Ismene Petrakis, MD

Alcohol use disorders (AUDs) are among the most prevalent substance use disorders. According to the World Health Organization, AUDs have the highest morbidity and mortality burden worldwide (2.5 million deaths every year) and are associated with wide-reaching social problems.

Disulfiram, oral naltrexone, injectable naltrexone, and acamprosate are FDA-approved for alcohol dependence. These medications are primarily used to prevent post-detoxification relapse. Several new treatment strategies using older medications and new medications may be effective on the basis of preclinical and/or clinical data.

In this review, we discuss the established medications as well as experimental therapeutic options that may emerge as future medications for alcohol intoxication, withdrawal, and/or long-term abstinence maintenance or harm-reduced drinking.

Alcohol intoxication describes the acute effects of alcohol ingestion: clinical symptoms are closely correlated with blood alcohol levels. The subjective effects of alcohol in amounts consistent with alcohol intoxication are likely due to alcohol’s effects on glutamatergic and Î³-aminobutyric acid (GABAergic) neurotransmission.

 These effects include stimulatory effects such as euphoria (“ascending limb” symptoms that predominate when blood alcohol levels are rising in early intoxication) and sedative effects (“descending limb” symptoms that predominate when blood alcohol levels are falling in later intoxication).

At present, there are no treatments to reduce the intoxicating effects of alcohol. Recently, dihydromyricetin, a flavonoid from the herb 

 that has been reported for more than a millennium as an antihangover treatment in traditional Chinese medicine, showed anti-intoxication and withdrawal effects in rats. These effects are mediated via the benzodiazepine site of the GABA

 Although mitigating alcohol’s intoxicating effects has not been an active area of investigation to date, such treatments could be very useful in reducing the rewarding effects of intoxication.

Compared with withdrawal syndrome from other substances, alcohol withdrawal syndrome is associated with the highest mortality. Repeated and prolonged alcohol intake can induce tolerance, and abrupt drinking cessation can lead to irritability, tremor, insomnia/anxiety, diaphoresis, vital sign instability (eg, tachycardia, elevated blood pressure), seizures, alcoholic hallucinosis, delirium, and death. Alcohol withdrawal may result from overactivation of the glutamatergic system with concomitant understimulation of the GABAergic system in the absence of alcohol.

 receptor agonists, benzodiazepines remain the standard of care in the treatment of alcohol withdrawal syndrome, especially to reduce the risk of seizures.

 There appears to be no statistically significant difference in the efficacy, safety, or tolerability of individual benzodiazepines, although some reports indicate that long-acting chlordiazepoxide is the preferred oral agent. The best predictor of a complicated alcohol withdrawal syndrome (eg, seizures, delirium tremens) is a past history of complicated withdrawal.

Patients with a history of complicated alcohol withdrawal syndrome should be treated with a standing benzodiazepine taper during detoxification. Patients with hepatic disease, benzodiazepines that are conjugated and renally cleared (lorazepam, oxazepam, and temazepam) should be used instead of those metabolized by the liver. Symptom-triggered withdrawal protocols, in which benzodiazepines are only given after symptoms appear and reach a critical threshold, seem to perform as well as standing benzodiazepine protocols for uncomplicated alcohol withdrawal syndrome.

Î³-Hydroxybutyrate (GHB), anticonvulsants, and Î±

-agonists have been studied as stand-alone or adjunctive agents in the treatment of alcohol withdrawal syndrome. Although these medications are promising for mild to moderate alcohol withdrawal syndrome, there is a dearth of information about their ability to prevent or treat complicated alcohol withdrawal.

. GHB, which gained notoriety as a “date rape” drug in the US during the 1990s and, more recently, as an athletic enhancement (because of its ability to stimulate growth hormone), is currently approved in Italy as an adjunctive agent for alcohol withdrawal syndrome. It has sedative and anxiolytic effects similar to those of benzodiazepines. It is a short-chain fatty acid that is structurally similar to GABA. GHB is a weak agonist at GABA

 receptors, which appears to be secondary to its recently discovered higher affinity for the Î±4Î²1Î´ GABA

 Exogenously administered GHB is also converted into GABA, which can serve as the natural agonist for GABA

 receptors. This may explain its sedative and anxiolytic effects and point toward its role in the hypoGABAergic alcoholic brain.

At low doses, GHB was found to stimulate dopamine release from the ventral tegmental area onto the nucleus accumbens; however, high-dose GHB has an inhibitory effect on dopamine release. Although these findings are promising for future research and development, a 2010 Cochrane Review concluded that there are insufficient data to support the use of GHB in the treatment of alcohol withdrawal syndrome.

. Although they are sometimes used clinically to treat alcohol withdrawal syndrome (especially in patients who have had a prior documented alcohol withdrawal seizure), there is inconsistent evidence for anticonvulsants in the treatment of alcohol withdrawal syndrome.

 To date, valproic acid and carbamazepine have been the most extensively studied anticonvulsants. A recent Cochrane review reported that anticonvulsants may be more effective than benzodiazepines in treating some aspects of alcohol withdrawal syndrome (ie, decreasing seizure risk).

 Findings from a retrospective cohort study of 453 patients treated with valproate and 374 patients treated with carbamazepine suggest that valproate may have more benefits because of its higher tolerability, shorter duration of treatment, and lower incidence of alcohol-withdrawal seizures.

The anticonvulsants gabapentin and pregabalin are used primarily for neuropathic pain and partial seizure prophylaxis. Because of their effects on GABAergic neurotransmission, they are also rational medications for alcohol withdrawal syndrome. Initially, gabapentin failed as an adjunctive agent to benzodiazepines in severe alcohol withdrawal syndrome; however, it has shown efficacy in mild to moderate alcohol withdrawal syndrome.

Pregabalin has been investigated for outpatient detoxification in patients with mild to moderate alcohol withdrawal syndrome. Forty alcohol-dependent patients received 250 to 400 mg of pregabalin daily during acute detoxification (up to 14 days) and reported improved symptoms of withdrawal and cravings.

 Recently, however, pregabalin was not shown to be more efficacious than placebo for alcohol withdrawal syndrome.

. Excessive activation of the sympathetic nervous system via norepinephrine may explain some of the symptoms of alcohol withdrawal (anxiety, agitation, tremor and, most importantly, increased vital sign parameters such as hypertension and tachycardia). Î±

-Adrenergic receptor agonists (eg, clonidine, dexmedetomidine) decrease norepinephrine release via activity on presynaptic neurons in the locus coeruleus, thereby dampening sympathetic activation, which is consistent with its mechanism of action in treating opioid withdrawal.

Several randomized controlled trials (RCTs) have demonstrated the lack of efficacy of clonidine over benzodiazepines in the treatment of alcohol withdrawal syndrome. However, several case reports indicate that dexmedetomidine may be effective as an adjunctive agent to benzodiazepines in alcohol withdrawal syndrome. Therefore, the use of adjunctive Î±

-agonists may be worth exploring as a strategy for alcohol withdrawal syndrome.

 After initial case reports of efficacy in maintenance, the GABA

 receptor agonist and antispastic agent baclofen has also been investigated in alcohol withdrawal syndrome. Hospitalized patients at risk for alcohol withdrawal syndrome were randomized to receive 10 mg of oral baclofen twice daily or placebo in addition to symptom-triggered lorazepam. The coadministration of baclofen decreased the use of high-dose lorazepam (as defined by more than 20 mg in the first 72 hours).

 To date, no other RCTs of baclofen have been reported for alcohol withdrawal syndrome.

After the withdrawal phase of treatment, the risk of relapse and return to heavy drinking remains high. FDA-approved medications for alcoholism have been primarily studied in relapse prevention. As revealed in the large multisite National Institute on Alcohol Abuse and Alcoholism–funded Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence (COMBINE) study

 and consistent with established interventions for other chronic neuropsychiatric disorders (eg, schizophrenia, MDD) available treatments are beneficial for some patients with AUDs. There is a critical need to develop more effective and personalized treatments that reduce the risk of relapse and harm from excessive alcohol intake.

. The Î¼-opioid receptor antagonist naltrexone is the most extensively studied treatment for alcohol dependence and should be considered as first-line treatment. Findings from 2 meta-analyses as well as the COMBINE study indicate that patients who received naltrexone had more days abstinent from alcohol and fewer heavy drinking days than patients who received placebo.

 However, the effect size is moderate, and naltrexone is not effective for all patients. Recent research with naltrexone has focused on alternative delivery strategies and identifying moderators of treatment response.

One alternative delivery strategy is to use targeted Î¼-opioid receptor antagonists. With this strategy, naltrexone is limited to days when or situations in which the patient is at higher risk for heavy drinking. Targeted opioid receptor antagonists are likely to be most effective in heavy drinkers who are not physically dependent and in vulnerable individuals during high-risk situations.

Several studies have shown this strategy to be effective. A large, multisite RCT of targeted nalmefene demonstrated fewer heavy drinking days and lower laboratory levels of markers for chronic hepatotoxicity.

 A more recent study of targeted naltrexone showed a decrease in the mean number of weekly drinks and in the final week of this 12-week open-label study, a decrease in daily drinks.

Long-acting injectable naltrexone (190 or 380 mg) was approved in 2006 by the FDA for alcohol dependence. A single monthly intramuscular injection of naltrexone has been shown to be more effective than monthly placebo injections in decreasing drinking in alcohol-dependent patients.

 There is also a clear dose response; the higher dose is more effective in promoting abstinence. Unfortunately, the widespread use of this medication has been limited, possibly because of its high cost and reports of injection site complications.

Another active area of research has been on moderators of naltrexone’s effects. Although results vary, a family history of alcoholism and antisocial behavior has been reported to decrease drinking in persons treated with naltrexone.

 The pharmacogenetics of naltrexone response, particularly at the Î¼-opioid receptor gene, 

 has also been extensively studied because functional variants of the Î¼-opioid receptor may be related to treatment response. A common functional variant in 

-identified more than 10 years ago-is the response to naltrexone seen in persons who carry at least 1 copy of the 118G haplotype.

Results from a PET study suggest that 118G carriers release more dopamine in response to alcohol, which is mediated via endogenous opioids. A future area of practical treatment may be the pharmacogenetic stratification of alcohol-dependent persons by 

. This medication was approved by the FDA in 2004. Several US studies subsequently demonstrated little to no effect over placebo. Nevertheless, a recent Cochrane review that evaluated all the studies to date found acamprosate to have a modest effect on promoting abstinence after detoxification and suggested that acamprosate may be beneficial in some patients who do not respond to other treatments.

 Acamprosate also has the added advantage of being the only FDA-approved medication that is not metabolized in the liver; thus, it may be of use in patients with chronic liver disease, such as hepatitis B or C.

. Several anticonvulsants have been investigated as experimental therapies in AUDs. Johnson and colleagues

 reported the efficacy results of an RCT of topiramate in 2003, which was extended to a multisite study.

 In the extension study, topiramate (up to 300 mg/d over 14 weeks) increased the percentage of abstinent days and decreased the percentage of heavy drinking days; the mean number of daily drinks; and Î³-glutamyltransferase level, a laboratory measure of long-term alcohol-related biliary and liver injury. A recent meta-analysis confirmed the effectiveness of topiramate.

 Moreover, topiramate outperformed naltrexone on several drinking-related outcomes, including abstinence, harm-reduced drinking, and psychosocial dysfunction.

The antiepileptic drug zonisamide also decreased the number of heavy drinking days, the number of drinks per week, and alcohol cravings scores in a single-site, 12-week RCT of alcohol dependence.

 Participants were given escalating doses of zonisamide (up to 500 mg/d) or placebo.

Antiepileptic drug treatment for alcohol dependence appears effective and may be considered in select patients, especially those whose drinking has not adequately responded to FDA-approved medications.

. Alcohol’s ability to alleviate negative emotional states in stressful situations (eg, social anxiety) has implicated neuropeptidergic systems in the psychopathology of alcoholism. Many preclinical studies have implicated the hypothalamic-pituitary-adrenal axis in stress-induced relapse and cravings, and these findings are presently being translated into humans, especially genetic variation in the corticotropin-releasing factor (CRF) system and alcohol-related endophenotypes.

Although they did not prove to be effective in other stress-related psychiatric disorders (eg, unipolar depression), CRF and other neuropeptide receptor targets are rational thera-pies to decrease stress-induced drinking.

. Although several studies have shown equivocal results with SSRIs, a recent study revealed enhanced response after stratification by age of onset and serotonin transporter genotype (

 S allele polymorphism with late-onset (older than 25 years) alcoholism had the best response to sertraline. On the other hand, S' allele carriers with early-onset (younger than 25 years) alcoholism displayed less drinking with placebo than with sertraline.

-adrenergic receptor antagonist prazosin is effective in reducing alcohol consumption in laboratory animals, a small pilot study was undertaken in humans. Prazosin (16 mg/d for 4 weeks) decreased stress- and cue-induced alcohol cravings, anxiety, and negative emotionality, presumably via its ability to dampen sympathetic activation.

 Given its potential to decrease stress-induced relapse and PTSD-related nightmares, prazosin is currently being evaluated in alcohol dependence as well as in alcohol dependence with comorbid PTSD.

The treatment of comorbid psychiatric disorders and AUDs has been especially fruitful in recent years. In a study of comorbid alcohol dependence and depression, patients were randomized to 200 mg/d of sertraline and 100 mg/d of naltrexone, sertraline alone, naltrexone alone, or double placebo.

 On drinking-related measures, the combination of the SSRI and naltrexone outperformed either treatment alone or double placebo. Interestingly, there was no significant difference in depression scores in the 4 treatment arms at the end of the 14-week study.

Our group has also completed an RCT that compared desipramine with paroxetine in co-occurring PTSD and alcohol dependence. The group that received desipramine had improved drinking-related outcome measures. Naltrex-one offered no additional benefit on drinking outcomes.

There are several phases in the treatment of AUDs: intoxication, withdrawal, abuse, and dependence. Standard treatments exist to treat alcohol withdrawal, and the FDA-approved medications focus on treatment post-detoxification to prevent relapse. These medications have limitations, so research to evaluate new pharmacological agents is a high clinical priority. Several novel pharmacological mechanisms for AUDs have been evaluated, but more novel targets are needed.

Our Category 1 CME articles are on hiatus. In the meantime, we invite you to test yourself: read the article, take the posttest below, and then check the answer key on page 12 of the September 2012 issue. 

1. Which of the following is FDA-approved for alcohol dependence?

2. In a recent study of comorbid alcohol dependence and depression, which of the following treatments showed the most promising results?

A. The combination of sertraline and naltrexone

3. Which of the following is a benzodiazepine that is conjugated and renally cleared and therefore safer to use in patients with hepatic disease?

4. Which of the following anticonvulsants has been extensively studied for efficacy in the treatment of alcohol withdrawal syndrome?

5. Some of the symptoms of alcohol withdrawal may be explained by the excessive activation of the sympathetic nervous system via norepinephrine.

6. The Î¼-opioid receptor antagonist naltrexone is the most extensively studied treatment for alcohol dependence and should be considered as first-line treatment.

7. One area of research has shown that naltrexone decreased drinking in persons with:

A. Frequent episodes of heavy drinking but not alcoholism

B. A family history of alcoholism and antisocial behavior

8. Persons with the OPRM1 variant who carry the 118G haplotype are at decreased risk for alcohol use disorders.

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 Gomez R, Behar KL, Watzl J, et al. Intravenous ethanol infusion decreases human cortical Î³-aminobutyric acid and N-acetylaspartate as measured with proton magnetic resonance spectroscopy at 4 tesla. 

 Shen Y, Lindemeyer AK, Gonzalez C, et al. Dihydromyricetin as a novel anti-alcohol intoxication medication. 

 Amato L, Minozzi S, Vecchi S, Davoli M. Benzodiazepines for alcohol withdrawal. 

 Elholm B, Larsen K, Hornnes N, et al. Alcohol withdrawal syndrome: symptom-triggered versus fixed-schedule treatment in an outpatient setting. 

 Absalom N, Eghorn LF, Villumsen IS, et al.Î±4Î²1Î´ GABAA receptors are high-affinity targets for Î³-aminobutyric acid (GHB). 

 Leone MA, Vigna-Taglianti F, Avanzi G, et al. Gamma-hydroxybutyrate (GHB) for treatment of alcohol withdrawal and prevention of relapses. 

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 Minozzi S, Amato L, Vecchi S, Davoli M. Anticonvulsants for alcohol withdrawal. 

 Eyer F, Schreckenberg M, Hecht D, et al. Carbamazepine and valproate as adjuncts in the treatment of alcohol withdrawal syndrome: a retrospective cohort study. 

 Bonnet U, Hamzavi-Abedi R, Specka M, et al. An open trial of gabapentin in acute alcohol withdrawal using an oral loading protocol. 

 Trevisan L, Ralevski E, Keegan, K, et al. Alcohol detoxification and relapse prevention using valproic acid versus gabapentin in alcohol-dependent patients. 

 Di Nicola M, Martinotti G, Tedeschi D, et al. Pregabalin in outpatient detoxification of subjects with mild-to-moderate alcohol withdrawal syndrome. 

 FÃ¶rg A, Hein J, Volkmar K, et al. Efficacy and safety of pregabalin in the treatment of alcohol withdrawal syndrome: a randomized placebo-controlled trial. 

 Muzyk AJ, Fowler JA, Norwood DK, Chilipko A. Role of Î±

-agonists in the treatment of acute alcohol withdrawal. 

 Lyon JE, Khan RA, Gessert CE, et al. Treating alcohol withdrawal with oral baclofen: a randomized, double-blind, placebo-controlled trial. 

 Anton RF, O’Malley SS, Ciraulo DA, et al; COMBINE Study Research Group. Combined pharmacotherapies and behavioral interventions for alcohol dependence: the COMBINE study: a randomized controlled trial. 

 Streeton C, Whelan G. Naltrexone, a relapse prevention maintenance treatment of alcohol dependence: a meta-analysis of randomized controlled trials. 

 Srisurapanont M, Jarusuraisin N. Naltrexone for the treatment of alcoholism: a meta-analysis of randomized controlled trials. 

 Karhuvaara S, Simojoki K, Virta A, et al. Targeted nalmefene with simple medical management in the treatment of heavy drinkers: a randomized double-blind placebo-controlled multicenter study. 

 Kranzler HR, Tennen H, Armeli S, et al. Targeted naltrexone for problem drinkers. 

 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 [published corrections appear in 

 Galloway GP, Koch M, Cello R, Smith DE. Pharmacokinetics, safety, and tolerability of a depot formulation of naltrexone in alcoholics: an open-label trial. 

 Capone C, Kahler CW, Swift RM, O’Malley SS. Does family history of alcoholism moderate naltrexone’s effects on alcohol use? 

Ismene Petrakis, MD

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