Early Increase in Blood-Brain Barrier Permeability in a Murine Model Exposed to Fifteen Days of Intermittent Hypoxia.

Obstructive sleep apnea (OSA) is characterized by intermittent repeated episodes of hypoxia-reoxygenation. OSA is associated with cerebrovascular consequences. An enhanced blood-brain barrier (BBB) permeability has been proposed as a marker of those disorders. We studied in mice the effects of 1 day and 15 days intermittent hypoxia (IH) exposure on BBB function. We focused on the dorsal part of the hippocampus and attempted to identify the molecular mechanisms by combining in vivo BBB permeability (Evans blue tests) and mRNA expression of several junction proteins (zona occludens (ZO-1,2,3), VE-cadherin, claudins (1,5,12), cingulin) and of aquaporins (1,4,9) on hippocampal brain tissues. After 15 days of IH exposure we observed an increase in BBB permeability, associated with increased mRNA expressions of claudins 1 and 12, aquaporins 1 and 9. IH seemed to increase early for claudin-1 mRNA expression as it doubled with 1 day of exposure and returned near to its base level after 15 days. Claudin-1 overexpression may represent an immediate response to IH exposure. Then, after 15 days of exposure, an increase in functional BBB permeability was associated with enhanced expression of aquaporin. These BBB alterations are possibly associated with a vasogenic oedema that may affect brain functions and accelerate neurodegenerative processes.

Could reasons for admission help to screen unhealthy alcohol use in emergency departments? A multicenter French study.

Background: Many patients admitted to general emergency departments (EDs) have a pattern of drinking that could lead to future alcohol-related complications. However, it is often difficult to screen these patients in the context of emergency. The aim of this study is to analyze whether reasons for admission could help to screen patients who have an unhealthy alcohol use. Method: Patients were recruited among six public hospital ED in France, between 2012 and 2014. During a one-month period in each hospital, anonymous questionnaires including sociodemographic questions, AUDIT-C and RAPS4-QF were administered to each patients visiting the ED. The reason for admission of each patient was noted at the end of their questionnaire by the ED practitioner. Results: Ten thousand Four hundred twenty-one patients were included in the analysis. Patients who came to the ED for injuries and mental disorders were more likely to report unhealthy alcohol use than non-harmful use or no use. Among male patients under 65 years old admitted to the ED for a mental disorder, 24.2% drank more than four drinks (40 g ethanol) in typical day at least four time a week in the last 12 months. Among these patients, 79.7% reported daily or almost daily heavy episodic drinking (HED, 60 g ethanol), and all were positive on the RAPS4-QF. Conclusion: This study highlights that unhealthy alcohol use is frequent among ED patients and particularly among those who come for injuries or mental disorders. Men under 65 years old with a mental disorder require special attention because of their increased prevalence of daily or almost daily HED.

Long-Acting Buprenorphine Formulations as a New Strategy for the Treatment of Opioid Use Disorder.

Long-acting buprenorphine formulations have been recently marketed for the Opioid Agonist Treatment (OAT) of opioid use disorder (OUD) associated with medical, social, and psychological support. Their duration of action ranges from one week up to 6 months. The non-medical use of opioids is increasing with a parallel rise in lethal overdoses. Methadone and buprenorphine are the standard treatment for opioid dependence. Methadone Maintenance Treatment (MMT) is widely recognized as one of the most effective ways of reducing the risks of overdose, crime, and transmission of HIV (Human Immunodeficiency Virus) in people who use opioids; however, its effectiveness has been hindered by low rates of uptake and retention in treatment. Furthermore, both methadone and buprenorphine are widely diverted and misused. Thus, a crucial aspect of treating OUD is facilitating patients' access to treatment while minimizing substance-related harm and improving quality of life. The newly developed long-acting buprenorphine formulations represent a significant change in the paradigm of OUD treatment, allowing an approach individualized to patients' needs. Strengths of this individualized approach are improved adherence (lack of peaks and troughs in blood concentrations) and a reduced stigma since the patient doesn't need to attend their clinic daily or nearly daily, thus facilitating social and occupational integrations as the quality of life. However, less frequent attendance at the clinic should not affect the patient-physician relationship. Therefore, teleconsulting or digital therapeutic services should be developed in parallel. In addition, diversion and intravenous misuse of buprenorphine are unlikely due to the characteristics of these formulations. These features make this approach of interest for treating OUD in particular settings, such as subjects staying or when released from prison or those receiving long-term residential treatment for OUD in the therapeutic communities. The long-lasting formulations of buprenorphine can positively impact the OUD treatment and suggest future medical and logistic developments to maximize their personalized management and impact.

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.

What is the potential for abuse of lisdexamfetamine in adults? A preclinical and clinical literature review and expert opinion.

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.

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.

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.

Prevalence and Characteristics of Chronic Pain in Buprenorphine and Methadone-Maintained Patients.

Chronic pain and substance use disorders frequently co-occur. Indeed, chronic pain is highly prevalent, affecting 23-68% of patients receiving opioid agonist treatments (OAT) worldwide. The majority of available estimates come from American studies, but data are still lacking in Europe. We aim to provide European estimates of the prevalence of chronic pain in patients receiving OAT using French data, since France is the first European country in terms of number of patients with OAT. The secondary objectives were to characterize the features and management of chronic pain, as well identify associated risk factors. We conducted a multicenter, cross-sectional study, recruiting patients treated either with buprenorphine or methadone in 19 French addiction centers, from May to July 2016. All participants had to complete a semi-directed questionnaire that collected sociodemographic and medical data, pain characteristics, and licit or illicit drug consumption. In total, 509 patients were included. The prevalence of chronic pain was estimated at 33.2% (95% CI: 29.1-37.3). Compared to non-chronic pain patients, chronic pain patients were older (38.4 vs. 36.1 years, p = 0.006), were more unemployed (66 vs. 52%, p = 0.003), had more psychiatric comorbidities (50 vs. 39%, p = 0.02), and split their OAT for pain management more frequently (24 vs. 7%, p = 0.009). Pain intensity was moderate or severe in 75% of chronic pain patients. Among patients with chronic pain, 15.4% were not prescribed, and did not self-medicate with, any analgesic drugs, 52.1% were prescribed analgesics (non-opioid analgesics, 76.3%; codeine, tramadol, opium, 27.2%; and morphine, fentanyl, oxycodone, 11.8%), and 32.5% exclusively self-medicated with analgesics. Moreover, 20.1% of patients with chronic pain also used illicit drugs for pain relief. On multivariate analysis, variables that remained significantly associated with chronic pain were age [OR = 1.03 (95% CI: 1.00-1.05], p = 0.02], anxiety [OR = 1.52 (1.15-2.02), p = 0.003], and depression [OR = 1.25 (1.00-1.55), p = 0.05]. Chronic pain is a highly prevalent condition in patients receiving OAT, and its appropriate management remains uncertain, since insufficient relief and frequent additional self-medications with analgesics or illicit drugs were reported by these patients. Increased awareness among caregivers is urgently needed regarding a systematic and careful assessment, along with an adequate management of chronic pain in patients receiving OAT.

Risk-Based Decision Making: A Systematic Scoping Review of Animal Models and a Pilot Study on the Effects of Sleep Deprivation in Rats.

Animals, including humans, frequently make decisions involving risk or uncertainty. Different strategies in these decisions can be advantageous depending the circumstances. Short sleep duration seems to be associated with more risky decisions in humans. Animal models for risk-based decision making can increase mechanistic understanding, but very little data is available concerning the effects of sleep. We combined primary- and meta-research to explore the relationship between sleep and risk-based decision making in animals. Our first objective was to create an overview of the available animal models for risky decision making. We performed a systematic scoping review. Our searches in Pubmed and Psychinfo retrieved 712 references, of which 235 were included. Animal models for risk-based decision making have been described for rodents, non-human primates, birds, pigs and honey-bees. We discuss task designs and model validity. Our second objective was to apply this knowledge and perform a pilot study on the effect of sleep deprivation. We trained and tested male Wistar rats on a probability discounting task; a "safe" lever always resulted in 1 reward, a "risky" lever resulted in 4 or no rewards. Rats adapted their preferences to variations in reward probabilities (p < 0.001), but 12 h of sleep deprivation during the light phase did not clearly alter risk preference (p = 0.21).

Opioid-related deaths in Europe: Strategies for a comprehensive approach to address a major public health concern.

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.

Consensus and Controversies Between Pain and Addiction Experts on the Prevention, Diagnosis, and Management of Prescription Opioid Use Disorder.

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.

Sleep and Microdialysis: An Experiment and a Systematic Review of Histamine and Several Amino Acids.

Sleep seems essential to proper functioning of the prefrontal cortex (PFC). The role of different neurotransmitters has been studied, mainly the catecholamines and serotonin. Less attention has been paid to the amino acid transmitters and histamine. Here, we focus on the activity of these molecules in the PFC during sleep and sleep deprivation (SD). We determined extracellular concentrations of histamine and 8 amino acids in the medial PFC before, during and after SD. Additionally, we systematically reviewed the literature on studies reporting microdialysis measurements relating to sleep throughout the brain. In our experiment, median concentrations of glutamate were higher during SD than during baseline (p = 0.013) and higher during the dark-active than during the resting phase (p = 0.003). Glutamine was higher during post-SD recovery than during baseline (p = 0.010). For other compounds, no differences were observed between light and dark circadian phase, and between sleep deprivation, recovery and baseline. We retrieved 13 papers reporting on one or more of the molecules of interest during naturally occurring sleep, 2 during sleep deprivation and 2 during both. Only two studies targeted PFC. Histamine was low during sleep, but high during sleep deprivation and wakefulness, irrespective of brain area. Glu (k = 11) and GABA (k = 8) concentrations in different brain areas were reported to peak during sleep or wakefulness or to lack state-dependency. Aspartate, glycine, asparagine and taurine were less often studied (1-2 times), but peaked exclusively during sleep. Sleep deprivation increased glutamate and GABA exclusively in the cortex. Further studies are needed for drawing solid conclusions.

Brain Microdialysate Monoamines in Relation to Circadian Rhythms, Sleep, and Sleep Deprivation - a Systematic Review, Network Meta-analysis, and New Primary Data.

Disruption of the monoaminergic system, e.g. by sleep deprivation (SD), seems to promote certain diseases. Assessment of monoamine levels over the circadian cycle, during different sleep stages and during SD is instrumental to understand the molecular dynamics during and after SD. To provide a complete overview of all available evidence, we performed a systematic review. A comprehensive search was performed for microdialysis and certain monoamines (dopamine, serotonin, noradrenaline, adrenaline), certain monoamine metabolites (3,4-dihydroxyphenylacetic acid (DOPAC), 5-hydroxyindoleacetic acid (5-HIAA)) and a precursor (5-hydroxytryptophan (5-HTP)) in PubMed and EMBASE. After screening of the search results by two independent reviewers, 94 publications were included. All results were tabulated and described qualitatively. Network-meta analyses (NMAs) were performed to compare noradrenaline and serotonin concentrations between sleep stages. We further present experimental monoamine data from the medial prefrontal cortical (mPFC). Monoamine levels varied with brain region and circadian cycle. During sleep, monoamine levels generally decreased compared to wake. These qualitative observations were supported by the NMAs: noradrenaline and serotonin levels decreased from wakefulness to slow wave sleep and decreased further during Rapid Eye Movement sleep. In contrast, monoamine levels generally increased during SD, and sometimes remained high even during subsequent recovery. Decreases during or after SD were only reported for serotonin. In our experiment, SD did not affect any of the mPFC monoamine levels. Concluding, monoamine levels vary over the light-dark cycle and between sleep stages. SD modifies the patterns, with effects sometimes lasting beyond the SD period.

[Alcohol use disorder: evolution of the nosography]. / Trouble de l'usage de l'alcool : évolution de la nosographie.

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.

Intracerebral Adenosine During Sleep Deprivation: A Meta-Analysis and New Experimental Data.

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 wash-out, 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.

Full-Profile Pharmacokinetic Study of High Dose Baclofen in Subjects With Alcohol Use Disorder.

Baclofen a gamma amino-butyric acid type B (GABA-B) receptor agonist, which has raised some interest for the treatment of alcohol use disorder (AUD), occasionally at dose up to 300 mg/d. We conducted the first full-profile pharmacokinetic study on baclofen in AUD subjects, up to the oral daily dose of 300 mg. Sixty subjects treated for AUD with marketed baclofen were enrolled in a prospective phase-1 study. Participants were divided into four dose groups (1: <60 mg/d; 2: 60-120 mg/d; 3: >120 mg/d-180 mg/d; and 4: >180 mg/d), and they underwent a full-profile pharmacokinetic analysis of baclofen, using a nonlinear mixed effects modeling. The influence of different clinical and biological covariates was assessed in an upward modeling. Fifty-seven participants completed the study (522 observed concentrations collected). Racemic baclofen showed a linear pharmacokinetic profile, corresponding to a one-compartment model, with no influencing clinical or biological factor. The pharmacokinetic parameters of baclofen were (bootstrap 95% confidence intervals): absorption constant (Ka) 1.64 1/h (1.34-2), clearance (Cl/F) 11.6 L/h (10.8-12.3) and volume of distribution (Vd/F) 72.8 L (66.5-80.4) leading to a half-life of 4.4 h. The interindividual variability (IIV) was 44% (19-65), 21% (16-27), and 22% (11-36) for Ka, Cl/F, and Vd/F, respectively. The residual variability was 24% (21-26). No serious adverse event was reported. Registration: EudraCT #2013-003412-46.

Efficacy and safety of sodium oxybate in alcohol-dependent patients with a very high drinking risk level.

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.

[Alcohol and Neurology]. / Alcool et neurologie.

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.

Neuroticism and anxious attachment as potential vulnerability factors of repeat suicide attempts.

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.

Recommendations for buprenorphine and methadone therapy in opioid use disorder: a European consensus.

INTRODUCTION: Management of patients with opioid use disorder (OUD) commonly includes opioid agonist therapy (OAT) as a part of an integrated treatment plan. These interventions are associated with proven benefits to the individual and society. Areas covered: The use of methadone and buprenorphine within an integrated treatment plan in the management of patients with OUD: this work provides consensus recommendation on pharmacotherapy in OUD to assist clinicians with practical decision making in this field. Expert opinion: Pharmacotherapy is recommended as part of an integrated OUD treatment approach with psychosocial interventions, with the goal of reducing risks of illicit opioid use, overdose mortality, infection with HIV or HCV, improving health, psychological and social outcomes. Access to OAT should be prioritised in the treatment of OUD. Treatment choices in OUD pharmacotherapy should be based on the needs of the individual and characteristics of medications. Recommendations for choices of OAT are based on clinical efficacy, safety, patient preference, side effects, pharmacological interactions, quality of life, dose titration potential and outcomes (control craving, ongoing opioids consumption or other drugs, and potentially psychiatric comorbidities). Special groups, pregnant women, prisoners, patients with mental health problems have specific needs which must be addressed with expert input.