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Selecting an appropriate alcohol pharmacotherapy

review of recent findings

Castrén, Saria,b; Mäkelä, Niklasc; Alho, Hannua,d

Current Opinion in Psychiatry: July 2019 - Volume 32 - Issue 4 - p 266–274
doi: 10.1097/YCO.0000000000000512
ADDICTIVE DISORDERS: Edited by John B. Saunders and Linda B. Cottler
Free

Purpose of review Only a few pharmacological treatments are available for treating alcohol use disorders (AUDs). Disulfiram, naltrexone and acamprosate are Food and Drug Administration (FDA)-approved and nalmefene is EMA-approved in European Union. Off-label medications, such as baclofen, gabapentin, ondansetron and topiramate are medications commonly prescribed for the treatment of AUD. The aim of this review is to give an update on recent randomized controlled trials (RCTs) and reviews evaluating pharmacological treatment for AUD.

Recent findings A literature search was conducted for pharmacological treatment for alcohol use disorder, published from January 2017 to January 2019. An additional search from two ongoing-study databases was performed. A total of 13 studies, 11 reviews and 7 on-going clinical trials were identified. Interest in studying baclofen as a treatment for AUD was greater compared with other medications, yet with inconclusive results. Three new RCTs of first-line medication naltrexone showed reduction in drinking.

Summary Three new published RCTs focus on baclofen and naltrexone. These results are consistent with old findings demonstrating that naltrexone reduces heavy drinking. Several RCT on baclofen do not support the use of baclofen for treatment of AUD. Encouraging results have been reported for topiramate, gabapentin and also varenicline, which might be useful in patients with comorbid nicotine dependence.

aNational Institute for Health and Welfare, Alcohol, Drugs and Addictions Unit, Helsinki

bFaculty of Social Sciences, Department of Psychology and Speech-Language Pathology, University of Turku, Turku

cFaculty of Medicine, Department of Internal Medicine

dAbdominal Center, University and University Hospital of Helsinki, University of Helsinki, Finland

Correspondence to Sari Castrén, PhD, Adjunct Professor, Alcohol, Drugs and Addictions Unit, National Institute for Health and Welfare, P.O. Box 30, FI-00271 Helsinki, Finland. E-mail: sari.castren@thl.fi

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INTRODUCTION

Alcohol consumption is a major cause of morbidity and mortality globally, and the global alcohol consumption has been on the rise in the 21st century [1]. The DSM-5 defines alcohol use disorders (AUD) into three levels of severity: mild, moderate and severe based on questions covering symptoms in alcohol consumption and craving, changes in the individual's behavior, social consequences, tolerance and symptoms of abstinence [2]. The psychopathology of alcohol use disorder is complex and partially unknown. A wide array of treatment methods exists with pharmacological, psychological and social methods being the most commonly used. However, treatment efficacy varies, and relapse is common.

In most European countries and in the United States, the drugs approved for the treatment of AUD are disulfiram, acamprosate and naltrexone. Disulfiram is an acetaldehyde dehydrogenase (ALDH) inhibitor and is used to promote alcohol abstinence. The buildup of acetaldehyde caused by ALDH inhibition causes nausea, flushing and headaches among other symptoms. Acamprosate is used to maintain abstinence and reduce cravings. Its mechanism of action is not fully understood, but it is thought to act on N-methyl-D-aspartate-receptors and GABA-signaling. Naltrexone is an unselective opioid antagonist. Its mechanism of action is thought to be reduction of dopamine and endorphin release in response to reward cues. Injectable naltrexone in XR form is approved in United States for the treatment of AUD by the FDA. Other medications are used off label, such as nalmefene, topiramate, baclofen and gabapentin [3,4▪▪].

A plethora of other medications of various classes of drugs have been trialed for the treatment of AUD. Psychological interventions can be used solitarily or in conjunction with pharmacotherapy. Cognitive–behavioral therapy (CBT) and mini-interventions are established psychological treatments used in the treatment of AUD [5].

Significant comorbidity, psychiatric and somatic, is associated with AUD. Common psychiatric comorbid conditions are major depression and generalized anxiety disorder [6]. Although psychiatric comorbidity is common in randomized control trials on AUD and these conditions have previously been sparse [7]. The relationship between these conditions and AUD is often unclear and multiple mechanism of psychopathogenesis have been proposed. The aim of this study is to review recent and on-going clinical studies on the pharmacotherapy of AUD and to help the clinician choose the appropriate pharmacotherapy for each patient.

Box 1

Box 1

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METHODS

Randomized controlled trials and reviews

The literature search was conducted on 30 January 2019. Published articles were systematically searched using EMBASE, MEDLINE, PsycINFO, PubMed and Cochrane Library with the search terms: pharmacological treatment and alcohol use disorder, and reviews, meta-analyses of medical trials (multiple medications and individual medications) as well as randomized trials (RCTs) published since 2017 to third week of January 2019.

Original research articles written in English were accepted. Publications in peer-reviewed journals, doctoral theses and institutional reports were accepted. The most recent review on the pharmacotherapy of AUD: ‘Diagnosis and pharmacotherapy of alcohol use disorder[4▪▪] (published on 16 June 2018) was used as a baseline of this review, meaning that only studies published after that review were included. Reviews and meta-analyses in which the study subject was pharmacotherapy of AUD or closely related, the primary endpoint of the study is alcohol craving, alcohol consumption or measurement of days of abstinence were included. Conference abstracts, study protocols, safety studies and nonadult studies were excluded (see Fig. 1). The joint probability of agreement was 98%. Disagreement was resolved by discussion.

FIGURE 1

FIGURE 1

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On-going clinical trials

An additional manual search was performed for on-going clinical trials in two different databases. The ClinicalTrials.gov (https://clinicaltrials.gov/), which is a resource provided by the US National Library of Medicine and is a database for privately and publicly funded clinical studies and the European Union Clinical Trials Register ((https://www.clinicaltrialsregister.eu/ctr-search/search, EudraCT), which is a database used by national medicines regulators for data-related trial protocols were searched for on-going studies. The EudraCT is also a primary registry in the WHO. Search words were: alcohol use disorder and pharmacological treatment. Only active (recruiting, active not recruiting, enrolling by invitation) interventional, adult, phase II, III and IV studies were included, for the EudraCT date range used (1.1.2016–1.2.2019) and for the Clinical Trials date range was 1.1.2017– 15.1.2019.

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RESULTS

Twenty-four articles were included in this review (Table 1); of these, 13 were RCTs and 11 were reviews. Of the 13 RCTs, one was on-going clinical trial and was moved to the on-going clinical trials-section. In addition, we identified six on-going clinical studies from two databases, totaling to seven on-going clinical trials (Table 2).

Table 1

Table 1

Table 2

Table 2

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Randomized controlled trials

The most often studied pharmacological treatment for AUD was baclofen [8▪,9▪,10,11], with the second most studied being naltrexone [12,13▪▪,14]. In addition, there were two studies on gabapentin [15▪,16], and one study of each of the following compounds: citicoline [17], mecamylamine [18], prazosin [19] acamprosate [20] and ABT-436, a novel vasopressin 1b-receptor antagonist [21].

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Reviews

Baclofen was also the most reviewed pharmacological treatment for AUD, being the drug of topic in five reviews [22,23▪▪,24,25] conducted, one being a Cochrane review [26▪▪]. One review on antidepressants [27▪▪] (Cochrane review) and one reviewing combined pharmacotherapy [28▪▪]. In addition, there was one review on gabapentin [29] and three general reviews on the pharmacotherapy of AUD [30–31,4▪▪].

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On-going clinical trials

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).

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OBSERVATIONS AND DISCUSSION

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.

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Baclofen

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.

In a clinical trial by Morley et al.[8▪], 104 patients with alcoholic liver disease (ALD) were randomized to baclofen (25 or 75 mg/day) or placebo for 12 weeks. Baclofen had a significant effect on time to lapse and time to relapse. A significant treatment effect for baclofen was observed for days abstinent (placebo 43%, baclofen 25 mg/day, 69% and baclofen 75 mg/day, 65%). Sedation or drowsiness was the most common adverse event reported. A baclofen overdose in the 75 mg group was deemed to be a serious adverse event related to the study medication. The authors conclude that baclofen may be effective for patients with AUD but because of adverse effects, treatment may be best limited to specialist services.

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Naltrexone and nalmefene

There are plenty of published RCT and systematic reviews on naltrexone [4▪▪]. These studies have confirmed the anticraving efficacy of naltrexone against alcohol drinking [32]. One earlier study indicates that naltrexone has more reliable anticraving benefit than acamprosate [33]. The new studies, included to this review, confirm these findings. One RCT tested the effects of naltrexone on drinking and alcohol cue-elicited brain activation and evaluated whether OPRM1 A118G genotype or smoking moderated these effects. OPRMI genotype did not significantly moderate these effects, but G-allele carriers who received naltrexone had an accelerated return to heavy drinking after medication was stopped. The authors conclude that naltrexone reduces heavy drinking and reward-related brain activation among treatment seeking individuals with AUD [14]. In a RCT on young adult heavy drinkers, it was observed that more ambitious drinking goals showed a further reduction in drinking during naltrexone treatment [12]. Subgroup analysis of the PREDICT study indicated that four phenotypes could be derived using the Inventory of Drinking Situations. Using naltrexone with individuals who are predominantly reward drinkers produces significantly higher effect sizes than prescribing the medication to a more heterogeneous sample [13▪▪].

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 [34]. 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 [35]. 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▪].

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Long-acting naltrexone

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 [37]. 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.

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Gabapentin

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 [39].

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Citicoline

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 [17].

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Ondansetron

Ondansetron is a serotonin 5-HT3 receptor antagonist. In some countries, ondansetron is only available in injectable formulation for controlling nausea and vomiting for cancer patients receiving chemotherapy. In earlier randomized controlled clinical trial, ondansetron has been found to reduce self-reported drinking [40].

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Disulfiram

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 [41] 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.

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Acetylcholine receptor antagonists

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 [18].

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Antidepressants

A meta-analysis of seven trials undertaken more than a decade ago showed that selective serotonin reuptake inhibitors did not effectively treat AUD patients who do not have comorbid depression [42]. A recent Cochrane review [27▪▪] concluded that there was (low-quality) evidence for using antidepressants in the treatment of alcohol dependence with co-occurring depression.

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Other compounds

In a study published by Wilcox et al. [19], the alpha-1 adrenergic receptor antagonist prazosin did not differ from placebo in reducing alcohol consumption in 36 participants. DBP, however, moderated reduction of drinks per day in the treatment group. ABt-436 is a novel vasopressin 1b (V1b)-receptor antagonist. Vasopressin is active in the human hypothalamic–pituitary–adrenal axis and stress systems. Extrahypothalamic vasopressin has played a significant role in regulating complex behaviors in previous studies, one of these behaviors being addiction. However, the novel V1b-receptor antagonist ABT-436 did not provide a statistically significant reduction in heavy drinking days in a placebo-controlled setting. However, the patients receiving ABT-436 had a statistically significant increase in days abstinent [21].

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Combination medications

Naglich et al.[28▪▪] reviewed combined pharmacotherapy for treatment of AUD in patients without comorbid conditions and concluded that naltrexone was the most used medication combined with other agents to reduce alcohol consumption. However, there was no significant benefit using combinations over single agents. Other general reviews [30–32] stressed the importance of using fist-line pharmacotherapy, psychosocial support and early identification of alcohol abuse.

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Limitations

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.

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CONCLUSION

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.

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Acknowledgements

None.

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Financial support and sponsorship

None.

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Conflicts of interest

H.A. reports being an advisory board member, consultant or continuing medical education speaker for Indivior, Opiant, Mundipharma, MSD and Lundbeck. The other authors S.C. and N.M. claim no conflict of interest.

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REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest
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REFERENCES

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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.

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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.

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An interesting multicenter study of investigating gababentin in reducing drinking outcomes among individuals with alcohol dependence, yet with negative results.

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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.

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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.

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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.

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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.

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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.

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Keywords:

alcohol use disorder; meta-analysis; on-going clinical; pharmacological treatment; randomized controlled trial; studies for alcohol use disorders

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