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

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

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.

Occurrence and severity of cocaine-induced hallucinations: Two distinct phenotypes with shared clinical factors but specific genetic risk factors.

Cocaine-induced transient hallucinations (CIH) are a frequent complication following cocaine intake that is associated with addiction severity. METHODS: Two hundred and forty-two non-psychotic and Caucasian lifetime cocaine users were included in a French multicentric study. Clinical variables and dopamine pathway genotype data were extracted and tested with CIH scores using a zero-inflated binomial model, which allows for the exploration of factors associated with occurrence and severity separately. RESULTS: Cocaine dependence (poccurrence= 6.18 × 10-5, pseverity= 9.25 × 10-8), number of cocaine dependence DSM IV-Tr criteria (poccurrence= 1.22 × 10-7, pseverity= 5.09 × 10-6), and frequency of intake during the worst period of misuse (poccurrence= 8.51 × 10-04, pseverity= 0.04) were associated with greater occurrence and higher severity of CIH. The genetic associations did not yield significant results after correction for multiple tests. However, some nominal associations of SNPs mapped to the VMAT2, DBH, DRD1, and DRD2 genes were significant. In the multivariate model, the significant variables were the number of cocaine dependence criteria, lifetime alcohol dependence, and the nominally associated SNPs. CONCLUSION: Our study shows that CIH occurrence and severity are two distinct phenotypes, with shared clinical risk factors; however, they likely do not share the same genetic background.

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

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

Can alcohol dependent patients adhere to an 'as-needed' medication regimen?

A pooled analysis of 'as-needed medication use' data from 1,276 patients in two randomised, double-blind, placebo-controlled, parallel-group trials of nalmefene in the treatment of alcohol dependence was performed to explore whether an 'as-needed' regimen is an acceptable and feasible strategy in patients seeking help for alcohol dependence. Adherence was defined as alcohol consumption and medication intake, or no alcohol consumption (with or without medication intake). Nalmefene was taken on approximately half of the study days; placebo was taken more often than nalmefene (52.8 vs. 64.5% of days, respectively). In each treatment group medication intake appeared to vary according to patients' needs in that intake correlated with the baseline drinking pattern. Sixty-eight percent of the nalmefene-treated patients (78% of the study completers) adhered to the as-needed treatment regimen on at least 80% of the study days. In conclusion, as-needed use is a feasible, patient-centred approach that engages patients with alcohol dependence in the active management of their illness.

[Changing alcohol abuse patterns]. / Evolution des modes d'alcoolisation.

While it has been steadily declining since the 1960s, though at a slower pace over the last 5 years, the average alcohol consumption per capita and per year in France remains one of the highest in Europe. The available general population surveys reveal that the most visible change is the type of alcohol abuse. Two emerging trends have been observed over the last ten years, and seem to be worsening: the transfer from daily drinking to weekend drinking, and the increase in isolated risk-taking related to acute alcoholization associated with more-or-less conscious inebriation episodes. These changes require adapting prevention messages, the development of alcohol risk screening strategies in emergency units and the assessment of therapeutic programs aiming at reducing the risks of alcohol consumption rather than maintaining abstinence.

The role of brief motivational intervention on self-efficacy and abstinence in a cohort of patients with alcohol dependence.

OBJECTIVES: Brief interventions are effective in reducing heavy drinking in the general population but few studies examined whether it is also effective in alcohol dependent patients, and whether brief intervention increases self-efficacy. METHOD: One hundred and seven patients with alcohol-dependence were randomized in a controlled trial examining the efficacy of a brief motivational intervention on both self-efficacy level and days of abstinence. RESULTS: We found that brief motivational interventions had no effect on days of abstinence, nor on self-efficacy, but that high self-efficacy was consistently correlated with a longer period of abstinence, at all assessment-points. CONCLUSION: Self-efficacy appears to be a crucial prognosis factor, and is not influenced by brief motivational interventions. Other types of specific psychotherapy, probably more intensive, may be more efficient in alcohol-dependent patients than motivational interventions.

The 3' part of the dopamine transporter gene DAT1/SLC6A3 is associated with withdrawal seizures in patients with alcohol dependence.

BACKGROUND: Some studies have reported that the A9 allele of the variable nucleotide tandem repeat (VNTR) of the gene which encodes the dopamine transporter (DAT1/SLC6A3) is associated with alcoholism withdrawal symptoms such as alcohol withdrawal seizures (WSs), whereas others did not. We investigated whether polymorphisms within the DAT1 gene are associated with WS taking into account some of the confounding factors such as the severity of alcohol dependence. METHODS: To further assess the role of this gene in WS, we genotyped the VNTR and 7 single nucleotide polymorphisms (SNPs) encompassing the DAT1 gene in a sample of 250 alcohol-dependent subjects (175 men and 75 women), of whom 24% exhibited WSs, taking into account the severity of alcohol dependence. RESULTS: The VNTR is associated with an increased risk of WSs (odd ratio = 3.5; p = 0.019), even when controlling for confounding factors (p = 0.031). As 2 SNPs, in roughly the same location of the gene (namely rs27072 and rs27048), are also associated with WSs, it is possible that the initial association of the VNTR polymorphism was tagging a specific haplotype of this gene. Indeed, in our sample of alcohol-dependent patients, 2 haplotypes were associated with a significantly different risk of WSs. CONCLUSIONS: The present study adds evidence for a significant role of the 3' part of the DAT1 gene in WS of alcohol-dependent patients, not only because it is in accordance with previous work, but also because of larger statistical power (as relying on a sample over sampled with the studied phenotype), as it gives a more precise analysis of different SNPs within the DAT1 gene, and as it confirms the association when major potentially confounding factors are taken into account in a logistical regression analysis.

[Maintaining abstinence after alcohol detoxification]. / Maintien de l'abstinence après le sevrage.

"To quit drinking" is not the panacea of alcohol dependence treatment; it is only its first step. Abstinence should be considered more as a mean than a purpose of the after-withdrawal cares. The frequent resistance of the alcoholic patient to undertake in a long term abstinence can be by-passed by suggesting to fix himself renewable terms for periods during which he feels rather confident to raise the bet of a "most accomplished possible" abstinence. To facilitate the realization and the preservation of this abstinence in the best conditions (potentiation of the profits and minimization of the difficulties), a "therapeutic menu" will be proposed to the patient besides a "minimum plan" containing a medical follow-up over one year, with variable frequency of visits according to the evolution and the prescription of one or two anti-craving drugs registered. Psychotherapies using different techniques as Cognitive Behavioural Therapy, group therapy or psychoanalysis could be proposed after a necessary clarification to the patients of the mechanism of action of each and the waited profits. In the final, two thirds of the patients with alcohol dependence fire in one year a profit of their treatments; the practitioner takes, actually, no risk and should propose systematically a project to the only 20% of them who come to consult him.

[Care network in addictive pathologies: where is it?]. / Réseaux de soins dans les conduites addictives: où en est-on?

Network practise is important in the care of addictive pathologies. It aims to fulfill patient needs on a social and health level, as part of a concertive approach from the different health workers. Co-ordinated practise seems to provide an adapted and proven response for more than twenty years now, but has only recently been recognised as such by the health authorities. It was originally initiated by militant care workers in response to a daily reality too complex to be managed alone. The bringing together of experience and competencies, an adapted response to the demands in a context of dependency, patient care facilitated by exchanges, complementarily and the sharing of competencies are the objectives of a rich and beneficial network. However, it seems necessary to supplement with financial, human and legal help in order maintain the continuity and improve this novel approach.

The A9 allele of the dopamine transporter gene is associated with delirium tremens and alcohol-withdrawal seizure.

BACKGROUND: The dopamine transporter (DAT) plays a key role in homeostatic regulation of dopaminergic neurotransmission and could thus be involved in the variability of two severe alcohol-withdrawal symptoms, alcohol-withdrawal seizure (AWS) and delirium tremens (DT). Interestingly, an association was found between the DAT gene (9-copy repeat) and the risk for these symptoms in two previous case-control studies. METHODS: We reanalyzed the role of the DAT gene in the lifetime risk for AWS and DT in 120 alcohol-dependent patients, taking into account potentially confounding factors. RESULTS: Alcohol-dependent patients with the A(9) allele had experienced AWS or DT at least once (odds ratio [OR] = 2.52, p =.03). This association persisted when excluding patients with antisocial personality comorbidity (OR = 3.48, p =.02) or limiting the analysis to older patients (OR = 8.3, p =.0008). CONCLUSIONS: This study provides convergent data in favor of a significant role of the DAT gene in the risk for some severe withdrawal symptoms. If further replicated in larger samples, the DAT genetic polymorphism could be one of the factors to be analyzed to further assess the risk of some severe alcohol-withdrawal symptoms.

Economic and social effects of high-dose buprenorphine substitution therapy. Six-month results.

The purpose of this study was to analyze the impact of high-dose buprenorphine substitution therapy in opiate-dependent patients in terms of use of psychoactive substances, associated risks, social integration, and the social cost generated by the use of these substances. This was a longitudinal quantitative survey carried out in 1083 patients who were evaluated at three times: at the beginning of substitution therapy (D0), at 6 months and then at 12 months follow up (M6, M12). Data were collected with an anonymous self-administered questionnaire, completed in the presence of an investigating physician. Results demonstrated that patients treated with high-dose buprenorphine for 6 months, consumed fewer psychoactive drugs (heroin, cocaine, benzodiazepines) and had fewer associated risks. Additionally, several criteria involved in social integration showed improvement; morbidity and mortality decreased after the first 6 months of substitution therapy. These improvements were followed by a reduction in the social cost of drug use generated by the group of patients considered. These initial results require confirmation in the final analysis of the study taking into account the 12-month follow up.

Reappraisal of the serotonin 5-HT(1B) receptor gene in alcoholism: of mice and men.

Because pharmacological and genetic data supported the idea that serotonin receptors of the 5-HT(1B) type can play a modulatory role in alcohol consumption in both human and rodents, the 5-HT(1B) receptor gene is considered as a candidate gene for alcohol dependence. However, contradictory results have been reported as a positive association between alcohol dependence, and either the 861C or the 861G allele of the G861C polymorphism of the 5-HT(1B) receptor gene can be found in the literature. Further investigations in a population of 136 male alcoholics compared with 72 male control subjects demonstrated that none of these alleles was actually associated with alcohol dependence. In addition, in contrast with previous results of the literature, ethanol intake under free choice conditions (i.e., ethanol solution vs. water) was found to be similar in 5-HT(1B)-/- knock mice and paired wild-type controls. The 5-HT(1B) receptor gene may thus not be a key component in the genetic background underlying alcohol dependence in human and alcohol preference in rodents, although these results should be considered as preliminary according to the small size of our sample.