Search

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

AimsThe 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 MethodsNetwork 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.ResultsEight 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 ConclusionsIn the retained studies with alcohol-dependent patients, high-severity population and longer treatment duration were associated with larger SMO effect sizes.

INTRODUCTION: Lisdexamfetamine dimesylate (LDX) is a prodrug approved for attention deficit/hyperactivity disorder and for moderate-to-severe binge eating disorder in adults in some countries. AREA COVERED: We aimed to specify the abuse potential of LDX in adults, using a review of pharmacokinetic/pharmacodynamic (PK/PD), animal, clinical, and pharmaco-epidemiological studies, through a PubMed search since inception until May 2021 using the following keywords: "lisdexamfetamine AND ('misuse' OR 'abuse' OR 'diversion' OR 'addiction')". EXPERT OPINION: Most of the studies highlighted a longer Tmax than dexamphetamine leading to a delayed onset of effects and a decreased Cmax. These PK parameters were often associated with a diminished feeling of euphoria, in comparison to immediate-release dexamphetamine. The potential for abuse was also limited by the prodrug property of LDX, thus reducing the risk of misuse. Nevertheless, all the data were not convergent, as some authors reported similar Cmax for LDX and dexamphetamine and reinforcing properties with a dose-dependent effect. Epidemiological studies found that abuse rates of LDX were substantially lower than those of immediate-release dexamphetamine. Overall, although LDX abuse seems possible, we did not find evidence concerning current safety signal. However, more long-term pharmaco-epidemiological studies are still needed to confirm this finding.

International audience; 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.

Alcohol use disorder: evolution of the nosography. The arrival of DSM-5 has represented a nosographic break with respect to the DSMIV- TR: by leaving the old biaxial view and its hierarchical gradation between abuse and dependence; by removing the term "dependence" with its stigma and amalgams between psychic and physical dependencies; and by integrating craving, a main therapeutic target, allowing the DSM-5 to join the ICD-10 (and soon the ICD-11). Without being a revolution, the DSM-5 is a real evolution, with a modern dimensional view of addictive behaviors, according to a progressive continuum between use and use disorder (from mild to severe). This approach allows the representation of addictions to change, and to propose various therapeutic strategies adapted to the patient's objectives and inspired by the harm reduction approaches, abstinence being only one of these strategies.Trouble de l’usage d’alcool : évolution de la nosographie. L’arrivée du DSM-5 a représenté une rupture nosographique vis-à-vis du DSM-IV-TR : en quittant la vision ancienne biaxiale et sa gradation hiérarchisée entre abus et dépendance ; en faisant disparaître le terme dépendance avec sa stigmatisation et ses amalgames entre dépendances psychique et physique ; et en intégrant le craving, une cible thérapeutique majeure, permettant au DSM-5 de rejoindre la CIM-10 (et prochainement la CIM-11). Sans être une révolution, le DSM-5 est donc une véritable évolution, avec une vision dimensionnelle moderne des conduites addictives, selon un continuum progressif entre usage et trouble de l’usage, de léger à sévère. Cette approche permet de changer la représentation des addictions, et de proposer des stratégies thérapeutiques variées et adaptées aux objectifs du patient, en s’inspirant des stratégies de réduction des risques et des dommages, l’abstinence n’étant que l’une de ces stratégies.

Resume Pathologies duelles et polyconsommation sont frequemment associees et rendent difficiles un diagnostic categoriel et des soins specifiques. La deconstruction du tableau clinique en dimensions fonctionnelles et en endophenotypes permet de proposer un traitement pragmatique adapte aux besoins, aux ressources et a l’ecologie du patient via une pharmacopsychotherapie incluant : (1) des strategies substitutives de reduction des risques et des dommages (modalite de consommation, produit, comportement) ; (2) une combinaison graduee de psychotherapies (approche de rehabilitation psychosociale) et ; (3) une pharmacologie dimensionnelle (dimensions elementaires et endophenotypes) et un traitement specifique lorsque le diagnostic categoriel est possible. Cette approche integrative permet de traiter en ambulatoire les patients les plus complexes.

Resume Les addictions restent associees a la notion stigmatisante de produits illicites, tandis que le trouble de l’usage des medicaments est banalise voire ignore. L’histoire nous montre que le statut de drogue attribue a un produit est avant tout une question d’epoque, d’ecosystemes et surtout de representations. Les addictions medicamenteuses sont devenues un enjeu de sante publique, leur emergence renforce la necessite de considerer l’usage plus que le produit.

Medication development for alcohol relapse prevention or reduction of consumption is highly challenging due to methodological issues of pharmacotherapy trials. Existing approved medications are only modestly effective with many patients failing to benefit from these therapies. Therefore, there is a pressing need for other effective treatments with a different mechanism of action, especially for patients with very high (VH) drinking risk levels (DRL) because this is the most severely affected population of alcohol use disorder patients. Life expectancy of alcohol-dependent patients with a VH DRL is reduced by 22 years compared with the general population and approximately 90 000 alcohol-dependent subjects with a VH DRL die prematurely each year in the EU (Rehm et al. ). A promising new medication for this population is sodium oxybate, a compound that acts on GABAB receptors and extrasynaptic GABAA receptors resulting in alcohol-mimetic effects. In this article, a European expert group of alcohol researchers and clinicians summarizes data (a) from published trials, (b) from two new-as yet unpublished-large clinical trials (GATE 2 (n = 314) and SMO032 (n = 496), (c) from post hoc subgroup analyses of patients with different WHO-defined DRLs and (d) from multiple meta-analyses. These data provide convergent evidence that sodium oxybate is effective especially in a subgroup of alcohol-dependent patients with VH DRLs. Depending on the study, abstinence rates are increased up to 34 percent compared with placebo with risk ratios up to 6.8 in favor of sodium oxybate treatment. These convergent data are supported by the clinical use of sodium oxybate in Austria and Italy for more than 25 years. Sodium oxybate is the sodium salt of γ-hydroxybutyric acid that is also used as a recreational (street) drug suggestive of abuse potential. However, a pharmacovigilance database of more than 260 000 alcohol-dependent patients treated with sodium oxybate reported very few adverse side effects and only few cases of abuse. We therefore conclude that sodium oxybate is an effective, well-tolerated and safe treatment for withdrawal and relapse prevention treatment, especially in alcohol-dependent patients with VH DRL.

Points essentiels Le systeme nerveux est un tissu cible particulier pour l’alcool en raison des effets recherches et de ses nombreuses consequences aigues et chroniques. Les consequences aigues sont liees aux episodes de surconsommation, aux syndromes de sevrage, ou aux decompensations de carences nutritionnelles associees. Les consequences chroniques sont dominees par les troubles du sommeil et cognitivo-comportementaux, la douleur chronique, les accidents vasculaires cerebraux et les atteintes de l’equilibre, des nerfs peripheriques et des muscles, notamment par toxicite directe et/ou carences nutritionnelles. Il existe une relation bidirectionnelle qui necessite de rechercher : l’usage d’alcool comme facteur causal ou aggravant devant tout trouble neurologique ; et des troubles neurologiques en cas d’usage d’alcool a fortiori problematique. La prise en charge des consequences neurologiques liees a l’alcool peut aider a reduire ou a arreter les consommations d’alcool, a prevenir les rechutes, et a ameliorer la qualite de vie des patients.

The recurrence risk of suicide attempts can reach 50% in the first year, each attempt increasing suicide-risk by 32%. No screening tool efficiently identifies potential repeat suicide attempters who are too often regarded as borderline personality. Our aim was to identify individual and interpersonal psychopathological dimensions that could represent a vulnerability to repeat suicide attempts. Sixty first-time and repeat suicide attempters consecutively admitted in emergency rooms were compared for fundamental dimensions of personality, patterns of attachment, personality and mental disorders using standardized questionnaires. Confounding and significantly different factors were evaluated using univariate and multivariate logistic regressions. Repeat suicide attempters differed from first-attempters by higher neuroticism and anxious attachment. Combined in an 11-item measure, these two parameters identified a 3.99 times higher risk of repeat suicide attempt. These traits associated with the other two best predictors (non-suicidal self-injury history, current psychotropic drugs) provide a vulnerability model with better screening performance compared to each factor individually. Repeat suicide attempters have more psychological features impairing emotional stability and social interactions than first attempters. Cross-sectional study design, sample size, lack of independent sample and of fearful-avoidant attachment evaluation are the main limitations. The model needs to be validated in a prospective and controlled study.

Sleep apnea syndrome is characterized by repetitive upper airway collapses during night leading to intermittent hypoxia (IH). The latter is responsible for metabolic disturbances that rely, at least in part, on abdominal white fat inflammation. Besides qualitative alterations, we hypothesized that IH could also modify body fat distribution, a key factor for metabolic complications. C57BL6 mice exposed to IH (21–5% FiO2, 60 s cycle, 8 h/day) or air for 6 weeks were investigated for topographic fat alterations (whole-body MRI). Specific role of epididymal fat in IH-induced metabolic dysfunctions was assessed in lipectomized or sham-operated mice exposed to IH or air. Whereas total white fat volume was unchanged, IH induced epididymal adipose tissue (AT) loss with non-significant increase in subcutaneous and mesenteric fat. This was associated with impaired insulin sensitivity and secretion. Epididymal lipectomy led to increased subcutaneous fat in the perineal compartment and prevented IH-induced metabolic disturbances. IH led to reduced epididymal AT and impaired glucose regulation. This suggests that, rather than epididymal AT volume, qualitative fat alterations (i.e. inflammation) could represent the main determinant of metabolic dysfunction. This deterioration of glucose regulation was prevented in epididymal-lipectomized mice, possibly through prevention of IH-induced epididymal AT alterations and compensatory increase in subcutaneous AT.

Aims Alcohol dependence is a major public health issue with a need for new pharmacological treatments. The ALPADIR study assessed the efficacy and safety of baclofen at the target dose of 180 mg/day for the maintenance of abstinence and the reduction in alcohol consumption in alcohol-dependent patients. Methods Three hundred and twenty adult patients (158 baclofen and 162 placebo) were randomized after alcohol detoxification. After a 7-week titration, the maintenance dose was provided for 17 weeks, then progressively decreased over 2 weeks before stopping. Results The percentage of abstinent patients during 20 consecutive weeks (primary endpoint) was low (baclofen: 11.9%; placebo: 10.5%) and not significantly different between groups (OR 1.20; 95%CI: 0.58 to 2.50; P = 0.618). A reduction in alcohol consumption was observed from month 1 in both groups, but the difference of 10.9 g/day at month 6 between groups, in favour of baclofen, was not statistically significant (P = 0.095). In a subgroup of patients with high drinking risk level at baseline, the reduction was greater with a difference at month 6 of 15.6 g/day between groups in favour of baclofen (P = 0.089). The craving assessed with Obsessive-Compulsive Drinking Scale significantly decreased in the baclofen group (P = 0.017). No major safety concern was observed. Conclusions This study did not demonstrate the superiority of baclofen in the maintenance of abstinence at the target dose of 180 mg/day. A tendency towards a reduction in alcohol consumption and a significantly decreased craving were observed in favour of baclofen. Short summary Baclofen was assessed versus placebo for maintenance of abstinence and reduction in alcohol consumption in alcohol-dependent patients. This study did not demonstrate the superiority of baclofen in the maintenance of abstinence. A tendency towards a reduction in alcohol consumption and a significantly decreased craving were observed in favour of baclofen.

Objectives Prescription opioid use disorder (POUD) is an established public health crisis in many countries, and current evidence indicates it is a growing problem in Europe. Many specialists play a role, including pain and addiction medicine specialists, in the diagnosis and management of POUD, but neither group can fully address these patients' needs alone. The purpose of this consensus process was to bring together experts from pain and addiction medicine to examine the positions of both specialties. Methods In all, 13 international pain medicine, addiction medicine, and addiction psychiatry experts convened a meeting to formulate a set of consensus statements on the diagnosis and management of POUD. The statements were further refined by a wider group of 22 European expert clinicians. At a second meeting of all 35 participants, a set of controversy statements was also developed to recognize some of the key areas of divergent opinion. Results/conclusions There was a high level of agreement between pain and addiction specialists. Key themes that emerged were the need to strengthen interdisciplinary communication, a desire for greater education and training for clinicians in both specialties, and mutual acknowledgment of the importance of multidisciplinary management of POUD. The blurred line between poorly managed pain and POUD was also a subject of much discussion, reflecting the difficulties in defining and diagnosing this complex condition.

Use of illicit opioids and misuse of prescription opioids are the main causes of drug-related deaths across the world, and the continuing rise in opioid-related mortality, especially affecting North America, Australia and Europe, is a public health challenge. Strategies that may help to decrease the high levels of opioid-related mortality and morbidity and improve care across Europe include risk assessment and interventions to improve the use of opioid analgesics, e.g. prescription drug-monitoring programmes, education on pain management to reduce opioid prescribing, and the implementation of evidence-based primary prevention programmes to reduce the demand for opioids. For patients who develop opioid use disorder (a chronic and relapsing problematic use of opioids that causes clinical impairment or distress), treatment combining opiate receptor full or partial agonist medications for opioid-use disorder (MOUD) with psychosocial interventions is essential. However, in Europe a substantial proportion of the 1.3 million high-risk opioid users (defined as injecting drug use or regular use of opioids, mainly heroin) remain outside of dedicated treatment programmes. More widespread and easier access to MOUD could reduce mortality levels; via approaches such as primary care-led treatment models, and efforts to improve patient retention and adherence to treatment programmes. Other harm-reduction strategies, such as the use of MOUD at optimal doses, the provision of take-home naloxone, the introduction of supervised drug-consumption facilities, and patient education to reduce the risk of overdose may also be beneficial.

Funding Information: The systematic review was funded by The Netherlands Organisation for Health Research and Development (ZonMW; 114024101); R2N, Federal State of Lower Saxony; and the DFG (FOR2591, BL 953/11-1). The microdialysis experiment was funded by Netherlands Organization for Scientific Research (NWO; 051-04-010, to Eus van Some-ren). The HPLC adenosine measurements were funded by the University of Helsinki sleep team and a travel grant from the European Sleep Research Society. Publisher Copyright: © 2018 Ubiquity Press. All rights reserved. The neuroregulator adenosine is involved in sleep-wake control. Basal forebrain (BF) adenosine levels increase during sleep deprivation. Only a few studies have addressed the effect of sleep deprivation on extracellular adenosine concentrations in other brain regions. In this paper, we describe a microdialysis experiment as well as a meta-analysis of published data. The 64 h microdialysis experiment determined the extracellular adenosine and adenosine monophosphate (AMP) concentrations in the medial prefrontal cortex of rats before, during and after 12 h of sleep deprivation by forced locomotion. The meta-analysis comprised published sleep deprivation animal experiments measuring adenosine by means of microdialysis. In the animal experiment, the overall median adenosine concentration was 0.36 nM and ranged from 0.004 nM to 27 nM. No significant differences were observed between the five conditions: 12 h of washout, baseline light phase, baseline dark phase, 12 h of sleep deprivation and 12 h of subsequent recovery. The overall median AMP concentration was 0.10 nM and ranged from 0.001 nM to 7.56 nM. Median AMP concentration increased during sleep deprivation (T = 47; p = 0.047) but normalised during subsequent recovery. The meta-analysis indicates that BF dialysate adenosine concentrations increase with 74.7% (95% CI: 54.1-95.3%) over baseline during sleep deprivation. Cortex dialysate adenosine concentrations during sleep deprivation were so far only reported by 2 publications. The increase in adenosine during sleep deprivation might be specific to the BF. At this stage, the evidence for adenosine levels in other brain regions is based on single experiments and insufficient for generalised conclusions. Further experiments are currently still warranted.

The nervous system is a particular target tissue for alcohol due to desired effects and numerous acute and chronic consequences. Acute consequences are due to episodes of overconsumption, withdrawal syndromes, or decompensation of nutritional deficiencies. Chronic consequences are dominated by sleep disorders, chronic pain and cognitive-behavioral disorders, stroke, and impairments of balance, peripheral nerves and muscles, resulting from direct toxicity and/or nutritional deficiencies. There is a bidirectional relationship requiring seeking: alcohol use as a causal or aggravating factor in any neurological disorder ; and neurological disorders in cases of alcohol use, especially when problematic. Management of alcohol-related neurological consequences can help reduce or stop alcohol consumption, prevent relapse, and improve patients' quality of life.

International audience

Study objectives Obstructive sleep apnea (OSA) induces cognitive impairment that involves intermittent hypoxia (IH). Because OSA is recognized as a low-grade systemic inflammatory disease and only some patients develop cognitive deficits, we investigated whether IH-related brain consequences shared similar pathophysiology and required additional factors such as systemic inflammation to develop. Design Nine-week-old male C57BL/6J mice were exposed to 1 day, 6 or 24 w of IH (alternating 21-5% FiO2 every 30 sec, 8 h/day) or normoxia. Microglial changes were assessed in the functionally distinct dorsal (dH) and ventral (vH) regions of the hippocampus using Iba1 immunolabeling. Then the study concerned dH, as vH only tended to be lately affected. Seven proinflammatory and anti-inflammatory cytokine messenger RNA (mRNA) were assessed at all time points using semiquantitative real-time reverse transcription polymerase chain reaction (RT-PCR). Similar mRNA analysis was performed after 6 w IH or normoxia associated for the past 3 w with repeated intraperitoneal low-dose lipopolysaccharide or saline. Measurements and results Chronic (6, 24 w) but not acute IH induced significant microglial changes in dH only, including increased density and morphological features of microglia priming. In dH, acute but not chronic IH increased IL-1β and RANTES/CCL5 mRNA, whereas the other cytokines remained unchanged. In contrast, chronic IH plus lipopolysaccharide increased interleukin (IL)-6 and IL10 mRNA whereas lipopolysaccharide alone did not affect these cytokines. Conclusion The obstructive sleep apnea component intermittent hypoxia (IH) causes low-grade neuroinflammation in the dorsal hippocampus of mice, including early but transient cytokine elevations, delayed but long-term microglial changes, and cytokine response alterations to lipopolysaccharide inflammatory challenge. These changes may contribute to IH-induced cognitive impairment and pathological brain aging.

Alcohol is a risk factor for suicide and is often involved in violent actions. The aim of the study was to assess the involvement of alcohol in suicides and its relationship with the lethality of suicide methods.In a retrospective study on autopsy reports, we compared suicide and non-suicide victims, suicides with positive and negative blood alcohol concentration (BAC), and studied the lethality of suicide methods using a multivariate analysis.Suicide victims (n=88) were not different to non-suicide victims (n=270) for positive BAC and narcotics, but were more often positive for prescription medications (59.1 vs. 35.6%, p=0.003) and medications in blood (72.7 vs. 54.8%, p=0.004). Whereas non-suicidal victims died mainly of traumas (60%, p0.001), two populations of suicides emerged with regard to BAC, self-poisoning predominating with positive BAC (38.9%, p=0.039) and asphyxiation with negative BAC (41.4%, p=0.025). Positive BAC appeared as the unique and strong independent predictive factor, increasing the risk of self-poisoning suicide by 4.36 [1.29-14.76], and decreasing the risk of suicidal asphyxiation by 84% (OR=0.16 [0.03-0.83]). Positive blood narcotics tended to behave in the similar way to alcohol.Recruitment bias (victims declared by the Forensic authorities) and incomplete autopsy reports are the two main limitations.Characteristics of suicide victims with positive BAC are suggestive of Deliberate Self-Harm Syndrome (low lethality methods, substance misuse). These being at high risk of repeated suicide attempts, previous self-harm involving alcohol may represent a warning sign and access to medication should be limited to prevent recidivism.

Since the 1990s, the use of prescription opioids has largely spread, which has brought a real progress in the treatment of pain. The long-term use of prescription opioid is sometimes required, and may lead to pharmacological tolerance and withdrawal symptoms, i.e. pharmacological dependence on prescription opioids. Occasionally, this may also lead to misuse of prescription opioids (MPO). MPO preferentially occurs in vulnerable individuals, i.e., those with a young age, history of other addictive or psychiatric disorders, especially anxious and depressive disorders. MPO is associated with numerous complications, including an increased risk of fatal overdose. Prevention of MPO begins before the opioid prescription, with the identification of potential vulnerability factors. A planned and personalized monitoring should be systematically implemented. In vulnerable patients, contractualizing the prescription is warranted. During follow-up, the relevance of the prescription should be regularly reconsidered, according to the benefit observed on pain and the potential underlying signs of MPO. Patients with suspected MPO should be referred early to pain or addiction centers. The treatment of MPO should be based on multidisciplinary strategies, involving both the addiction and pain aspects: progressive opioid withdrawal, non-pharmacological measures against pain, or switching to medication-assisted treatment of addiction (i.e., buprenorphine or methadone).

Hypoxia is a primary factor in many pathological conditions. Hypoxic cell death is commonly attributed to metabolic failure and oxidative injury. cAMP-dependent protein kinase A (PKA) is activated in hypoxia and regulates multiple enzymes of the mitochondrial electron transport chain, thus may be implicated in cellular energy depletion and hypoxia-induced cell death. Wild type (WT) PC-12 cells and PKA activity-deficient 123.7 PC-12 cells were exposed to 3, 6, 12 and 24h hypoxia (0.1% or 5% O2). Hypoxia, at 24h 0.1% O2, induced cell death and increased reactive oxygen species (ROS) in WT PC-12 cells. Despite lower ATP levels in normoxic 123.7 cells than in WT cells, hypoxia only decreased ATP levels in WT cells. However, menadione-induced oxidative stress similarly affected both cell types. While mitochondrial COX IV expression remained consistently higher in 123.7 cells, hypoxia decreased COX IV expression in both cell types. N-acetyl cysteine antioxidant treatment blocked hypoxia-induced WT cell death without preventing ATP depletion. Transient PKA catα expression in 123.7 cells partially restored hypoxia-induced ROS but did not alter ATP levels or COX IV expression. We conclude that PKA signaling contributes to hypoxic injury, by regulating oxidative stress rather than by depleting ATP levels. Therapeutic strategies targeting PKA signaling may improve cellular adaptation and recovery in hypoxic pathologies.

In France, 1-2 million drinkers suffer from alcohol use disorder (AUD). Fewer than 200,000 patients are treated for their AUD whereas 1.4 million patients are treated for alcohol-related consequences. Established pharmacological treatments have modest efficacy and no drugs are in development. AUD is underpinned by alterations of the endogenous opioid system which is currently modulated by naltrexone or nalmefene. Mu- and kappa-transmissions are respectively down- and upregulated. This imbalance may contribute to chronic stress and dysphoria in AUD patients and consequently to the persistence of consumption and relapse [1]. Long acting opioid agonists (LAOA) such as high-dose buprenorphine (HDB) may provide effective therapy. In opioid use disorder (OUD), individualized dose adaptations of LAOA allow patients to reduce or stop use of short acting opioids and associated substances such as alcohol [2]. The effect on alcohol consumption was also reported in rodents [3]. LAOA have psychotropic properties, as they can relieve psychiatric disorders (mood, suicidal ideation) in non-addicted subjects [4]. These symptoms are common in severe AUD and resistant to antidepressants when alcohol intake persists. Because HDB appears more effective and safer than methadone in reducing alcohol consumption, we assessed HDB in an ambulatory pilot study, including 17 patients (male: 47 %) with treatment-resistant and life-threatening AUD and free of OUD. Wilcoxon tests were used to compare clinical characteristics between the inclusion and each time of the evaluation (month 1, 3, 6, 12) for each group of patients evaluated (17, 15, 10 and 5, respectively). According to the preliminary results, a careful HDB titration led to significant decreases in daily consumption of alcohol from (mean (SD)) 98 (126) to 30 (42) and 14 (31) g/day, after 1 and 12 months of treatment respectively, without safety issues (transient dizziness, nausea), including HDB misuse. In patients with non-daily alcohol use but episodic heavy drinking days (HDD) (n=7), HDB decreased the number of HDD, from 7.3 (6.8) to 4 (7.3) and 0 at month 6 and 12, respectively. HDB, a safe medication used for 23 years in France, could constitute a last resort therapeutic option usable in outpatient settings, allowing long-lasting reduction in alcohol consumption and related harmful consequences with low safety issues.

Our objective is to present a focused review of the scientific literature on the effect of alcohol consumption on violence related-injuries assessed in the emergency room (ER) and to show how psychological and behavioral sciences could lead to a better understanding of the factors contributing to alcohol-related injuries in the ER. We retrieved published literature through a detailed search in Academic Search Premier, MEDLINE with Full Text PsycARTICLES, Psychology and Behavioral Sciences Collection, PsycINFO, PUBMed and SocINDEX with Full Text for articles related to emergency rooms, medical problems and sociocognitive models addressing alcohol intoxication articles. The first search was conducted in June 2011 and updated until August 2013. Literature shows that compared to uninjured patients; injured ones have a higher probability of: (i) having an elevated blood-alcohol concentration upon arrival at the ER; (ii) reporting having drunk alcohol during the six hours preceding the event; and (iii) suffering from drinking-related consequences that adversely affect their social life. The main neurocognitive and sociocognitive models on alcohol and aggression are also discussed in order to understand the aetiology of violence-related injuries in emergency rooms. Suggestions are made for future research and prevention.

Background Binge drinking (BD) consists of heavy episodic alcohol use. Whereas the World Health Organization (WHO) defines BD as 60 g of alcohol or more per occasion, the National Institute on Alcoholism and Alcohol Abuse (NIAAA) conceives BD as drinking 70 g (men) or 56 g (women) in less than two hours. We compared the subjects delineated by each definition. Methods Eight-center cross-sectional study among 11,695 subjects hospitalized in emergency wards. Participants completed the Alcohol Use Disorders Identification Test – Consumption (AUDIT-C), CAGE and Rapid Alcohol Problem Screen 4 (RAPS4-QF) questionnaires. The WHO criteria were investigated using the RAPS4-QF. Independent questions assessed the NIAAA criteria. The main medical admission motive was noted. The characteristics of subjects meeting respectively: 1) the exclusive WHO criteria (BD1); 2) the NIAAA criteria (BD2); and 3) no BD criteria (noBD) were compared using multinomial regression analyses. Binary age- and gender-adjusted regression analyses directly compared BD1 and BD2. Subjects with at least four drinking occasions per week were excluded from the analyses, to withdrawn regular heavy drinking. Results Compared to BD1, BD2 subjects were more frequently males (OR = 1.67 [1.39–2.0]), single (aOR = 1.64 [1.36–1.98]) and unemployed (aOR = 1.57 [1.27–1.90]). BD2 reported significantly more drinks per occasion, and higher heavy drinking frequencies. Previous alcohol-related remarks from family (aOR = 3.00 [2.53–3.56]), ever drinking on waking-up (aOR = 2.05 [1.37–2.72]), and admission for psychiatric motive (aOR = 2.27 [1.68–3.07]) were more frequent among BD2 subjects. Conclusions Compared to WHO criteria, NIAAA criteria for BD delineate subjects with more concerning drinking patterns and alcohol aftermaths.

Study Objectives: Task-switching is an executive function involving the prefrontal cortex. Switching temporarily attenuates the speed and/or accuracy of performance, phenomena referred to as switch costs. In accordance with the idea that prefrontal function is particularly sensitive to sleep loss, switch-costs increase during prolonged waking in humans. It has been difficult to investigate the underlying neurobiological mechanisms because of the lack of a suitable animal model. Here, we introduce the first switch-task for rats and report the effects of sleep deprivation and inactivation of the medial prefrontal cortex. Design: Rats were trained to repeatedly switch between 2 stimulus-response associations, indicated by the presentation of a visual or an auditory stimulus. These stimulus-response associations were offered in blocks, and performance was compared for the first and fifth trials of each block. Performance was tested after exposure to 12 h of total sleep deprivation, sleep fragmentation, and their respective movement control conditions. Finally, it was tested after pharmacological inactivation of the medial prefrontal cortex. Settings: Controlled laboratory settings. Participants: 15 male Wistar rats. Measurements & Results: Both accuracy and latency showed switch-costs at baseline. Twelve hours of total sleep deprivation, but not sleep fragmentation, impaired accuracy selectively on the switch-trials. Inactivation of the medial prefrontal cortex by local neuronal inactivation resulted in an overall decrease in accuracy. Conclusions: We developed and validated a switch-task that is sensitive to sleep deprivation. This introduces the possibility for in-depth investigations on the neurobiological mechanisms underlying executive impairments after sleep disturbance in a rat model.

Exposure to shiftwork has been associated with multiple health disorders and cognitive impairments in humans. We tested if we could replicate metabolic and cognitive consequences of shiftwork, as reported in humans, in a rat model comparable to 5 wks of non-rotating night shifts. The following hypotheses were addressed: (i) shiftwork enhances body-weight gain, which would indicate metabolic effects; and (ii) shiftwork negatively affects learning of a simple goal-directed behavior, i.e., the association of lever pressing with food reward (instrumental learning), which would indicate cognitive effects. We used a novel method of forced locomotion to model work during the animals' normal resting period. We first show that Wistar rats, indeed, are active throughout a shiftwork protocol. In contrast with previous findings, the shiftwork protocol attenuated the normal weight gain to 76 +/- 8 g in 5 wks as compared to 123 +/- 15 g in the control group. The discrepancy with previous work may be explained by the concurrent observation that with our shiftwork protocol rats did not adjust their between-work circadian activity pattern. They maintained a normal level of activity during the "off-work" periods. In the control experiment, rats were kept active during the dark period, normally dominated by activity. This demonstrated that forced activity, per se, did not affect body-weight gain (mean +/- SEM: 85 +/- 11 g over 5 wks as compared to 84 +/- 11 g in the control group). Rats were trained on an instrumental learning paradigm during the fifth week of the protocol. All groups showed equivalent increases in lever pressing from the first (3.8 +/- .7) to the sixth (21.3 +/- 2.4) session, and needed a similar amount of sessions (5.1 +/- .3) to reach a learning criterion (>= 27 out of 30 lever presses). These results suggest that while on prolonged non-rotating shiftwork, not fully reversing the circadian rhythm might actually be beneficial to prevent body-weight gain and cognitive impairments. (Author correspondence: C.Leenaars@nin.knaw.nl)

Objectif Sur la base de la litterature, nous faisons l’hypothese que l’hypoxie intermittente (HI) du syndrome d’apnees du sommeil (SAOS) jouerait un role majeur dans la genese des nombreuses complications neurologiques en favorisant l’apparition de modifications cerebrales propices au developpement de pathologies neurodegeneratives. Methodes Nous proposons que l’alteration de la barriere hemato-encephalique (BHE) par l’HI jouerait un role dans ces processus deleteres. Nous avons teste cette hypothese chez un modele murin en couplant test de permeabilite de la BHE (bleu Evans), neuroanatomie et biologie moleculaire. Resultats Notre etude a mis en evidence une augmentation significative de la permeabilite de la BHE chez les souris exposees a l’HI. Notre etude revele egalement une augmentation significative de l’expression des acteurs moleculaires de la BHE que nous pouvons interpreter comme un processus adaptatif destine a compenser un effet deletere de l’HI sur d’autres elements de la BHE. Conclusion Des etudes complementaires sont necessaires a la comprehension des mecanismes cellulaires et moleculaires sous-jacents. L’objectif a long terme est d’anticiper et ameliorer la prise en charge des complications associees au SAOS.

The function of sleep in physiology, behaviour and cognition has become a primary focus of neuroscience. Its study inevitably includes experimental sleep deprivation designs. However, concerns exist regarding confounds like stress, increased locomotor activity levels, and decreased motivation to perform operant tasks induced by the methods employed. We here propose a novel procedure for sleep deprivation in rats and evaluate how it affects sleep, corticosterone concentration profiles, locomotor activity levels, and motivation to perform an operant task. Before, during and after 12. h of total sleep deprivation by means of gradually increasing the rotation variability and the speed of a novel automated, two-compartment sleep deprivation device, sleep-wake states were assessed by electroencephalography (n= 21), brain extracellular corticosterone concentrations using microdialysis (n= 11), locomotor activity by infrared measurements (n= 8), and operant performance using a fixed-interval-fixed-ratio task (n= 16). Sleep was effectively prevented during the procedure; rats on average slept less than 1% of the time (0.8 ± 0.2%, mean ± standard error). Brain corticosterone concentrations were mildly increased during the procedure, but did not exceed normal peak concentrations. Locomotor activity was not only increased during the procedure, but also did not exceed the peak levels found during undisturbed wakefulness. Food restriction to 12. g/rat/day prevented sleep deprivation from reducing the motivation to perform an operant task. This novel procedure can be applied to sleep deprive rats in a highly effective way, while keeping corticosterone and locomotor activity within the normal range. © 2011 Elsevier B.V.

International audience; Obstructive sleep apnea (OSA) is a highly prevalent sleep disorder leading to cardiovascular and metabolic complications. OSA is also a multicomponent disorder, with intermittent hypoxia (IH) as the main trigger for the associated cardiovascular and metabolic alterations. Indeed, recurrent pharyngeal collapses during sleep lead to repetitive sequences of hypoxia-reoxygenation. This IH induces several consequences such as hemodynamic, hormonometabolic, oxidative, and immuno-inflammatory alterations that may interact and aggravate each other, resulting in artery changes, from adaptive to degenerative atherosclerotic remodeling. Atherosclerosis has been found in OSA patients free of other cardiovascular risk factors and is related to the severity of nocturnal hypoxia. Early stages of artery alteration, including functional and structural changes, have been evidenced in both OSA patients and rodents experimentally exposed to IH. Impaired vasoreactivity with endothelial dysfunction and/or increased vasoconstrictive responses due to sympathetic, endothelin, and renin-angiotensin systems have been reported and also contribute to vascular remodeling and inflammation. Oxidative stress, inflammation, and vascular remodeling can be directly triggered by IH, further aggravated by the OSA-associated hormonometabolic alterations, such as insulin resistance, dyslipidemia, and adipokine imbalance. As shown in OSA patients and in the animal model, genetic susceptibility, comorbidities (obesity), and life habits (high fat diet) may aggravate atherosclerosis development or progression. The intimate molecular mechanisms are still largely unknown, and their understanding may contribute to delineate new targets for prevention strategies and/or development of new treatment of OSA-related atherosclerosis, especially in patients at risk for cardiovascular disease.

Intermittent hypoxia, a hallmark of sleep apnea, is a major factor for hypertension and impaired vasoreactivity.To examine the temporal occurrence of these two outcomes in order to provide insight into mechanisms and early cardiovascular disease identification.Functional and structural cardiovascular alterations were assessed in C57BL6 mice exposed to intermittent hypoxia (21-4% Fi(O(2)), 30-s cycle, 8 h/d) or air for up to 35 days. Blood pressure, heart rate, and urinary catecholamines were measured at Days 1 and 14. Hindquarter vasoreactivity was assessed at Days 14 and 35, including vasoconstriction to norepinephrine, endothelium-, and non-endothelium-dependent vasodilation. Aorta, heart, and hindquarter skeletal muscles were immunostained for vascular markers PECAM-1 and collagen IV.Hemodynamic alterations occurred from Day 1, characterized by blood pressure surges with bradytachyarrhythmia driven by cyclic hypoxia. At Day 14, blood pressure at normoxia was elevated, with predominant diastolic increase. With hypoxia, vasopressive catecholamines were elevated, blood pressure surged with a lower hypoxic threshold, whereas heart rate fluctuations decreased. Histologic alterations started from Day 14, with decreased endothelial PECAM-1 expression in descending aorta and left heart. Impaired peripheral vasoreactivity occurred at Day 35, including hypervasoconstriction to norepinephrine secondary to sympathetic hyperactivity, without changes in pre- and postsynaptic alpha-adrenoceptors or in endothelium- and non-endothelium-dependent vasodilation.Intermittent hypoxia induces sequential cardiovascular events suggesting increased chemoreflex and depressed baroreflex, resulting in sympathoadrenal hyperactivity, early hemodynamic alterations with proximal histologic remodeling, and delayed changes in peripheral vasoreactivity. Such early alterations before overt cardiovascular disease strengthen the need for identifying at-risk individuals for systematic treatment.

International audience; 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 multi-professional 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 1) alcohol detoxification / abstinence maintenance programs or 2) drinking reduction programs. - The therapeutic objective is the result of a decision made jointly by the physician and the patient.- Benzodiazepines (BZDs) are the first-line medication for detoxification (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 one-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 four weeks (GRADE C). - The dosing and duration of thiamine (vitamin B1) during detoxification should be adapted to nutritional status (EC). - Medications for relapse prevention should be automatically associated with adapted psychosocial support (GRADE A). - Acamprosate and naltrexone are the first-line options for relapse prevention (GRADE A). - Disulfiram can be proposed as second-line treatment in patients who are correctly informed and adequately supervised (EC).- Medications for reducing alcohol consumption are only indicated in dependent individuals (EC). - Nalmefene is indicated as a first-line treatment for reducing alcohol consumption (GRADE A). - The second-line prescription of baclofen, up to 300 mg/d, to prevent relapse or reduce drinking should be carried out according to the “temporary recommendation for use” (TRU) issued by the French Health Agency (EC).- Abstinence is recommended throughout pregnancy (EC).- If medically‐assisted withdrawal is necessary during pregnancy, BZD use is recommended (GRADE B).- No medication other than those for alcohol withdrawal 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, the goal of 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).

Patients with severe apnoea may have an impaired pharyngeal dilating reflex related to decreased pharyngeal sensitivity. The accuracy of a simple new procedure to measure pharyngeal sensitivity and to diagnose sleep disordered breathing (SDB) was investigated.Pharyngeal disappearance and appearance sensory perception thresholds were measured by delivering different airflow rates on the soft palate using an intraoral device in 17 controls and 50 patients suffering from SDB evaluated by overnight polygraphy. The procedure was performed before (baseline) and after three successive administrations of a topical anaesthetic to sensitise the pharyngeal sensory impairment. Pharyngeal sensitivity was then evaluated according to SDB severity. SDB was classified as mild, moderate or severe according to the relative proportion of obstructive apnoeas-hypopnoeas and the amount of desaturation.Patients had higher baseline disappearance and appearance sensory thresholds than controls (mean (SD) 0.62 (0.44) v 0.26 (0.06) l/min and 0.85 (0.40) v 0.40 (0.19) l/min, p0.001, respectively). Such differences were enhanced by topical anaesthesia. Impairment of pharyngeal sensitivity and the number of patients with impaired sensitivity increased from the least to the most severe SDB group as indicated by the test sensitivity for a respiratory disturbance index of20/hour (50%, 73.7% and 88.5% in the mild, moderate, and severely affected groups, respectively).This simple and safe procedure showed that impairment of pharyngeal sensitivity is correlated with severity of SDB. Using this test in routine clinical practice may simplify the diagnosis of sleep apnoea, particularly for the most severe patients.

OBJECTIVES: Sleep disturbance constitutes a major risk factor for drinking relapse after alcohol withdrawal and necessitates regular follow-up. We reported previously that the sum-score of the 4 sleep items of the Hamilton Anxiety and Depression Scales (the Short Sleep Index [SSI]) constitutes a valid and simple sleep measurement tool. The objective of this study was to evaluate the psychometric features of the SSI relative to the lengthier Pittsburgh Sleep Quality Index (PSQI), which is widely used for measuring sleep disturbance in patients with alcohol use disorders during and after alcohol withdrawal. METHODS: In this French, multicenter, cross-sectional survey, alcoholic patients were recruited in 2 academic hospitals and 1 community treatment center. Demographic data, alcohol history, and current consumption of alcohol and other abused substances were documented. The SSI and the PSQI questionnaires were completed in face-to-face interviews by a trained clinical research associate. RESULTS: A total of 257 patients were studied (88 females), with a mean age of 49 years (range: 24-80 years). The prevalence of sleep disturbance as measured by the PSQI and the SSI was 73.5% and 74.3%, respectively. The correlation between the 2 indices was strong (r = 0.764; 95% CI: 0.709-0.811), with negative and positive predictive values for the SSI (score > 1) of 71.2% and 89%, respectively, and an area under the receiver operating characteristic curve of 0.91 (95% CI: 0.85-0.92). The discriminant and convergent validity of the SSI was found to be noninferior to the PSQI. CONCLUSIONS: Compared to the PSQI, the SSI represents a quick, quantifiable, and reliable method that could help clinicians assess and manage sleep disturbance in alcoholic patients. Language: en

Objective. Intermittent hypoxia (IH) is a major component of sleep apnea syndrome as its cardiometabolic complications have been mainly attributed to IH. The pathophysiology is still poorly understood but there are some similarities with the obesity-associated cardiometabolic complications. As the latter results from inflammation involving toll-like receptor-4 (TLR4) signaling, we assessed this pathway in the cardiometabolic consequences of IH.Methods. Lean adult male TLR4-deficient (TLR4−/−) mice and their controls (C57BL/6 mice) were exposed to either IH (FiO221-5%, 1 min cycle, 8 h/day) or air (normoxic mice) for 4 weeks. Animals were assessed at 1-week exposure for insulin tolerance test and after 4-week exposure for morphological and inflammatory changes of the epididymal fat and thoracic aorta.Results. IH induced insulin resistance, morphological and inflammatory changes of the epididymal fat (smaller pads and adipocytes, higher release of TNF-αand IL-6) and aorta (larger intima-media thickness and higher NFκB-p50 activity). All these alterations were prevented by TLR4 deletion.Conclusion. IH induces metabolic and vascular alterations that involve TLR4 mediated inflammation. These results confirm the important role of inflammation in the cardiometabolic consequences of IH and suggest that targeting TLR4/NFκB pathway could represent a further therapeutic option for sleep apnea patients.

International audience; Background: According to a 2014 report by the World Health Organization, the highest alcohol consumption levels per capita continue to be found in the developed world, particularly in the European region. Drinking alcohol does not only lead to alcohol dependence; it also be linked to a higher risk for acute medical and surgical events. In France, recent data show that alcohol consumption levels in the general population are important and have remained relatively stable since 2010. In the Emergency Department population, few French data are available, while studies conducted across the Atlantic show that patients admitted into emergency rooms are reported to have high levels of alcohol consumption. Emergency Departments are an important location for the identification and early intervention of issues related to alcohol consumption. Therefore, the aim of this study is to carry out an epidemiological picture of alcohol consumption and search for indicators of harmful alcohol use in patients in the French emergency rooms of the Rhône-Alpes-Auvergne interregion. Methods and Analysis: This observational, and descriptive and randomized clinical study on human beings will consists of a collection of clinical variables on all patients that will be admitted to the Emergency Departments of the RAA Rhône-Alpes-Auvergne interregion aged of (16 years or older) and who will be agree to participate to the study. It will include one visit where the patient will respond to three auto-administrating screening tests on his or her alcohol consumption: Alcohol Use Disorders Identification Test – C (AUDIT C), Cut-down, Annoyed, Guilty, Eye-opener test (CAGE) and the Rapid Alcohol Problems Screen – Quantity Frequency test (RAPS4 – QF). Similarly, they will answer two self-administering questionnaires on socio-demographic and emergency data.

International audience; The author would like to update "Conflicts of Interest" section of their previous publication [1] as follows: Conflicts of Interest Georges Brousse has received sponsorship to attend scientific meetings, speaker honoraria, and consultancy fees from Lundbeck and Merck-Lipha. Patrick Bendimerad received honoraria and travel reimbursements for conferences and consultancy by Lundbeck Laboratory and participated as a coinvestigator.in the multicenter investigational drug studies of Lundbeck. [...].During many years in France, risk reduction strategies for substance abuse concerned prevention strategies in the general population or interventions near users of illicit substances. In this spirit, the reduction of consumption only concerned opiate addicts. With regard to alcohol, the prevention messages relative to controlled consumption were difficult to transmit because of the importance of this product in the culture of the country. In addition, methods of treatment of alcoholism rested on the dogma of abstinence. Several factors have recently led to an evolution in the treatment of alcohol use disorders integrating the reduction of consumption in strategies. Strategies for reducing consumption should aim for consumption below recommended thresholds (two drinks per day for women, three for the men) or, at least, in that direction. It must also be supported by pharmacotherapy and psychotherapy, which offer possibilities. Failure to manage reduction will allow the goals to be revisited and to reconsider abstinence. Finally this evolution or revolution is a new paradigm carried in particular by a pragmatic approach of the disease andnew treatments. The aims of this article are to give elements of comprehension relating to the evolution of the practices in France in prevention and treatment of alcohol use disorders and in particular with regard to the reduction of consumption.