Summary by Daniel Eckroth, MD
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Based on “Principles of Addiction Medicine” Chapter by Hugh Myrick, MD, Henry R. Kranzler, MD, Domenic A. Ciraulo, MD, Andrew J. Saxon, MD, and Jerome H. Jaffe, MD
MEDICATIONS USED TO REDUCE OR STOP DRINKING
Alcohol-sensitizing agents alter the body’s response to alcohol, making its ingestion unpleasant or toxic. Disulfiram (Antabuse) is the only alcohol-sensitizing medication approved in the United States for the treatment of alcohol use disorder. It works by inhibiting the enzyme aldehyde dehydrogenase, which catalyzes the oxidation of acetaldehyde to acetic acid. The ingestion of alcohol while this enzyme is inhibited elevates blood acetaldehyde concentration, resulting in the disulfiram–ethanol reaction (DER). Symptoms and signs of the DER include warmness and flushing of the skin, increased heart rate, palpitations, decreased blood pressure, nausea, vomiting, shortness of breath, sweating, dizziness, blurred vision, and confusion. Most DERs are self-limited, lasting about 30 minutes. Severe DERs are associated with marked tachycardia or bradycardia, hypotension, and, rarely, cardiovascular collapse, congestive heart failure, and convulsions. Severe reactions are usually associated with high doses of disulfiram (over 500 mg/day).
Despite a lack of evidence demonstrating its efficacy in relapse prevention, disulfiram has long been used in the rehabilitation of patients with alcohol use disorder. In the studies conducted, the difference in outcome between subjects receiving disulfiram and those given placebo has been modest. However, when compliance is ensured, these medications may be useful, and disulfiram may limit the severity of relapse when it occurs. There are no guidelines that can be offered to either identify patients for whom disulfiram is likely to benefit or to match specific psychosocial interventions with particular patients to enhance compliance. In one large multicenter trial, among patients who resumed drinking, those receiving 250 mg of disulfiram reported significantly fewer drinking days than did patients receiving lower doses or an inactive placebo. Thus, disulfiram may be helpful in reducing the frequency of drinking in patients who cannot remain abstinent and in those with whom special efforts are made to ensure compliance. Supervision of patients being treated with disulfiram may be an essential element in ensuring compliance and enhancing the beneficial effects of the medication.
Disulfiram is almost completely absorbed orally. Because it binds irreversibly to aldehyde dehydrogenase, renewed enzyme activity requires the synthesis of new enzyme, so that the potential exists for a DER to occur 2 weeks from the last ingestion of disulfiram. Disulfiram commonly produces a variety of adverse effects, including drowsiness, lethargy, and fatigue. Although more serious adverse effects, such as optic neuritis, peripheral neuropathy, and hepatotoxicity occur rarely, patients should be monitored regularly for visual changes and neurologic symptoms and the medication discontinued if these appear. Further, liver enzymes should be monitored monthly during the first 3 months of treatment and quarterly thereafter to identify hepatotoxic effects. Psychiatric effects, such as psychosis or depression, are uncommon and probably occur only at higher dosages of the drug. These effects are mediated by disulfiram’s inhibitory effect on enzymes involved in the metabolism of dopamine.
Due to the correlation between adverse effects and dosage, the daily dosage prescribed in the United States has been limited to 250 to 500 mg/day. However, efforts to titrate the dosage of disulfiram in relation to a challenge dose of ethanol have shown that some patients require in excess of 1 g/day of disulfiram to reach blood levels sufficient to produce a DER.
In deciding whether disulfiram should be used to treat alcohol use disorder, patients should be made aware of the hazards of the medication, including the need to avoid OTC preparations with alcohol and drugs that can interact with disulfiram and the potential for a DER to be precipitated by alcohol used in food preparation. Disulfiram is contraindicated in patients who do not have a goal of abstinence from alcohol and those who have not attained at least 48 hours of abstinence prior to the first administration of the drug. Given its potential to produce serious adverse effects when combined with alcohol, disulfiram cannot be recommended for use as part of a moderation approach to alcohol.
MEDICATIONS THAT DIRECTLY REDUCE ALCOHOL CONSUMPTION
Several neurotransmitter systems appear to influence the reinforcing or discriminative stimulus effects of ethanol: endogenous opioids; catecholamines, especially dopamine; serotonin (5-HT); and excitatory amino acids such as glutamate. Although these systems function interactively to influence drinking behavior, many of the medications used to treat alcohol use disorder affect neurotransmitter systems relatively selectively.
Naltrexone and, to a lesser extent, nalmefene, both of which are opioid antagonists with no intrinsic agonist properties, have been studied for the treatment of alcohol use disorder. Naltrexone was approved by the FDA for the treatment of opioid dependence in 1984 and for alcohol use disorder in 1994. Nalmefene is approved in the United States as a parenteral formulation for the acute reversal of opioid effects (e.g., after opioid overdose or analgesia).
The approval by the FDA of naltrexone for alcohol use disorder was based on the results of two single-site studies, which showed it to be efficacious in the prevention of relapse to heavy drinking. In a 12-week trial in a sample of alcohol-dependent veterans, naltrexone was found to be well tolerated and to result in significantly less craving for alcohol and fewer drinking days than placebo. Among those who drank, naltrexone also limited the progression from initial sampling of alcohol to a relapse to heavy drinking, presumably because of their experiencing less euphoric effects of alcohol, suggesting that naltrexone blocked the endogenous opioid system’s contribution to alcohol’s “priming effect.” Another study showed the medication to be well tolerated and superior to placebo in increasing the rate of abstinence and reducing the number of drinking days and relapse events and the severity of alcohol-related problems. For patients who drank, those who received naltrexone and coping skills therapy were least likely to relapse to heavy drinking.
Naltrexone was shown to reduce craving for alcohol, alcohol’s reinforcing properties, the experience of intoxication, and the chances of continued drinking following a slip. The literature on naltrexone treatment of alcohol use disorder shows a clear advantage for naltrexone over placebo on a number of drinking outcomes, including relapse rates, time to relapse, percentage of drinking days, number of drinks per drinking days, and total consumption of alcohol during treatment. Naltrexone has also been shown to reduce the likelihood of heavy drinking, suggesting that it may be useful in patients who want to reduce their drinking to safe levels.
Since naltrexone only targets certain aspects of alcohol use disorder (i.e., reduced alcohol reinforcement or cue-induced craving), there has been an interest in combining it with medications that might influence other signs/symptoms of alcoholism. Symptoms often seen after alcohol cessation are difficulty sleeping, anxiety, irritability, decreased concentration, and depressed mood. This constellation of symptoms has been called protracted withdrawal. If not addressed, these symptoms are thought to lead to relapse of alcohol use. The anticonvulsant gabapentin may help reduce these symptoms. As such, naltrexone has been evaluated in combination with gabapentin to determine if the combination was superior to naltrexone and/or placebo in decreasing alcohol use. When gabapentin was combined with naltrexone, the combination group had a longer interval to heavy drinking than did the naltrexone-alone group, had fewer heavy drinking days than did the naltrexone and placebo groups, and had fewer drinks per drinking day than did the naltrexone and placebo groups. There was also some suggestion that the combination may work best in individuals who had previously experienced alcohol withdrawal.
Poor compliance with oral naltrexone has been shown to reduce the potential benefits of the medication. This has generated interest in the development and evaluation of long-acting injectable formulations of the medication, with the rationale that monthly administration would improve medication adherence and that parenteral administration would increase bioavailability by avoiding first-pass metabolism. Based on multiple studies that showed reduced rates of heavy drinking, greater likelihood of total abstinence, greater median time to a first drinking day, greater median time to a first heavy drinking day, lower median number of drinking days per month, and lower median heavy drinking days per month, the FDA approved long-acting naltrexone for monthly administration at a dosage of 380 mg/day.
The clinical use of naltrexone is relatively straightforward, despite the presence of a “boxed” warning on the label concerning hepatotoxicity. The medication should be prescribed at the time that psychosocial treatment is initiated. Because of adverse effects that could compound the adverse effects of alcohol withdrawal, the initiation of naltrexone therapy is probably best delayed until after the acute withdrawal period. Initial testing for liver enzyme abnormalities is warranted to avoid prescribing in the context of extreme elevations. Ongoing monitoring is required only if symptoms warrant it because the consistent effect of naltrexone in studies of alcohol use disorder has been to decrease liver enzyme concentrations. Oral naltrexone should be initially dosed at 25 mg/day to minimize adverse effects. The dosage can then be increased in 25-mg increments every 3 to 7 days to a maximum dosage of 150 mg/day using desire to drink or other symptoms that the patient identifies as reflective of risk of relapse to heavy drinking. It should be noted, however, that there is no clear evidence that a higher dosage is more efficacious than is the FDA-approved dosage of 50 mg/day. Nausea and other GI symptoms are most common early in treatment, as are neuropsychiatric symptoms (e.g., headache, dizziness, lightheadedness, weakness) and are usually transient. Delaying or avoiding a dosage increase can be used to address more persistent adverse events. In some patients, flulike symptoms occur, and the patient may not be willing to consider options other than discontinuation.
Long-acting naltrexone is only available as a 380-mg dose, which is administered as a deep IM injection in the upper, outer quadrant of the gluteal muscle of the buttock every 4 weeks. The medication is approved for use in patients who are abstinent from alcohol and who are also receiving psychosocial treatment. The precise length of the period of abstinence is not specified, and there is no evidence of any risk of consuming alcohol with naltrexone. Adverse effects with this formulation are similar to those of the oral medication, though pain and inflammation at the injection site may also occur. Local interventions, such as warm compresses, and NSAIDs can be used to treat such injection site reactions.
Nalmefene has also been evaluated as a treatment for alcohol use disorder. Nalmefene is an opioid antagonist without agonist properties. Its affinity for the μ- and κ-opioid receptors is similar to that of naltrexone, though its affinity for the δ-opioid receptor is greater than that of naltrexone. Like naltrexone, nalmefene has been shown to be useful in the prevention of relapse to heavy drinking in alcohol-dependent patients, to reduce the number of self-reported heavy drinking days, to reduce the number of drinks per drinking day, and to increase the number of abstinent days.
Acamprosate is an amino acid derivative that increases gamma-aminobutyric acid (GABA) neurotransmission and also has complex effects on excitatory amino acid neurotransmission, which is most likely the important therapeutic effect. It was first shown in a single-site study to be twice as effective as placebo in reducing relapse rates. Additionally, among patients who relapsed to drinking, acamprosate treatment was associated with less quantity and frequency of drinking than placebo, and it has been shown to reduce the risk of heavy drinking (i.e., 5 or more drinks per day).
Acamprosate is FDA approved at a dosage of 1,998 mg/day (i.e., two 333-mg capsules three times per day) in patient who are abstinent from alcohol and receiving psychosocial treatment. The most common adverse effects of the drug are generally mild and transient and may include gastrointestinal (e.g., diarrhea, bloating) and dermatologic (e.g., pruritus) complaints. In contrast to disulfiram and naltrexone, which are metabolized in the liver, acamprosate is excreted unmetabolized so that renal function is the rate-limiting factor in the drug’s elimination. Renal function testing is warranted prior to initiation of the drug, particularly in individuals who have a history or are otherwise at risk of renal disease.
The efficacy of anticonvulsants for the treatment of alcohol use disorder was initially demonstrated in placebo-controlled studies of carbamazepine, divalproex, and topiramate. Although these medications have different mechanisms of action, it is likely that these exert beneficial effects through their actions as glutamate antagonists and GABA agonists, helping to normalize the abnormal activity in these neurotransmitter systems seen following chronic heavy drinking. Carbamazepine has been found to be superior to be placebo in increasing the time to the first heavy drinking day and in reducing drinks/drinking day and the number of consecutive heavy drinking days. Divalproex has been shown to reduce the risk of relapse to heavy drinking and to decrease irritability. Topiramate has been shown to significantly reduce drinks per day, drinks per drinking day, drinking days, heavy drinking days, and γ-glutamyl transpeptidase levels. The most common adverse effect of topiramate is numbness and tingling, with other common side effects including a change in the sense of taste, tiredness/sleepiness, fatigue, dizziness, loss of appetite, nausea, diarrhea, weight decrease, and difficulty concentrating, with memory, and in word finding. Of clinical concern also are suicidal thoughts or actions, which have been reported uncommonly but at a frequency greater than that seen with placebo.
Baclofen, a GABA B receptor agonist, has been approved as an antispasmodic for more than 30 years and has recently been studied as a treatment for alcohol use disorder, although it is not FDA approved for such treatment. Patients treated with baclofen have been shown to be more likely to remain abstinent over a 1-month treatment period, as well as showing a greater number of cumulative abstinence days. There is, however, evidence of misuse, overdose, and other complications (e.g., withdrawal reactions, including delirium) associated with baclofen, which underscores the need for more research on this medication before it can be recommended as a safe and efficacious treatment for alcohol use disorder.
Studies of the effects of serotonin reuptake inhibitors on drinking behavior have been conducted in diverse subject samples. A recent meta-analysis concluded that there was, overall, no benefit to the use of any antidepressant in patients with alcohol use disorder without comorbid depression. Prospective studies are needed to evaluate whether there is a clearer role for the serotonergic medications in the treatment of heavy drinking or alcohol use disorder in individuals differentiated by alcohol use disorder subtype (i.e., early vs. late onset).
MEDICATIONS TO TREAT CO-OCCURRING PSYCHIATRIC SYMPTOMS OR DISORDERS IN PATIENTS WITH ALCOHOL USE DISORDER
Although most patients with alcohol use disorders report a reduction in mood or anxiety symptoms following acute withdrawal, for some, these symptoms may persist for months. Even among patients without substantial symptoms of alcohol withdrawal, low-level mood or anxiety symptoms may develop, a condition that has been called “subacute withdrawal.” In a substantial minority of these patients, these symptoms may reflect a diagnosable psychiatric disorder. Although medications are often prescribed during the postwithdrawal period in hopes of relieving these symptoms, there is no good evidence that the treatment of persistent or subacute withdrawal symptoms that do not meet diagnostic criteria for a co-occurring psychiatric disorder results in better outcomes in patients with alcohol use disorder.
Many of the early studies of the efficacy of medications to treat mood disturbances targeted symptoms of depression and anxiety in unselected groups of patients with alcohol use disorder after withdrawal. These and other methodologic limitations make the failure to demonstrate an advantage over control conditions through reductions in either psychiatric symptoms or drinking behavior difficult to interpret. Community studies have shown high rates of co-occurrence of psychiatric disorders in individuals with alcohol use disorder, most commonly mood disorders, drug dependence, antisocial personality disorder, and anxiety disorder. Antidepressants, benzodiazepines and other anxiolytics, antipsychotics, and lithium have been used to treat anxiety and depression in the postwithdrawal state.
In patients with unipolar depression and alcohol use disorder, several studies have shown a significant or near-significant advantage for antidepressants over placebo in reducing symptoms of depression. However, most episodes of postwithdrawal depression will remit without specific treatment if abstinence from alcohol is maintained for a period of days or weeks. If depression persists after this period, treatment is warranted. SSRIs and newer-generation antidepressants have become the first-line treatment of depression because these have a favorable side effect profile. However, SSRIs may exacerbate the tremor, anxiety, and insomnia often experienced by recently detoxified alcohol-dependent patients and may slightly increase the risk of GI bleeding (particularly in combination with NSAIDs or aspirin).
Bipolar disorder co-occurs commonly with alcohol use disorder. The presence of comorbid alcohol use disorder is associated with an increased rate of mixed or dysphoric mania and rapid cycling, as well as greater bipolar symptom severity, suicidality, and aggressivity. However, controlled trials of medication to treat these comorbid disorders are difficult to conduct. A placebo-controlled trial of divalproex sodium in bipolar patients with DSM-IV alcohol dependence taking lithium showed that the drug significantly decreased the proportion of heavy drinking days, and manic and depressive symptoms improved equally in both groups.
Despite the risks that the use of benzodiazepines may create in patients with alcohol use disorder beyond the period of acute withdrawal, judicious use of the drugs in this setting may be justified. Early relapse, which commonly disrupts alcohol rehabilitation, can result from protracted withdrawal-related symptoms such as anxiety, depression, and insomnia. To the extent that these symptoms can be suppressed by low doses of benzodiazepines, retention in treatment could be increased. Moreover, for some patients, benzodiazepine dependence, if it does occur, may be more benign than alcohol use disorder.
Buspirone, a nonbenzodiazepine anxiolytic, exerts its effects largely via its partial agonist activity at serotonergic autoreceptors. Although comparable to diazepam in the relief of anxiety and associated depression in outpatients with moderate-to-severe anxiety, buspirone is less sedating than is diazepam, does not interact with alcohol to impair psychomotor skills, and does not have abuse liability. This pharmacologic profile makes buspirone more suitable than benzodiazepines to treat anxiety symptoms among alcohol-dependent patients.
KEY POINTS
1. Disulfiram is the only alcohol-sensitizing medication approved in the United States for the treatment of alcohol use disorder. It works by inhibiting the enzyme aldehyde dehydrogenase, and its ingestion elevates blood acetaldehyde concentration, resulting in the DER.
2. Naltrexone and nalmefene are opioidergic medications that have both been shown to directly reduce alcohol consumption. Only naltrexone is approved for use in the United States for alcohol use disorder.
3. Acamprosate is an amino acid derivative that increases GABA neurotransmission and also has complex effects on glutamate neurotransmission, which is most likely responsible for its therapeutic effect. Acamprosate treatment has been shown to reduce relapse rates and is associated with less quantity and frequency of drinking, as well a reduction in heavy drinking.
4. Anticonvulsants such as topiramate and carbamazepine, as well as the antispasmodic baclofen, may be of limited use in patients with alcohol use disorder. However, none of these medications are FDA approved for this use, and further research is needed into the utility of these medications.
5. Although medications are often prescribed during the postwithdrawal period in hopes of relieving mood and anxiety symptoms, there is a lack of evidence that the treatment of persistent or subacute withdrawal symptoms that do not meet diagnostic criteria for a co-occurring psychiatric disorder results in better outcomes in patients with alcohol use disorder.
REVIEW QUESTIONS
1. Disulfiram works by inhibiting the enzyme ________, which leads to elevated serum levels of acetaldehyde and initiation of the disulfiram–ethanol reaction.
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