Anticonvulsants. 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.8 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).9 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.10
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.11,12
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.13 Recently, however, pregabalin was not shown to be more efficacious than placebo for alcohol withdrawal syndrome.14
α2-Agonists. 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). α2-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 α2-agonists may be worth exploring as a strategy for alcohol withdrawal syndrome.15
Baclofen After initial case reports of efficacy in maintenance, the GABAB 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).16 To date, no other RCTs of baclofen have been reported for alcohol withdrawal syndrome
Relapse prevention
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) study17 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.
Naltrexone/nalmefene. The μ-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.17-19 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 μ-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.20 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.21
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.22 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.23
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.24-26 The pharmacogenetics of naltrexone response, particularly at the μ-opioid receptor gene, OPRM1, has also been extensively studied because functional variants of the μ-opioid receptor may be related to treatment response. A common functional variant in OPRM1—identified more than 10 years ago—is the response to naltrexone seen in persons who carry at least 1 copy of the 118G haplotype.27-29 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 OPRM1 genotype.
Acamprosate. 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.30 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.
Anticonvulsants. Several anticonvulsants have been investigated as experimental therapies in AUDs. Johnson and colleagues31 reported the efficacy results of an RCT of topiramate in 2003, which was extended to a multisite study.32 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 γ-glutamyltransferase level, a laboratory measure of long-term alcohol-related biliary and liver injury. A recent meta-analysis confirmed the effectiveness of topiramate.33 Moreover, topiramate outperformed naltrexone on several drinking-related outcomes, including abstinence, harm-reduced drinking, and psychosocial dysfunction.34
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.35 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.
Neuropeptides. 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.36 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.
Other treatments and conditions. 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 (5-HTTLPR).7,37 Carriers of the 5-HTTLPR 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.
After findings suggested that the α1-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.38 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.3 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.40
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