Three studies fulfilling search criteria were found on ClinicalTrials.gov and EudraCT search resulted in 14 studies. Eleven studies were excluded because the primary medical condition studied, such as asthma, cataplexia or major depressive disorder, was deemed irrelevant to this review. Six studies from these databases and one on-going study found in literature search, totaling to seven on-going studies, were included and are presented (Table 2).
This review aims to investigate current updates on pharmacological treatments in AUD. The most recent comprehensive update on pharmacotherapy for AUD was published in June 2018 by Kranzler and Soyka [4▪▪]. In this review, Kranzler and Soyka note that the following FDA-approved medications are recommended: naltrexone to reduce the risk of binge drinking, acamprosate to maintain abstinence and disulfiram under supervision to promote treatment adherence. An alternative drug, such as topiramate, is also suggested for use if naltrexone is ineffective after a month of treatment, despite not being approved by the FDA for treatment of AUD [4▪▪]. Our review highlights the recent interest in pharmacological treatment for AUD and is in line with the work of Kranzler and Soyka [4▪▪]. However, we found interesting new approaches for the treatment of AUD on the databases of on-going studies.
The effects of baclofen have been disputed, and trials have often had mixed results. A previous meta-analysis featured in our baseline review found that baclofen was effective at promoting time to lapse and abstinence [4▪▪]. A recent meta-analysis from Bschor et al.[23▪▪] featuring 14 RCTs (n = 1522) found baclofen to be slightly superior to placebo; however, the results were not statistically significant. Excluding studies that included patients with comorbid conditions provided a statistically significant result in favor of baclofen. Heterogeneity among studies in the analysis was deemed to be an issue, and some studies found very positive results in favor of baclofen. The authors conclude that current evidence does not support baclofen as first-line treatment of AUD. This statement stands in line with the Cochrane review of baclofen for AUD [26▪▪], which included 12 RCTs (n = 1128), which also found no difference between baclofen and placebo. However, authors in both studies conclude that trial results are promising and further research is warranted.
Clinical depression is a common comorbidity of AUD. A secondary analysis from the BacALD study by Heng et al.[9▪] explores the effect of concurrent antidepressants during baclofen treatment. In the 12-week study, participants were treated with baclofen (either 25 or 75 mg/day) or placebo. Patients had been concurrently receiving antidepressant medication for at least 2 months before enrollment. The study found an association for lapse and relapse in the group of patients receiving baclofen and antidepressants; however, the authors conclude that this may be because of preexisting factors in the study group receiving antidepressants. Frequency of adverse events did not increase in the groups receiving both baclofen and antidepressants.
Nalmefene is a μ-opioid antagonist and partial κ agonist. Nalmefene has been approved by European Medicines Agency (EMA) for the treatment of AUD, but in the United States by the FDA only for opioid overdose. There were no new RCT on nalmefene to be included to this review. However, nalmefene was recently studied in European Union in three multisite trials in Europe. In a randomized, double-blind, placebo-controlled, efficacy study of nalmefene, as-needed use, in AUD patients, the efficacy analyses showed a significant effect of nalmefene compared with placebo in having less heavy drinking days from baseline to 6 months . In a post hoc analysis of patients with high/very-high drinking risk levels at screening and at randomization (the target population), nalmefene has been found to have decreased total alcohol consumption at month 6 and decreased both heavy drinking days and total alcohol consumption at month 13 in nalmefene patients compared with those in placebo group . However, the efficacy of nalmefene for anticraving therapy for AUD patients has not been shown to be any better than placebo in clinical trials in the United States [36▪].
There are no new RCTs on long-acting injectable naltrexone to be included in this study. One earlier study evaluated the feasibility and effects of the long-acting injectable form of naltrexone on baseline drinking behavior over the course of 12 weeks . The study's short duration and small sample size did not allow an adequate test of the difference between the two long- acting naltrexone formulations.
Gabapentin is used and approved (FDA) to treat epilepsy and neuropathic pain. Our observations are coming from two placebo-controlled, RCTs (total N = 611 patients) [15▪,16]. The larger of these trials (N = 346) [15▪] compared extended release gabapentin 600 mg/ twice a day with placebo for 24 weeks and showed no difference either on craving or alcohol consumption. The most common adverse events associated with gabapentin treatment compared with placebo are dizziness, somnolence, ataxia or gait disorder and peripheral edema [38▪▪]. Gabapentin is often misused; earlier research suggests that approximately 1% of the general population abuses gabapentin .
Citicoline, an over-the-counter supplement, has previously shown promising results in reducing cocaine use in two previous clinical trials. The mechanism of action is not fully understood but activation of the citicoline pathway has provided beneficial effects in lab studies. In a 12-week trial of citicoline (titrated up to 2000 mg daily) vs. placebo with 62 participants with AUD. Citicoline was well tolerated but did not reduce alcohol consumption compared with placebo as measured by the time line follow back-method. The authors conclude that although citicoline has shown promise on many fields, it did not prove beneficial in treating AUD in these patients .
Disulfiram inhibits aldehyde dehydrogenase, which metabolizes acetaldehyde, a toxic metabolite of alcohol. There were no new RCT studies with disulfiram. However, in a recent meta-analysis  of 22 studies (N = 2414), 13 showed an association of disulfiram with sustained abstinence from alcohol compared with control conditions only in open-label studies and with a better response than control conditions when medication adherence was supervised.
The nicotinic-acetylcholine receptor (nAchR)-antagonist mecamylanine has been found to reduce the stimulus produced by ethanol in human lab studies. The nAchR-antagonist varenicline has also displayed positive effect in reducing alcohol consumption in multiple clinical trials. In this 12-week double-blind trial, participants (n = 126) were randomized to either mecamylamine (10 mg daily) or placebo. No medication effect was found for reducing heavy drinking days (HDD) or alcohol craving. Smoking status had no effect on the results. The authors suggest that broad-spectrum nAchR-antagonists may not be beneficial in treating AUD .
This review has several limitations. This review is not exploring the efficacy, optimal duration or medication combination with psychosocial therapies as there are several excellent previous recent meta-analysis and reviews on the pharmacotherapy of AUD. Secondly, different study outcomes, different measures of effect size and the small number of new RCTs for testing the efficacy of medications for AUD is inadequate to draw definitive conclusions. However, the study provides coverage of the new literature and an outlook on future trends in the treatment of AUD.
First-line pharmacological treatments for AUD remains disulfiram, naltrexone, nalmefene and acamprosate. The case of baclofen still warrants further research. The trials and reviews here manage to prove only minor if any effect compared with placebo. Yet, baclofen is widely used especially in some parts of Europe. None of the outcomes of the review showed evidence of a difference between baclofen and placebo. The high heterogeneity among the study results limits the interpretation of the results. Even though some results from RCTs are promising, current evidence remains uncertain regarding the use of baclofen as a first-line treatment for people with AUDs.
Papers of particular interest, published within the annual period of review, have been highlighted as:
1. Global status report on alcohol and health 2018. Geneva: World Health Organization; 2018.
2. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 5th ed.Arlington, VA: American Psychiatric Publishing; 2013.
4▪▪. Kranzler HR, Soyka M. Diagnosis and pharmacotherapy of alcohol use disorder
: a review. JAMA 2018; 320:815–824.
An excellent review of the diagnosis and pharmacologic treatment of Alcohol Use Disorder (AUD) (both FDA-approved medications and those used off-label). Psychosocial therapies that are most commonly provided to both the active and placebo groups in pharmacotherapy trials are also briefly reviewed. Recommended approach to treatment is also provided.
5. Riper H, Andersson G, Hunter SB, et al. CBT/MI for comorbid alcohol use disorders and depression. Addiction 2014; 109:394–406.
6. Cornelius JR, Bukstein O, Salloum I, Clark D. Galanter M. Alcohol and psychiatric comorbidity. Recent developments in alcoholism. recent developments in alcoholism. Boston, MA: Springer; 2002. 16.
7. Lev-Ran S, Balchand K, Lefebvre L, et al. Pharmacotherapy of alcohol use disorders and concurrent psychiatric disorders: a review. Can J Psychiatry 2012; 57:342–349.
8▪. Morley KC, Baillie A, Fraser I, et al. Baclofen in the treatment of alcohol dependence with or without liver disease: multisite, randomised, double-blind, placebo-controlled trial. Br J Psychiatry 2018; 212:362–369.
The trial found a positive effect of baclofen treatment and time to lapse, relapse and days abstinent in patients receiving 25 or 75 mg of baclofen daily. The authors suggest that baclofen should be left for specialist treatment because of the safety profile.
9▪. Heng S, Jamshidi N, Baillie A, et al. Baclofen response in alcohol dependent patients concurrently receiving antidepressants: secondary analysis from the BacALD study. Front Psychiatry 2018; 9:576.
The study found a trend of significance for the interaction of antidepressants and baclofen in the treatment of patients with AUD receiving antidepressant medication. The authors conclude that concurrent antidepressant medication does not negatively impact drinking outcomes, and further research is warranted.
10. Morley KC, Lagopoulos J, Logge W, et al. Neurometabolite levels in alcohol use disorder
patients during baclofen treatment and prediction of relapse to heavy drinking. Front Psychiatry 2018; 9:412.
11. Krupitskii EM, Rybakova KV, Kiselev AS, et al. Efficacy and safety of the use of baclofen in the treatment of alcohol dependent (a double-blind, randomized, placebo-controlled pilot study). Neurosci Behav Physiol 2017; 47:153–162.
12. DeMartini KS, Foster DW, Corbin WR, et al. Drinking goals and attainment in a naltrexone trial of young adult heavy drinkers. J Consult Clin Psychol 2018; 86:765–774.
13▪▪. Mann K, Roos CR, Hoffmann S, et al. Precision medicine in alcohol dependence: a controlled trial testing pharmacotherapy response among reward and relief drinking phenotypes. Neuropsychopharmacology 2018; 43:891–899.
This article's goal was to examine whether reward vs. relief drinking significantly moderated the treatment response using the subgroup analysis of the PREDICT study of Mann et al. using mixture modelling to test whether individuals could be classified into different patterns based on reward and relief drinking, and whether patterns of reward and relief drinking predicted differential treatment response to naltrexone and acamprosate. Using naltrexone with individuals who are predominantly reward drinkers produces significantly higher effect sizes than prescribing the medication to a more heterogeneous sample.
14. Schacht JP, Randall PK, Latham PK, et al. Predictors of naltrexone response in a randomized trial: reward-related brain activation, OPRM1 genotype, and smoking status. Neuropsychopharmacology 2017; 42:2640–2653.
15▪. Falk DE, Ryan ML, Fertig JB, et al. National Institute on Alcohol Abuse and Alcoholism Clinical Investigations Group (NCIG) Study Group. Gabapentin enacarbil extended-release for alcohol use disorder
: a randomized, double-blind, placebo-controlled, multisite trial assessing efficacy and safety. Alcohol Clin Exp Res 2019; 43:158–169.
An interesting multicenter study of investigating gababentin in reducing drinking outcomes among individuals with alcohol dependence, yet with negative results.
16. Chompookham P, Rukngan W, Nilaban S, et al. A randomized trial of low-dose gabapentin for post hospitalization relapse prevention in a Thai clinical sample of alcohol dependence. Psychiatry Res 2018; 270:34–40.
17. Brown ES, Van Enkevort E, Kulikova A, et al. A Randomized, double-blind, placebo-controlled trial of citicoline in patients with alcohol use disorder
. Alcohol Clin Exp Res 2018; 43:317–323.
18. Petrakis IL, Ralevski E, Gueorguieva R, et al. Mecamylamine treatment for alcohol dependence: a randomized controlled trial
. Addiction 2018; 113:6–14.
19. Wilcox CE, Tonigan JS, Bogenschutz MP, et al. A randomized, placebo-controlled, clinical trial of prazosin for the treatment of alcohol use disorder
. J Addict Med 2018; 12:339–345.
20. Mann K, Roos CR, Hoffmann S, et al. Precision medicine in alcohol dependence: a controlled trial testing pharmacotherapy response among reward and relief drinking phenotypes. Neuropsychopharmacology 2018; 43:891–899.
21. Ryan ML, Falk DE, Fertig JB, et al. A phase 2, double-blind, placebo-controlled randomized trial assessing the efficacy of ABT-436, a novel V1b receptor antagonist, for alcohol dependence. Neuropsychopharmacology 2017; 42:1012–1023.
22. Thompson A, Owens L, Richardson P, Pirmohamed. Systematic review: baclofen-dosing protocols for alcohol use disorders used in observational studies. Eur Neuropsychopharmacol 2017; 27:1077–1089.
23▪▪. Bschor T, Henssler J, Muller M, Baethge C. Baclofen for alcohol use disorder
-a systematic meta-analysis
. Acta Psychiatr Scand 2018; 138:232–242.
Fourteen double-blind RCTs (n = 1522) showed a slight effect for baclofen over placebo, but the effect was not statistically significant. Authors conclude that the most likely effect size is probably slightly above placebo.
24. Agabio R, Leggio L. Baclofen in the treatment of patients with alcohol use disorder
and other mental health disorders. Front Psychiatry 2018; 9:464.
25. de Beaurepaire R, Sinclair JMA, Heydtmann M, et al. The use of baclofen as a treatment for alcohol use disorder
: a clinical practice perspective. Front Psychiatry 2018; 9:708.
26▪▪. Minozzi S, Saulle R, Rosner S. Baclofen for alcohol use disorder
. Cochrane Database Syst Rev 2018; 11:CD012557.
Twelve studies comparing baclofen to placebo were identified. No significant difference between baclofen and placebo could be identified. Baclofen increased the rate of adverse events. Heterogenity of the studies was an issue.
27▪▪. Agabio R, Trogu E, Pani PP. Antidepressants for the treatment of people with co-occurring depression and alcohol dependence. Cochrane Database Syst Rev 2018; Art. No.: CD008581. DOI: 10.1002/14651858.CD008581.pub2.
In 22 placebo-controlled RCTs with patients with concurrent AUD and antidepressant medication, the effects on depression for antidepressant-receiving patients remained unclear. A statistically significant increase in days abstinent and reduction in drinks consumed on drinking days was found.
28▪▪. Naglich AC, Lin A, Wakhlu S, Adinoff BH. Systematic review of combined pharmacotherapy for the treatment of alcohol use disorder
in patients without comorbid conditions. CNS Drugs 2018; 32:13–31.
A review of 16 articles evaluating drug combinations for the treatment of alcohol use disorder. The authors concluded that naltrexone was the drug most frequently combined with other agents to reduce alcohol consumption. No combination of drugs has demonstrated a significantly larger treatment effect when compared with the individual components of the combination.
29. Mason BJ, Quello S, Shadan F. Gabapentin for the treatment of alcohol use disorder
. Exp Opin Investig Drugs 2018; 27:113–124.
30. Goh ET, Morgan MY. Review article: pharmacotherapy for alcohol dependence - the why, the what and the wherefore. Aliment Pharmacol Ther 2017; 45:865–882.
31. Kim Y, Hack LM, Ahn ES, Kim J. Practical outpatient pharmacotherapy for alcohol use disorder
. Drugs Context 2018; 7:212–308.
32. Jonas DE, Amick HR, Feltner C, et al. Pharmacotherapy for adults with alcohol use disorders in outpatient settings: a systematic review and meta-analysis
. JAMA 2014; 311:1889–1900.
33. Morley KC, Teesson M, Reid SC, et al. Naltrexone versus acamprosate in the treatment of alcohol dependence: a multicentre, randomized, double-blind, placebo-controlled trial. Addiction 2006; 101:1451–1462.
34. Gual A, He Y, Torup L, et al. ESENSE 2 Study Group. A randomised, double-blind, placebo-controlled, efficacy study of nalmefene, as-needed use, in patients with alcohol dependence. Eur Neuropsychopharmacol 2013; 23:1432–1434.
35. van den Brink W, Sørensen P, Torup L, et al. ESENSE 2 Study Group. Long-term efficacy, tolerability and safety of nalmefene as-needed in patients with alcohol dependence: a 1-year, randomised controlled study. J Psychopharmacol 2014; 28:733–744.
36▪. Lyon J. More treatments on deck for alcohol use disorder
. JAMA 2017; 317:2267–2269.
An excellent brief discussion paper on a current status of treatments for alcohol use disorders.
37. Garbutt JC, Kranzler HR, O’Malley SS, et al. Vivitrex Study Group. Efficacy and tolerability of long-acting injectable naltrexone for alcohol dependence: a randomized controlled trial
. JAMA 2005; 293:1617–1625.
38▪▪. Wiffen PJ, Derry S, Bell RF, et al. Gabapentin for chronic neuropathic pain in adults. Cochrane Database Syst Rev 2017.
Excellent systematic review. Gabapentin at doses of 1800 mg to 3600 mg daily (1200 mg to 3600 mg gabapentin encarbil) can provide good levels of pain relief to some people with postherpetic neuralgia and peripheral diabetic neuropathy. Evidence for other types of neuropathic pain is very limited.
39. Smith RV, Havens JR, Walsh SL. Gabapentin misuse, abuse and diversion: a systematic review. Addiction 2016; 111:1160–1174.
40. Johnson BA, Roache JD, Javors MA, et al. Ondansetron for reduction of drinking among biologically predisposed alcoholic patients: a randomized controlled trial
. JAMA 2000; 284:963–971.
41. Skinner MD, Lahmek P, Pham H, Aubin HJ. Disulfiram efficacy in the treatment of alcohol dependence: a meta-analysis
. PLoS One 2014; 9:e87366.
42. Torrens M, Fonseca F, Mateu G, Farré M. Efficacy of antidepressants in substance use disorders with and without comorbid depression: a systematic review and meta-analysis
. Drug Alcohol Depend 2005; 78:1–22.