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.

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.

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

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

[Baclofen in the treatment of alcohol addiction : a French saga]. / Le baclofène dans le traitement de la dépendance à l'alcool : une saga française.

In 2018, France granted an approval to baclofen for the treatment of alcohol-dependency. It is the culmination of a long saga that began in 2005 with the publication of the personal case of Dr Ameisen, followed in 2008 by a public book which achieved great success and an important echo in the French population and in the media. The weakness of scientific data contradicting peremptory positions on its effectiveness has generated strong tensions between supporters of scientific medicine and activists supporting baclofen. Indeed, the data from published clinical trials do not confirm a high level of efficacy. Nevertheless, baclofen has allowed new patients to consult in the hope of an improvement. This long story confirms the need to evaluate therapeutics according to scientifically validated experimental protocols in order to avoid the risks of deviance.

En 2018, la France a octroyé au baclofène une autorisation de mise sur le marché dans le traitement de l'alcoolo-dépendance. C'est l'aboutissement d'une longue saga, commencée en 2005 avec la publication du cas personnel du Dr Ameisen, suivie en 2008 par un livre grand public qui a rencontré un fort écho dans la population française et les médias. La faiblesse des données scientifiques, en contradiction avec des prises de position péremptoires sur une efficacité très importante, a généré de fortes tensions entre tenants d'une médecine scientifique et militants du baclofène. Les essais cliniques publiés ne confirment pas le niveau d'efficacité allégué. Malgré tout, le baclofène a permis à des patients qui n'étaient jamais venus, de consulter dans l'espoir d'une amélioration. Cette longue saga confirme la nécessité d'évaluer les thérapeutiques selon des protocoles scientifiquement validés pour éviter les déviances.

[Competency-based pedagogical approach: illustration applied to the care relationship]. / Approche pédagogique par compétences : illustration appliquée à la relation de soins.

The reform of health studies and the inclusion in the Bachelor-Master-Doctorate curriculum implies a new way of teaching, with an inverted pedagogical relationship between student and teacher. The competency-based approach contributes to the development of the student's professional and interpersonal skills, in the same way as the support provided by the nurse in the care relationship, particularly in therapeutic education, in order to promote patient autonomy.

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.

A Randomized, Placebo-Controlled Study of High-Dose Baclofen in Alcohol-Dependent Patients-The ALPADIR Study.

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.

People with alcohol use disorders in specialized care in eight different European countries.

AIM: To provide a description of patients receiving alcohol treatment in eight different European countries, including the level of comorbidities and functional limitations. METHODS: Drinking behaviours, DSM-IV alcohol use disorder (AUD), mental and somatic comorbidities, disability and health services utilization of 1767 patients from various specialized treatment settings were assessed as representative for regions of eight European countries. Severity of alcohol dependence (AD) in terms of drinking level was compared with a large representative US sample. RESULTS: Patients in specialized care for AUDs showed high levels of consumption [average level of daily ethanol intake: 141.1 g, standard deviation (SD): 116.0 g], comorbidity [e.g. liver problems: 19.6%, 95% confidence interval (CI): 17.5-21.6%; depression: 43.2%, 95% CI: 40.7-45.8%; anxiety: 50.3%, 95% CI: 47.8-52.9%], disability and health services utilization (average number of nights spent in hospital(s) during the last 6 months: 8.8, SD: 19.5 nights). Severity of AD was similar to the US sample, but European men consumed on average more alcohol daily. CONCLUSIONS: High levels of consumption, somatic and mental comorbidities, disability and functional losses were found in this representative treatment sample, indicating that treatment was initiated only at severe stages of AUDs. Earlier initiation of treatment could help avoid some of the health and social burden.

[Cognitive impairment of alcohol-dependent subjects]. / Troubles cognitifs du sujet alcoolodépendant.

Chronic excessive alcohol consumption induces multiple brain damages. Secondary cognitive disorders include executive functions, episodic memory and visuospatial capacities. The severity of these alcohol induced disorders may vary between sub-clinical manifestations (that may, nevertheless, interfere with medical management) and more important ones like Korsakoff syndrome or dementia. The latter are usually irreversible but many of these manifestations are potentially reversible with persistent abstinence. It therefore appears of particular importance to clearly define neuropsychological management in order to identify and evaluate the type and severity of alcohol-related cognitive disorders. The patients may then be offered rehabilitation for these cognitive impairments. This is the first step of a complete addiction program based especially on cognitive behavioral therapies.

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.

[Misuse of alcohol and new drug treatments]. / Mésusage de l'alcool et nouveaux traitements médicamenteux.

Three drugs are currently marketed in France in the prevention of relapse in alcohol-dependent patients. Their efficacy though real remains limited and it is useful to develop other molecules. Some products are at present under evaluation, and are already or could be used in the near future in the treatment of alcohol dependence: baclofene, oxybate de sodium (GHB), nalmefene, topiramate, ondansetron and aripiprazole. The available studies on these molecules are still limited and the results sometimes clinically modest. Nevertheless, some of them open interesting future prospects. If there is no big revolution to wait in the short term in the treatment of alcohol dependence, we can consider some interesting orientations: better effectiveness on alcohol consumption, but also change of paradigm concerning the objectives and the methods of this treatment: reduction of consumption versus abstinence, treatment on request, choice of the molecule guided by objective criteria (psychosocial, biological, genetic...).

[Thiamin and alcohol use disorder: A national survey of practice]. / Thiamine et trouble de l'usage d'alcool : une enquête de pratique nationale.

OBJECTIVE: The survey aimed to estimate, in the presence of alcohol use disorder, the frequency of systematic prescription of thiamine, the factors associated with it, and those related to the administration (oral, intravenous, intramuscular) when Wernicke's encephalopathy is suspected. METHODS: A self-questionnaire available on Internet was sent by e-mail to doctors and nurses taking care patients with alcohol use disorder. RESULTS: In all, 565 professionals responded. The systematic prescription frequency of thiamine was 84.8 %, addiction care centers and medical-psychological centers prescribed it 5 times less than in psychiatric hospitals (OR=0.2 IC [0.1-0.5] P<0.0001), and medicine/surgery/obstetrics (MSO) services 10 times more than psychiatric hospitals (OR=10.7 IC [2.5-45.3] P<0.0001). The prescription decreased with the exercise period, the interns prescribing it 10 times more systematically (OR=10.9 IC [3.6-32.9] P<0.0001). In the presence of symptoms related to Wernicke's encephalopathy, thiamine administration was mainly oral (67.1 %). Intravenous administration was used more by the MSO services (OR=18.3 IC [10.2-32.7] P<0.0001), while the intramuscular injection was used more in psychiatric hospitals (OR=4.6 IC [1.7-11.9] P=0.0353). CONCLUSION: The prescription of thiamine is rather systematic. In contrast, intravenous administration is underused, in the presence of symptoms related to Wernicke's encephalopathy, in favor of oral administration, and the more specific use of the intramuscular injection in psychiatry.

[Medical management of alcohol use disorders]. / Prise en charge médicamenteuse des troubles de l'usage de l'alcool.

Medical management of alcohol use disorders. Psychosocial support remains the key element of treatment of patients with an alcohol use disorder in order to either decrease or cease their alcohol consumption. However two drugs can now be used to reduce alcohol consumption: nalmefene and baclofen. Currently available studies have shown weak to moderate effect sizes in this indication. Four molecules are available to help patients maintain abstinence: acamprosate, naltrexone, disulfiram and baclofen (off-label use). Effect sizes calculated by various metaanalyses are also low to moderate. Disulfiram appears to be more effective when the patient has understood its mechanism of action and when it is used under supervision. However, the use of disulfiram is limited by the risk of rare, but potentially serious adverse effects. Identification of patient subgroups obtaining better responses to certain drugs constitutes a major research challenge, but only a few criteria have been defined to date. However, regardless of the drug considered, heavy drinking and difficulty to maintain abstinence significantly improve the efficacy of the drugs. After an initially promising period, identification of genetic markers has not yet resulted in any clinical applications. Promising molecules currently under evaluation include sodium oxybate and topiramate.

Prise en charge médicamenteuse des troubles de l'usage de l'alcool. L'accompagnement psychosocial reste l'élément clé du traitement des patients ayant un trouble de l'usage de l'alcool, qu'il s'agisse de réduire leur consommation ou de l'arrêter. Des médicaments peuvent cependant augmenter son efficacité. Actuellement, deux médicaments peuvent être prescrits pour réduire la consommation d'alcool : le nalméfène et le baclofène ; les études disponibles à ce jour montrent des tailles d'effet faibles à modérées dans cette indication. Par ailleurs, quatre molécules sont disponibles pour aider les patients à maintenir une abstinence : l'acamprosate, la naltrexone, le disulfirame et le baclofène (hors AMM). Les tailles d'effet calculées par les méta-analyses sont également faibles à modérées. L'efficacité du disulfirame paraît intéressante lorsque le patient a compris son mécanisme d'action et qu'il est utilisé avec une supervision. Son utilisation est cependant limitée par un risque d'effets indésirables rares mais potentiellement graves. La caractérisation de sous-groupes de patients répondant mieux à certains médicaments est un enjeu important de la recherche. À ce jour, peu de critères peuvent être retenus. Soulignons cependant que, quel que soit le médicament considéré, une consommation d'alcool élevée et une difficulté à maintenir l'abstinence améliorent de façon significative l'efficacité des médicaments. La recherche de marqueurs génétiques n'a pas pour l'instant débouché sur des applications cliniques pratiques. Des molécules prometteuses sont actuellement en cours d'évaluation, notamment l'oxybate de sodium et le topiramate.