This review is organized into sections based on drug approval status, namely approved medications, repurposed medications, and novel agents. Within each medication section, we examine the basic mechanism of action, evaluate preclinical research testing the efficacy of the medication in mitigating alcohol-related behaviors in animal models, and review clinical findings from human laboratory studies and randomized controlled trials where available. We also examine the tolerability and potential personalized applications of each drug by identifying populations in which the drug may be particularly effective, and indicate treatment targets . This information is summarized in Table 1. We conclude by discussing future directions for the development of pharmacological treatments and precision medicine for AUD.This section briefly describes medications currently approved by agencies in many countries including the US FDA and EMA for the treatment of AUD: disulfram, acamprosate, and naltrexone , as well as nalmefene, which is EMA-approved. This section also reviews baclofen and sodium oxybate, which are medications approved for AUD treatment by agencies in European countries but not by the FDA or EMA. As many of these pharmacotherapies have been extensively discussed in the literature, our review of these medications primarily focuses on clinical trials and recent meta-analyses.Disulfram, the first medication FDA-approved for AUD treatment ,vertical racking is an aldehyde dehydrogenase inhibitor that acts by blocking the metabolism of alcohol, increasing acetaldehyde concentration. Acetaldehyde, a toxic metabolite of ethanol, produces an alcohol-induced aversive response, characterized by nausea, vomiting, sweating, flushing, and heart palpitations. Unsurprisingly, these unpleasant effects give disulfram a relatively poor adherencerate.
Disulfram may also act on dopamine systems, as its major metabolite inhibits the enzyme dopamine betahydroxylase , which aids in metabolizing dopamine into noradrenaline. Serum DBH activity is associated with withdrawal symptoms, and disulfram has been shown to reduce serum DBH levels. A meta-analysis of 22 RCTs found that disulfram saw increased success rates compared to placebo in open-label studies only—blinded trials yielded no statistical significance between disulfram and placebo. However, while these findings do not appear to support the use of disulfram for treating AUD, this outcome may be due to placebo effects. Research showed that placebo-treated individuals showed decreases in cue-reactivity to alcohol stimuli in a sample of 38 participants, and experiencing an acetaldehyde reaction did not necessarily improve treatment response in a sample of 46 participants. Instead, a patient simply being aware of a potential adverse reaction appears to be enough to influence drinking behavior. Disulfram ingestion under supervision saw significantly better success rates compared to non-supervised treatment, suggesting that supervised administration of disulfram may still have a place in treating individuals struggling to attain sobriety, and unsupervised disulfram may also be helpful for individuals highly motivated for abstinence. However, adherence management issues limit the utility of disulfram in the treatment of AUD, and the disulfram-ethanol interaction can sometimes present as a medical emergency. Therefore, disulfram is only recommended in the maintenance of abstinence; using this medication to reduce drinking is not advised.While the specific mechanisms through which acamprosate works to treat AUD remain under investigation, it is thought to act on the glutamatergic system as an N-methyl-d-aspartic acid receptor partial co-agonist.
This may reduce neuronal hyperexcitability, a phenomenon that occurs in acute withdrawal and protracted abstinence from alcohol. A meta-analysis of 27 RCTs with a total of 7519 participants found that acamprosate treatment reduced risk of abstinent patients returning to any drinking, but did not reduce rates of binge drinking. A number of trials have also found that acamprosate did not show a significant benefit over placebo. In particular, a large scale trial , which compared acamprosate, naltrexone, and behavioral therapies, both individually and combined with each other, against placebo , found that acamprosate had no significant effect on drinking in comparison to placebo, either alone or in combination with naltrexone and/or behavioral intervention. Placebo effects in this trial may explain some of these negative outcomes, as might differences in trial design and patient characteristics: COMBINE required 4 days of pre-trial abstinence while European trials with positive outcomes were typically conducted in inpatient populations requiring complete detoxifcation. Overall, however, a Cochrane meta-analysis of 24 RCTs with 6915 participants found that acamprosate significantly reduced the risk of any drinking and increased cumulative duration of abstinence. Acamprosate is generally well tolerated and may also have neuroprotective effects. As chronic alcohol abuse is associated with neuronal changes related to NMDA receptors, this neuroprotection may be particularly important in AUD treatment. Acamprosate is recommended for the achievement and maintenance of complete abstinence, rather than for the reduction of drinking or prevention of relapse in the event of drinking. It is FDA-approved for abstinence maintenance in AUD patients who are abstinent when beginning treatment.
Naltrexone, the best-studied of these three commonly approved medications, was originally approved to treat opioid use disorder. Naltrexone is an antagonist of the mu opioid receptor . By attenuating alcohol-induced opioidergic activity in the mesolimbic dopamine system, opioid antagonists like naltrexone, modulate the rewarding effects of alcohol , thereby reducing alcohol consumption. In 1994, the FDA approved oral naltrexone to treat alcohol dependence after two independent 12-week trials, which included 97 and 70 participants, respectively, found that naltrexone significantly decreased drinking days and relapse rates. Additional recent trials demonstrate that naltrexone reduces the rewarding effects of alcohol, alcohol craving, drinks per drinking day, and relapse rates, strengthening the initial findings. Extended-release injectable naltrexone , administered once monthly by a medical professional, may be beneficial for individuals who are more sensitive to naltrexone’s adverse side effects or have difficulty adhering to oral medication. A six-month multisite trial of 380 mg injectable naltrexone in 624 patients with alcohol dependence found significant reductions in heavy-drinking days versus placebo. However, evidence for naltrexone remains mixed. Another RCT reported no significant differences between naltrexone and placebo , and that the clinical utility of naltrexone was limited by its adverse effects. Additionally, clinical trials of naltrexone often yield modest effect sizes. A meta-analysis of 53 naltrexone RCTs with a total of 9140 participants found naltrexone to significantly reduce both the risk of return to any drinking and return to binge drinking; however, both of these associations were modest in magnitude. Oral and injectable naltrexone show similar decreases in likelihood of binge drinking and both are generally well tolerated, with fairly mild side effects. Importantly, however, naltrexone does block the therapeutic effects of opioid analgesics and can precipitate opioid withdrawal in patients who have developed physical dependence to opioids; therefore, individuals who are prescribed naltrexone for AUD must be monitored for opioid use and withdrawal. Of note, naltrexone is contraindicated for patients with acute hepatitis or liver failure,bud drying rack and should be “carefully considered” in patients with acute liver disease, potentially limiting its use in the alcohol-associated liver disease population. In summary, naltrexone appears to have a moderate effect on the reduction of alcohol use.Nalmefene works in a similar manner to naltrexone as an antagonist at the mu and delta opioid receptor, but is also a kappa opioid receptor partial agonist. Via its kappa agonist activity, particularly centered in dopaminergic nucleus accumbens circuitry, nalmefene may reduce motivation for self-administration and withdrawal-induced alcohol consumption. Nalmefene was approved by the EMA in 2013 for the reduction of alcohol consumption among patients with AUD. Approval followed findings from three multi-center 6-month clinical trials enrolling 604, 667, and 718 individuals, respectively, in which participants took the medication or placebo on an as-needed basis.
In these trials, nalmefene decreased total alcohol consumption and heavy-drinking days. However, the drug’s approval based on these studies has received criticism due to limited evidence of efficacy, especially as these trials were conducted only against placebo rather than an active medication comparison. A more recent meta-analysis of the efficacy of nalmefene, which included fve RCTs , found that participants treated with nalmefene had 1.65 fewer heavy-drinking days per month than participants treated with placebo after 6 months. Studies indicate that nalmefene is associated with more adverse events and study dropouts compared to placebo, and the most frequently reported of these are dizziness, nausea, vomiting, insomnia, and headache. Overall, while nalmefene may reduce heavy-drinking rates, its effects on other outcomes remain small-to-moderate, and study withdrawals related to adverse events are common in nalmefene trials. However, similar to naltrexone, this medication may appeal to patients with goals of reducing alcohol consumption and those reluctant to engage in abstinence based treatment.Baclofen acts on the γ-amino butyric acid system as a GABAB agonist. It was approved for treatment of AUD in France in 2018 and has been used of-label for AUD for over a decade in other countries, especially other European countries and Australia. Clinical trials of baclofen have produced mixed results.A recent meta-analysis of 12 RCTs showed that baclofen in comparison to placebo was associated with higher abstinence rates; however, it did not increase abstinent days or decrease craving, heavy drinking, depression, or anxiety. Another meta-analysis of 13 RCTs indicated that baclofen was associated with longer time to relapse and a larger percentage of abstinent patients. Furthermore, greater alcohol use at baseline was correlated with a greater treatment effect. In contrast, however, another recent meta-analysis of 12 RCTs with 1128 total participants found no significant differences between baclofen and placebo in primary or secondary outcomes of interest ; however, baclofen did increase depression and adverse effects including sedation and vertigo. Baclofen’s significant adverse side effects include drowsiness, sedation, headache, vertigo, confusion, perspiration, muscle stiffness and/or abnormal movements, slurred speech, and numbness.Additionally, dose and sex may moderate baclofen tolerability and response; escalation of dosage in response to developing tolerance can increase sedative side effects, which affect women significantly more than men at the same dose. Importantly, cessation or reduction in dose can precipitate potentially life-threatening withdrawal syndrome. The variability in baclofen’s effectiveness seen across studies may be partially explained by high baclofen pharmacokinetic variability seen among individuals with AUD. This heterogeneity is an important factor to take into account when considering baclofen as an AUD treatment . Of note, there is also some evidence that baclofen might be particularly useful in treatment of AUD among individuals with liver disease. In summary, baclofen seems to effectively promote abstinence; however, it shows mixed results regarding its clinical effects on non-abstinence outcomes , significant adverse side effects, and inter-individual variability in response. As such, baclofen as a treatment of AUD—as well as its optimal dosage—continues to be debated.Sodium oxybate , the sodium salt of gamma-hydroxybutyrate , has been utilized as a medication for a number of disorders. SMO is approved in Italy and Austria for the treatment of AUD. SMO acts on the GABA system both directly as a GABAB partial agonist and indirectly through GHB-derived GABA. A Cochrane meta-analysis of 13 RCTs with a total of 649 participants found that SMO was effective compared to placebo in the treatment of alcohol withdrawal syndrome and in preventing relapses in previously detoxifed participants, and that SMO was more effective than naltrexone and disulfram in maintaining abstinence. Another recent meta-analysis found that SMO, compared to placebo, increased abstinence rates by up to 34% in a sample of 711 participants with very high drinking risk levels. However, use of GHB as a recreational drug raises concern regarding the abuse potential of SMO. Indeed, in another clinical study with a sample of 48 participants, craving for SMO was observed in 10% of participants with psychiatric comorbidities, indicating that patients may be at risk of developing craving for and abusing SMO. SMO may be particularly effective in combination with other pharmacotherapies. It was shown to reduce relapses when administered with naltrexone and escitalopram.A study of 52 subjects with chronic, treatment-resistant alcohol dependence found that participants stayed in treatment significantly longer when SMO was co-administered with disulfram than with SMO alone. Additionally, in a case study of seven partial- and non-responders to SMO treatment, co-administration with nalmefene was effective in promoting abstinence, reducing heavy-drinking episodes, and importantly, suppressing craving for SMO.SMO craving and abuse potential may limit its use; however, at therapeutic doses, SMO abuse seems to be a relatively infrequent phenomenon among patients without psychiatric comorbidities or poly-drug use. Safety data show that serious adverse events with SMO treatment are rare, with the most common adverse effects being transitory dizziness and vertigo. Overall, the effectiveness of SMO lies largely in reducing withdrawal symptoms and increasing abstinence rates.