Prospects for Pharmacotherapies to Treat Alcohol Use Disorder

An Update on Recent Human Studies

Mehdi Farokhnia; Brittney D. Browning; Lorenzo Leggio

Curr Opin Psychiatry. 2019;32(4):255-265.

Abstract and Introduction

Abstract

Purpose of review: The aim of this study was to provide an update on medication development efforts for alcohol use disorder (AUD) by reviewing recently published (past 2 years) human studies that evaluated medications' effects on alcohol-related outcomes.

Recent findings: Forty-five publications were found suitable for this review. A variety of compounds have been tested in the past 2 years as potential pharmacological options for AUD, including medications that act on multiple targets (topiramate, aripiprazole, quetiapine), calcium channels (gabapentin), gamma-Aminobutyric acid receptors (baclofen, diazepam), glutamate receptors (ifenprodil, memantine, glycine), nicotinic acetylcholine receptors (varenicline, mecamylamine), α1 adrenergic receptors (prazosin, doxazosin), neuroendocrine pathways (oxytocin, a vasopressin receptor 1b antagonist, a ghrelin receptor inverse agonist) and others (samidorphan, ibudilast, N-acetylcysteine, citoline). Important findings and limitations regarding the effects of these medications on alcohol-related outcomes are discussed.

Summary: There is a critical need to increase the armamentarium of medications for AUD. Human laboratory studies may help screen and prioritize promising targets and compounds before running large clinical trials. Given the complexity of AUD and the heterogeneity of afflicted patients, future studies should also investigate potential moderators and predictors of response to each pharmacological intervention.

Introduction

Alcohol represents a leading risk factor for premature death and disability, and alcohol use disorder (AUD) affects nearly 283 million people worldwide.^[1,2] In addition to psychosocial interventions that play an important role in AUD treatment, four medications have been approved by the United States Food and Drug Administration and/or the European Medicines Agency: disulfiram, acamprosate, naltrexone and nalmefene (the latter is only approved in Europe). Although meta-analyses show that currently approved medications are effective,^[3] there is a critical need to increase the armamentarium of pharmacotherapies for AUD. Neuroscientific advances have led to identification of novel therapeutic targets and development of new medications in this regard.^[4] The goal of this article is to provide an update on medication development efforts for AUD by reviewing human studies published in the past 2 years.

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Table 1. List and summary of records found suitable for this review
Medications	References
Topiramate
Treatment with topiramate (up to 200 mg/day) was not superior to placebo in preventing alcohol relapse or helping smoking cessation in alcohol-dependent, nicotine-smoking male individuals.	[5]
Treatment with topiramate (up to 200 mg/day), compared with placebo, reduced alcohol drinking in a naturalistic setting but not in a laboratory experiment, suppressed alcohol craving and increased alcohol-induced stimulation in nontreatment-seeking, alcohol-dependent individuals.	[6]
Ari pi prazole
Treatment with aripiprazole (up to 15 mg/day) was not superior to placebo in reducing alcohol drinking or craving in nontreatment-seeking, alcohol-dependent individuals.	[6]
Treatment with aripiprazole (15 mg/day), compared with placebo, reduced alcohol drinking in alcohol-dependent individuals with low self-control and prolonged the latency to drink alcohol in nontreatment-seeking, alcohol-dependent individuals with high impulsivity.	[7]
Variation of dopamine-related genes moderated the effect of aripiprazole treatment (15 mg/day), compared with placebo, on alcohol drinking and on cue-elicited brain activation (fMRI) in ventral striatum in nontreatment-seeking, alcohol-dependent individuals.	[8]
Quetiapine
Treatment with quetiapine extended-release (up to 300 mg/day), compared with placebo, resulted in trend-level, but not significant, reduction of alcohol drinking in highly depressed and anxious patients with bipolar I or II disorder.	[9]
Gabapentin
Treatment with gabapentin immediate-release (300–1200 mg/day), compared with placebo, reduced the percentage of heavy drinking days, but did not affect overall amount of alcohol consumption in alcohol-dependent individuals.	[10]
Treatment with gabapentin enacarbil extended-release (1200 mg/day) was not superior to placebo in reducing alcohol drinking or craving in patients with AUD. Higher exposure to gabapentin (based on population pharmacokinetic analysis) was associated with less alcohol consumption.	[11]
Receipt of gabapentin (≥1500 mg/day) for any indication, compared with a propensity score matched group not receiving gabapentin, was associated with decreased AUDIT-C scores in patients with AUD.	[12]
Baclofen
Treatment with baclofen (30 mg/day) was not superior to placebo in reducing alcohol drinking or craving in alcohol-dependent veterans with chronic HCV.	[14]
Treatment with baclofen (30 mg/day), compared with benfothiamine, increased abstinent days and reduced heavy drinking days and craving, but did not affect time to first relapse in alcohol-dependent individuals.	[44]
Treatment with baclofen (30 mg/day, open-label) reduced alcohol consumption and severity of alcohol dependence in alcohol-dependent individuals with alcohol-related liver problems.	[45]
Treatment with baclofen (50 mg/day) was not superior to placebo in reducing alcohol drinking or craving in alcohol-dependent individuals.	[15]
Treatment with baclofen (180 mg/day), compared with placebo, reduced alcohol craving, but did not improve abstinence in alcohol-dependent individuals. Baclofen, compared with placebo, resulted in a trend-level, but not statistically significant, reduction of alcohol consumption in a subgroup of participants with very high drinking levels at baseline.	[16]
Treatment with high-dose baclofen (>150 mg/day), compared with medium-dose baclofen (90–150 mg/day), improved alcohol drinking outcomes. Treatment with medium-dose baclofen (90–150 mg/day), compared with low-dose baclofen (<90 mg/day), resulted in less favourable drinking outcomes. No differences between high-dose and low-dose baclofen were found.	[19]
Treatment with baclofen (30 or 75 mg/day), compared with placebo, prolonged the time to first lapse and relapse in alcohol-dependent individuals with alcoholic liver disease. No differences were found between the two baclofen doses.	[21]
Treatment with baclofen (30 or 75 mg/day), compared with placebo, increased parietal concentrations of glutathione and N-acetylaspartate in recently drinking alcohol-dependent individuals. Higher glutathione predicted lower heavy drinking days at follow-up.	[46]
A single nucleotide polymorphism on GABBR1 (rs29220) moderated the clinical response to baclofen treatment (30 or 75 mg/day) in alcohol-dependent individuals.	[47]
Treatment with baclofen (75 mg/day), compared with placebo, attenuated alcohol cue-elicited brain activation (fMRI) in prefrontal regions in alcohol-dependent individuals.	[48]
Treatment with baclofen (up to 60 mg/day), compared with placebo, enhanced alcohol cue-elicited brain activation (fMRI) in DLPFC and ACC and reduced the IC activation in alcohol-dependent individuals. ACC activation and IC deactivation were associated with longer time to first lapse in baclofen-treated individuals.	[49]
Treatment with baclofen (30–270 mg/day), compared with placebo, attenuated alcohol cue-elicited brain activation (fMRI) in OFC, amygdala and VTA, as well as alcohol cue-modulated functional connectivity (fMRI) between VTA and both ACC and MPFC.	[50]
Treatment with baclofen (30 mg/day), compared with placebo, increased subjective response to alcohol and decoupled the link between post-priming breath alcohol concentration and the amount of alcohol self-administration in nontreatment-seeking anxious alcohol-dependent individuals.	[22]
Treatment with baclofen (30 mg/day), compared with placebo, decoupled the link between post-priming variables (craving, sedation) and the amount of alcohol self-administration in nontreatment-seeking, anxious, alcohol-dependent individuals. Maximum concentration of baclofen in the blood negatively correlated with cue-induced alcohol craving and alcohol-induced rating of 'like more'.	[24]
Single-dose administration of baclofen in healthy controls (0, 10, 60 mg), compared with abstinent alcohol-dependent individuals (0, 60, 90 mg), increased subjective response to alcohol, blood GH concentrations and EEG theta power. No pharmacokinetic differences were found between alcohol-dependent individuals and healthy controls.	[23]
Pharmacokinetic parameters were characterized in 143 alcohol-dependent individuals treated with baclofen (up to 250 mg/day, open-label). A linear pharmacokinetic profile and high inter-individual variability was observed.	[26]
Pharmacokinetic parameters were characterized in 57 alcohol-dependent individuals treated with baclofen (up to 300 mg/day, open-label). A linear pharmacokinetic profile and high inter-individual variability was observed.	[27]
Diazepam
Treatment with diazepam (up to 40 mg/day, open label) for 30 days, compared with 10 days, reduced alcohol drinking, craving and anxiety in alcohol-dependent individuals at 3 months follow-up. Note: It is critical to keep in mind the abuse liability of diazepam and benzodiazepines in general. Although benzodiazepines represent the gold standard treatment of alcohol withdrawal syndrome, there is no evidence that benzodiazepines may be effective for treating AUD. The lack of efficacy combined with the significant risk of abuse does not support any efforts to use or test this class of medications for AUD. There is also a significant risk of serious benzodiazepine-alcohol interactions in patients who take benzodiazepines and may relapse, another concern that should discourage any effort to consider benzodiazepines as a treatment for AUD.	[51]
Ifenprodil
Treatment with ifenprodil (60 mg/day), compared with placebo, reduced alcohol drinking in alcohol-dependent individuals.	[28]
Memantine
Add-on treatment with memantine (5 mg/day, open label) reduced alcohol drinking in patients with bipolar II disorder and comorbid alcohol dependence who were being treated with valproic acid.	[52]
Glycine
Add-on treatment with glycine (0.8 g/kg/daya) was not superior to placebo in reducing alcohol drinking or craving in patients with schizophrenia and comorbid alcohol dependence who were being treated with antipsychotics.	[29]
Varenicline
Treatment with varenicline (2 mg/day), compared with placebo, reduced alcohol drinking in alcohol-dependent, nicotine-smoking individuals.	[30]
Treatment with varenicline (2 mg/day), compared with placebo, reduced alcohol drinking in alcohol-dependent, nicotine-smoking male individuals.	[31]
Treatment with varenicline (2 mg/day), compared with placebo, reduced cue-elicited alcohol craving in heavy-drinking individuals.	[32]
Treatment with varenicline (1, 2 mg/day), compared with placebo, dose-dependently reduced alcohol drinking and tonic craving in depressed, heavy-drinking, alcohol-dependent individuals.	[33]
Treatment with varenicline (1, 2 mg/day), compared with placebo, dose-dependently improved cognitive performance in heavy-drinking, alcohol-dependent individuals. This improvement was associated with less alcohol drinking among those treated with 2 mg/day.	[34]
Mecamylamine
Treatment with mecamylamine (10 mg/day) was not superior to placebo in reducing alcohol drinking or craving in heavy-drinking, alcohol-dependent individuals.	[35]
Prazosin
Treatment with prazosin (16 mg/day), compared with placebo, reduced alcohol drinking in heavy-drinking, alcohol-dependent individuals.	[36]
Treatment with prazosin (16 mg/day), compared with placebo, reduced alcohol drinking in heavy-drinking, alcohol-dependent individuals with optimal treatment exposure. Diastolic blood pressure was a significant moderator of prazosin's effect.	[37]
Doxazosin
Diastolic blood pressure was a significant moderator of response to treatment with doxazosin (up to 16 mg/day), compared with placebo, in reducing alcohol drinking in heavy-drinking, alcohol-dependent individuals.	[38]
Oxytocin
Treatment with intranasal oxytocin (24 IU, single dose^a), compared with placebo, reduced alcohol cue-elicited brain activity in IC, hippocampal/parahippocampal formation, cingulate cortex, inferior/medial frontal gyrus and visual/motor regions in social drinking men.	[39]
ABT-436 (Vasopressin Receptor 1b Antagonist)
Treatment with ABT-436 (up to 800 mg/day), compared with placebo, increased abstinent days in heavy-drinking, alcohol-dependent individuals.	[40]
PF-5190457 (Ghrelin Receptor Inverse Agonist)
Compared with placebo, PF-5190457 combined with alcohol was well tolerated, with no drug–alcohol interactions. Treatment with PF-5190457 (200 mg/day), compared with placebo, reduced alcohol craving and attention to alcohol in heavy-drinking individuals.	[43]
Samidorphan
Treatment with samidorphan (1, 2.5 or 10 mg/day), compared with placebo, dose-dependently reduced alcohol drinking in heavy-drinking, alcohol-dependent individuals. Furthermore, the highest dose of samidorphan (10 mg/day), compared with placebo, reduced alcohol craving.	[53]
Ibudilast
Treatment with ibudilast (100 mg/day), compared with placebo, reduced tonic craving for alcohol and improved mood (post cue and stress exposure) in nontreatment-seeking individuals with AUD. Baseline ratings of depression moderated the effect of ibudilast on subjective response to alcohol.	[54]
N-acetylcysteine
Treatment with N-acetylcysteine (2400 mg/day), compared with placebo, decreased alcohol drinking in cannabis-dependent individuals.	[55]
Citicoline
Treatment with citicoline (up to 2000 mg/day) was not superior to placebo in reducing alcohol drinking or craving in heavy-drinking, alcohol-dependent individuals	[56]

ACC, anterior cingulate cortex; AUD, alcohol use disorder; AUDIT-C, alcohol use disorders identification test-consumption; DLPFC, dorsolateral prefrontal cortex; EEG, electroencephalogram; fMRI, functional magnetic resonance imaging; GABBR1, GABA-B receptor subunit 1 gene; GH, growth hormone; HCV, hepatitis C virus; IC, insular cortex; MPFC, medial prefrontal cortex; OFC, orbitofrontal cortex; VTA, ventral tegmental area.
^aDosage was confirmed through communication with the authors.