Background: Alcohol use disorder (AUD) is among the leading causes of morbidity and mortality worldwide, and over 95 million people live with alcohol dependence globally. The estimated heritability of AUD is 50-60 %, and multiple genes are thought to contribute to various endophenotypes of the disease. Previous clinical trials support a precision medicine approach using ondansetron (AD04, a 5-HT3 antagonist) by segregating AUD populations by the bio-genetic endophenotype of specific serotonergic genotypes and the bio-psychosocial endophenotype of the severity of drinking or both. By targeting the modulation of biogenetic signaling within the biopsychosocial context of AUD, low-dose AD04 holds promise in reducing alcohol consumption among affected individuals while minimizing adverse effects. Methods: This was a phase III, 6-month, 25-site, randomized, placebo-controlled clinical trial using AD04 to treat DSM-V-categorized AUD individuals who were pre-stratified into the endophenotypes of heavy or very heavy drinking individuals and possessed a pre-defined profile of genetic variants related to the serotonin transporter and serotonin-3AB receptor. Participants (N = 303) presented moderate to severe AUD, >80 % were men, mostly in their fifties, and >95 % were of European descent. Low-dose AD04 (approx. 033 mg twice daily) or a matching placebo was administered twice daily for 6 months. Brief Behavioral Compliance Enhancement Treatment (BBCET [53]) was administered every two weeks to enhance medication compliance and clinic attendance. Results: There was a significant reduction in the monthly percentage of heavy drinking days, PHDD (-467 % (27 %), 95 %CI: -521 % to -412 % vs. -381 % (29 %), 95 %CI: -438 % to -325 %, respectively; LS mean difference=-85 %; p = 0.03) among AD04-treated vs. placebo-receiving heavy drinking individuals at month 6. Heavy drinking individuals were also less likely to be diagnosed with AUD [Month 1: -320 % (28 %), 95 %CI: -375 % to -265 % vs. -232 % (29 %), 95 %CI: -289 to -175 %; LS mean difference= -88 %; p = 0026)], and improved on the WHO quality of life BREF scale with a significant effect for at least a 1-level downward shift (OR = 3.4; 95 % CI: 103-1145, p = 0044). Importantly, heavy drinking individuals, as distinct from very heavy drinking individuals, were the bio-psychosocial endophenotype more predictive of therapeutic response to AD04. AD04 had an exceptional safety and tolerability profile, like the placebo's. Conclusions: In this Phase 3 clinical trial, AD04 was shown to be a promising treatment for currently drinking heavy drinking individuals with AUD who also possess a specific genotypic profile in the serotonin transporter and serotonin-3AB receptor complex. Using AD04 to reduce the harm of AUD in heavy drinking individuals who are currently drinking, without the necessity of abstinence or detoxification from alcohol use, is an important advance in the field of precision medicine. AD04's adverse events profile, which was like placebo, should enhance accessibility and acceptance of modern medical treatment for AUD by lowering the incorrect but commonly perceived stigma of personal failure.

This chapter presents some tests of the hypothesis and reviews some of the data on its utility, including published and unpublished data collected at the Royal Edinburgh Hospital. The concept of reinstatement after abstinence has recently been subjected to careful laboratory study in clinics where it has not been regarded as unethical to give large amounts of alcohol, or alcohol over successive days, to abstinent alcoholics. In a prison population, Edwards, Gattoni and Hensman found that dependence symptoms correlated with whether or not the man had drunk at the time of his arrest, the number of drunken arrests, the number of times he had been in prison and with unemployment, and with 'often' having amnesia. In response to some informal social control or a threat or some newly acquired attitude, the drinker may decide to change his habits.

Abstract This 6-month, double-blind, randomized, Phase-3 clinical trial in Alcohol Use Disorder (AUD; n = 303) tested ondansetron 0.33 mg/twice daily (AD04) vs placebo in reducing the Percentage of Heavy Drinking Days (PHDD) among a genetic subgroup with variations at the serotonin transporter and 5-HT3A/5-HT-3B receptors who consumed < 10 Standard Drinks/Drinking Day (DDD) (heavy drinkers) or ≥ 10 DDD (very heavy drinkers). At Month 6, the least square (LS) mean change in PHDD from baseline was 8.5% greater in the heavy drinkers AD04 group compared with placebo (LS mean (SD): -46.7% (2.7%), 95%CI: -52.1% to -41.2% vs. -38.1% (2.9%), 95%CI: -43.8% to -32.5%; p = 0.03) with lower effect (LS mean difference: 7.0%, p = 0.07) for Months 5 and 6 combined. At Month 6, for the total AD04 group compared with the placebo group, heavy drinkers had a better quality of life (OR = 3.4, 95% CI: 1.03–11.45, p = 0.04), fewer AUD symptoms (Mild: AD04 group 33% vs. placebo group 39%; Severe: AD04 group 10% vs. placebo group 24%) (p = 0.05), and similar adverse event profiles. No treatment-related effects differentiated AD04 and placebo in very heavy drinkers. This study showed AD04’s promise as a precision medicine treatment for heavy drinkers with a specific genetic profile.

This chapter reviews the evidence showing that problem drinkers can be identified in general hospitals. It has proved difficult to conduct randomised controlled studies in problem drinkers to compare the effect of intervention versus no intervention. In the general ward the problem drinker has often not yet begun to see his problem as alcohol-related or accept that it would be advisable to alter his drinking habits; he may be very resistant to the physician's advice. There is no dearth of evidence for the association of alcohol consumption with physical illness and injury. In summary, however, even in screening general hospital populations, where it is more commonly physical harm from alcohol that is the cause for admission as opposed to social or personal harm in psychiatric clinics, physical tests and examination are no substitute for an enquiry into drinking habits and history of problems from drinking.

Abstract Genetic predisposition may determine treatment response in alcohol use disorder (AUD). This 6-month, double-blind, randomized trial assessed ondansetron (0.33 mg twice daily; AD04) in genotype-specific AUD subjects stratified by drinking endophenotype (<10 (‘heavy’) or ≥10 (‘severe’) drinks per drinking day). In heavy drinkers, at study end (Month 6), the least-squares (LS) mean change in percentage of heavy drinking days from baseline was 8.5% greater with AD04 vs. placebo treatment (LS mean (standard deviation): -46.7% (2.7%) vs. -38.1% (2.9%); p<0.03), with a non-significant effect (LS mean difference: 7.0%, p=0.07) for Months 5 and 6 combined. AD04 vs. placebo treatment increased quality of life (odds ratio=3.4, 95% Confidence Interval: 1.03-11.45; p=0.04) and reduced AUD symptoms (mild symptoms: 33% vs. 39%; severe symptoms: 10% vs. 24%; p=0.05). AD04 had a similar adverse events profile to placebo. ADO4 showed promise as a precision medicine treatment for genotype-specific heavy drinkers.

AIM:Investigate changes in alcohol use and related harm using the first multisite, controlled, longitudinal study of Managed Alcohol Programs (MAPs). MAPs provide regular doses of alcohol, accommodation, social supports and healthcare to unstably housed people with alcohol dependence.METHODS:A multisite, quasi-experimental, longitudinal study was conducted in day centres, shelters and residential programs for unstably housed people. There were 59 MAP participants from six Canadian cities and 116 local controls. Self-reported alcohol consumption and harms were assessed at 0-2, 6 and 12 months. Liver function test results were accessed for MAP participants.RESULTS:Both groups had similar reductions in mean drinks per day (MAP: -8.11; controls: -8.54 controls, P < 0.001) and days drinking per month (MAP: -2.51 days, P < 0.05; control: -4.81 days, P = 0.0001) over 6--12 months. Both reduced non-beverage alcohol consumption. MAP participants reported significantly fewer harms at both 0-2 and 6 months than controls. MAP participants had similar total consumption to controls, but spread out over more days (25.41 versus 19.64 days per month, P = 0.001). After leaving a MAP, participants' liver status deteriorated, with increases in both aspartate transaminase and bilirubin levels. MAP sites with effective policies on outside drinking drank less and had fewer harms.CONCLUSION:MAP participants drank less hazardously than controls, especially with effective management of non-MAP drinking. Reductions in alcohol use and harms occurred for both groups, although MAP participants reported fewer harms at 0-6 months. Departing an MAP was associated with deterioration in liver status. Although providing stable housing, MAPs did not worsen health or increase alcohol use.

Abstract Aims Two post-authorisation studies assessed the safety and persistence of patients’ use of nalmefene. Methods The START study (EUPAS5678) was a non-interventional, multi-country, prospective, 18-month (8 follow-up visits) cohort study including outpatients initiating nalmefene for the first time. The multi-database retrospective cohort study (MDRC, EUPAS14083) included baseline and follow-up data from German, Swedish and UK healthcare databases. Both studies permitted ‘all comers’ without explicit exclusion criteria; predefined subgroups of interest included the elderly (≥65 years) as well as patients with significant psychiatric and/or somatic comorbidities. Results START study: Overall, the mean duration of nalmefene treatment was 10.3 ± 7.3 months (N = 1348), with 49.0% of patients treated for ≥1 year; frequent reasons for treatment discontinuation were ‘goal reached’ and ‘drug cost’. The most frequently reported adverse drug reactions (ADRs) were nausea (4.7%), dizziness (3.2%) and insomnia (2.0%). ADR rates appeared higher in the elderly subpopulation (18.6% reported ≥1 ADR vs. 12.0% in the total population) but were not higher in the other predefined subgroups. MDRC study: The database follow-up analysis followed 2892 patients over 18 months for whom the duration of nalmefene treatment was between 2 and 3 months and <5% of patients used nalmefene for ≥1 year. Conclusions Despite the inclusion of a wider patient population (e.g. elderly patients and those with relevant co-morbidities), the safety and tolerability profile of nalmefene given in routine practice was consistent with previous clinical studies. The differing rates of persistence beyond 1 year likely reflect the different methodologies and highlight the relevance of psychosocial support at follow-up visits.

Alcohol use disorder (AUD) is a brain disorder associated with high rates of mortality and morbidity worldwide. Baclofen, a selective gamma-aminobutyric acid-B (GABA-B) receptor agonist, has emerged as a promising drug for AUD. The use of this drug remains controversial, in part due to uncertainty regarding dosing and efficacy, alongside concerns about safety. To date there have been 15 randomized controlled trials (RCTs) investigating the use of baclofen in AUD; three using doses over 100 mg/day. Two additional RCTs have been completed but have not yet been published. Most trials used fixed dosing of 30-80 mg/day. The other approach involved titration until the desired clinical effect was achieved, or unwanted effects emerged. The maintenance dose varies widely from 30 to more than 300 mg/day. Baclofen may be particularly advantageous in those with liver disease, due to its limited hepatic metabolism and safe profile in this population. Patients should be informed that the use of baclofen for AUD is as an "off-label" prescription, that no optimal fixed dose has been established, and that existing clinical evidence on efficacy is inconsistent. Baclofen therapy requires careful medical monitoring due to safety considerations, particularly at higher doses and in those with comorbid physical and/or psychiatric conditions. Baclofen is mostly used in some European countries and Australia, and in particular, for patients who have not benefitted from the currently used and approved medications for AUD.

We are grateful for the opportunity to respond to the letter from the DrinkAware medical advisory panel [...].

A recent paper in Drug and Alcohol Review analysed the information on cancer disseminated by 27 alcohol industry funded organisations. The independent UK alcohol education charity Drinkaware was among the organisations whose information was studied, and based on the analysis claims were made of misrepresentation of evidence about the alcohol-related risk of cancer and alcohol industry influence. This commentary challenges the validity of these findings in respect to the evidence relating to the Drinkaware information, as the analysis is found to be misrepresenting the information by both disregarding the wider information content provided and the order and prominence with which alcohol-related cancer risk is presented. Furthermore, it is argued that the public has a right to be provided with relevant evidence-based information about cancer risk. It is critical that Drinkaware's important public health function is not compromised by unjustified allegations of inaccuracy and by unwarranted attacks on its independence and integrity.