutic setting. Here we report on a phase IIb double-blind, randomized, placebo-controlled trial for the maintenance of abstinence in AD patients with a new abuse and misuse deterrent formulation of SMO. A total of 509 AD patients were randomized to 12 weeks of placebo or one of four SMO doses (0.75, 1.25, 1.75 or 2.25 g t.i.d.) followed by a one-week medication-free period. The primary endpoint was the percentage of days abstinent (PDA) at end of treatment. An unexpectedly high placebo response (mean 73%, median 92%) was observed. This probably compromised the demonstration of efficacy in the PDA, but several secondary endpoints showed statistically significant improvements. A post-hoc subgroup analysis based on baseline severity showed no improvements in the mild group, but statistically significant improvements in the severe group: PDA: mean difference +15%, Cohen's d = 0.42; abstinence: risk difference +18%, risk ratio = 2.22. No safety concerns were reported. Although the primary endpoint was not significant in the overall population, several secondary endpoints were significant in the intent-to-treat population and post-hoc results showed that treatment with SMO was associated with a significant improvement in severe AD patients which is consistent with previous findings. New trials are warranted that take baseline severity into consideration.

Use of Nalmefene in Routine Practice: Results from a French Prospective Cohort Study and a National Database Analysis.

AIMS: Two complementary studies were used to assess the real-life use of nalmefene in alcohol-dependent patients and its impact on alcohol use health status. METHODS: USE-PACT was a prospective cohort study designed to evaluate the real-life effectiveness of nalmefene in the management of alcohol dependence, as assessed by total alcohol consumption (TAC) and number of heavy drinking days (HDD) at 1 year. USE-AM was a cohort study using data from the French nationwide claims database and was used to evaluate the external validity of the population in the prospective study. RESULTS: Overall, 256 of 700 new nalmefene users enrolled in the USE-PACT study had valid data at 1 year. After 1 year, patients treated with nalmefene showed a mean ± SD reduction from baseline in TAC (-41.5 ± 57.4 g/day) and number of HDD (-10.7 ± 11.7 days/4 weeks). Patients took a mean ± SD of 20.0 ± 12.0 tablets/4 weeks (median of 1 tablet/day) for the first 3 months and then reduced the dose. The proportion of patients who no longer took nalmefene gradually increased from 5% at 1 month to 52% at 1 year. The USE-AM study identified 486 patients with a first reimbursement for nalmefene in 2016; baseline characteristics confirmed external validity of the USE-PACT study. Overall, 46.3% of initial USE-AM prescriptions were made by GPs; most (91.8%) patients stopped treatment during follow-up. However, 15.2% of patients resumed treatment after stopping. CONCLUSIONS: In this analysis of French routine practice, patients with alcohol dependence treated with nalmefene showed reduced alcohol consumption, and nalmefene was generally well tolerated.

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.