Alcohol is similar to other general anesthetics in that it depresses the central nervous system (CNS). Clinically, however, it may appear to be a stimulant because it first suppresses inhibitory control mechanisms, resulting in early disinhibition. In general, the effect of alcohol on the CNS is proportionate to its blood concentration, but the effects are more marked when the concentration is increasing.

In the alert intoxicated patient, general management is primarily supportive and protective. Thiamine (100 mg intramuscularly) is given initially and repeated three times a day orally for the next several weeks. A multivitamin preparation should also be given orally each day. If the patient is restless, a short-acting benzodiazepine (BZD) such as lorazepam (1 to 2 mg intravenously, intramuscularly, or orally) may be given and repeated as often as needed. If the patient is violent or severely agitated, an antipsychotic may be necessary with low-dose, highpotency agents, such as haloperidol (HPDL; 2 to 5 mg intramuscularly or intravenously as needed). If larger doses are necessary, the clinician should reconsider the diagnosis.

This syndrome has similarities to the paradoxical reaction seen with barbiturates or BZDs, as well as epileptoid syndromes, including temporal lobe seizures and intermittent explosive disorder. Brain injury from trauma or encephalitis may also predispose some to an abnormally excessive response to even small amounts of alcohol.

Clinical signs and symptoms include sudden onset of irrational, combative, or destructive behavior after ingesting relatively small amounts of alcohol. The behavior is atypical of the individual when not drinking, and it usually begins within minutes to hours. After the acute outburst, the patient usually lapses into deep sleep and upon awakening, has only fragmentary memory or total amnesia for the episode. Treatment should attempt to diminish stimulation as much as possible, and antipsychotics, such as HPDL (2 to 5 mg orally or intramuscularly), may reduce combative or destructive behavior.

Alcohol withdrawal or abstinence syndrome may emerge after a period of relative or absolute abstinence, with the cause unknown. The duration of drinking and quantity of alcohol required to produce noticeable symptoms vary widely. Abstinence may also result from intercurrent illness, hospitalization for an unrelated illness, or lack of money to buy alcohol. The full spectrum of this syndrome, which ranges from an early, mild withdrawal picture to delirium, is commonly seen in large urban hospital emergency rooms.

Early withdrawal peaks at about 24 hours and rarely can emerge several days after cessation.
Symptoms can clear in a few hours or last up to 2 weeks and include

Treatment. The treatment of alcohol withdrawal incorporates general supportive, nonjudgmental, but assertive measures, as well as management of specific symptoms (30). Supportive measures include abstinence from alcohol, ample rest, adequate general nutrition, and reality orientation. It is important to treat the syndrome vigorously and, when appropriate, to prevent it by using sufficient doses of medication.

One meta-analysis of 11 trials found that over 48 hours, BZDs reduced withdrawal symptoms to a significantly greater degree than placebo (31). Typically, these agents are used on an as-needed basis to treat objective signs of withdrawal, such as tremor, tachycardia, or hypertension. The longer-acting BZDs, such as chlordiazepoxide and diazepam, have the advantage of less frequent dosing but the risk of drug accumulation. The intermediate-acting agents, such as lorazepam, are less likely to accumulate but need to be administered more frequently to prevent reemergence of signs and symptoms. One approach might be lorazepam, 2 mg orally every 2 hours as needed, for as long as needed. The acute dose is then tapered over a 1- to 2-week period, using a two- or three-times-daily regimen. Total daily doses of more than 10 to 12 mg are rarely required. A fixed-dose regimen may not work because of the variability in duration and severity of symptoms. In the severely agitated patient, lorazepam (intramuscularly 2 mg/hr) or diazepam (intravenously 5 to 10 mg slowly) may be necessary

Treatment of withdrawal seizures depends on whether there is a prior history. For example, in one study of patients who had experienced a withdrawal seizure, lorazepam (2 mg intravenous) was significantly more effective than normal saline placebo in reducing the risk of a recurrent seizure (32). If there is no history, prophylactic anticonvulsants will probably not help. Furthermore, BZDs used for sedation also have anticonvulsant properties, so adequate doses should minimize the risk of seizures. However, anticonvulsants such as carbamazepine (CBZ) and valproate (VPA) demonstrated benefit for alcohol withdrawal symptoms in controlled trials (33,34). One controlled pilot study also found CBZ to benefit alcohol dependence (35).

In addition, patients with a more complicated history of withdrawal or other seizure disorders are at greater risk and should receive an anticonvulsant. If the patient is currently receiving a maintenance dose, it should be continued. If the patient is not receiving medication or if it was discontinued 5 or more days previously, a loading dose of phenytoin (15 mg/kg intravenously in saline) could be given at a rate not to exceed 50 mg/min. Maintenance doses are started 24 hours later. Some withdrawal seizures can be prevented by restoring serum magnesium levels with magnesium sulfate (2 mL of a 50% solution, up to three doses), given with intravenous fluids over 8 hours.

Occasionally, antipsychotics such as HPDL (2 to 10 mg intramuscularly or orally) may be needed. Antipsychotics that lower the seizure threshold, cause extrapyramidal symptoms (EPSs) or hypotension should be avoided.

In treating delirium

Alternative adjunctive strategies with some evidence for efficacy include

Ninety-five percent of alcohol is metabolized in the liver; the remaining 5% is excreted via the kidneys and the lungs (see also Chapter 2). The rate of metabolism increases with fasting and after protracted periods of drinking. Although alcohol has a direct toxic effect on the liver, significant hepatic damage develops in only 10% to 20% of long-term heavy drinkers. In this context, BZDs must be used cautiously because they are primarily metabolized by this organ. If there is evidence of disease, oxazepam and lorazepam are preferred because they are not metabolized by the liver. When oral drugs cannot be used, lorazepam (2 to 8 mg intramuscularly daily) is preferred.

As discussed in Chapter 2, the phases of alcohol consumption can have varying effects on the metabolism of concomitantly administered psychotropics. Thus, acute alcohol ingestion generally interferes with the metabolism of drugs, increasing plasma concentration. Ingestion over several weeks stimulates hepatic enzymes, accelerating the metabolism of many drugs. Finally, cirrhosis induced by long-term alcohol consumption diminishes enzyme concentration and liver mass, again increasing plasma levels of concurrently administered drugs metabolized by this system. Fluid and electrolyte therapy must take into account the development of ascites and the possibility of right-sided heart failure. Salt restriction (i.e., 500 mg/day) and bed rest are the initial conservative treatments, with medical consultation usually required (9).

Because heavy cigarette smoking is typically associated with alcohol dependence and may lead to impaired pulmonary function, BZDs are used more cautiously to reduce the risk of oversedation and respiratory depression. Hypoxia can cause agitation and is exacerbated by treatment with sedative drugs. Again, shorter half-life agents and those with fewer active metabolites are preferred (e.g., oxazepam or lorazepam). Alcoholic patients also have an increased risk of aspiration of gastric contents or infected oropharyngeal material, with resulting aspiration pneumonia.

Erosive gastritis caused by recent excessive ingestion of alcohol is the most common cause of gastrointestinal bleeding in alcoholics. Bleeding usually subsides with cessation of drinking and administration of antacids. If the patient has cirrhosis, bleeding from esophageal varices should be considered.

Disulfiram (Antabuse) is an aversive drug that can be prescribed in conjunction with other forms of therapy such as Alcoholics Anonymous (AA) and individual counseling. Although controlled trials have not consistently demonstrated benefit with this agent in comparison with placebo, many clinicians believe it has a psychological effect that may attenuate impulsive drinking in selected patients (46,47).

This agent works by blocking the conversion of acetaldehyde to acetate by aldehyde dehydrogenase. This strategy is recommended only for those with good compliance and no serious physical condition (e.g., cardiovascular disease). A patient who drinks alcohol while taking this agent may experience facial flushing, sweating, headaches, nausea, vomiting, chest pain, dyspnea, weakness, dizziness, blurred vision, and confusion within minutes. Respiratory depression, shock, arrhythmias, seizures, and death are rare. Therefore, before disulfiram is prescribed, patients must be informed about these adverse effects and about the possibility of a serious disulfiram-ethanol reaction. Also, patients must be aware that many foods and aftershave lotion contain alcohol, as well as some over-thecounter (OTC) mouthwashes and cough syrups. Written informed consent should be obtained. Disulfiram may also interfere with the action of other commonly coprescribed drugs such as anticoagulants, phenytoin, and isoniazid. After 6 to 12 months, disulfiram may be stopped if a patient has been able to remain sober; however, some patients may require the drug indefinitely to ensure sobriety. The usual loading dose is 250 to 500 mg/day for 3 to 5 days, although adverse effects may require a lower dose. Most patients are adequately maintained on 125 to 200 mg/day.

Although disulfiram is sometimes helpful as an adjunct to nonpharmacological treatments for alcoholism, it has the potential to worsen psychosis. Kofoed (48) notes, however, that these findings are based on untreated chronically affected patients given high doses. He and his colleagues used disulfiram with a small number of dually diagnosed psychotic and alcohol-dependent patients after they were stabilized on appropriate antipsychotic medications. They found that compliance with disulfiram therapy in their dualdiagnosis group was as good as in primary alcoholic outpatients. They also reported no particular problems, concluding that disulfiram seemed less of a risk than continued alcohol misuse (49).

Several studies indicate that the opioid system is involved in the regulation of alcohol intake in various animals. Naltrexone, an opiate antagonist, can reduce alcohol consumption in alcoholcraving animals (50). In this context, a within-subject, double-blind, placebo-controlled clinical trial implicated the A1186 SNP of the OPRMI gene as a moderator of naltrexone’s ability to blunt the alcohol-induced high (51). Further, the OPRMI Asp 40 allele may predict response to naltrexone in alcoholic patients (52).

Two well-controlled studies using naltrexone in humans produced dramatically effective results (53,54). The results of these trials led to US Food and Drug Administration (FDA) approval of this agent (under the trade name Revia) as an adjunct to a comprehensive treatment plan (55). A placebo-controlled trial also found that the combination of naltrexone plus cognitive behavioral therapy (CBT) decreased relapse rates or increased time between relapses (56). Not all trials have been positive, however. For example, subsequent to FDA approval, a 12-month, multicenter, placebo-controlled trial in 627 male veterans with chronic, severe alcohol dependence did not demonstrate a benefit for naltrexone over placebo (57).

Given the problem with adherence to the oral formulations in this population, a 6-month, randomized, placebo-controlled trial assessed the benefit of long-acting injectable naltrexone (380 mg, n = 205; 190 mg, n = 210) in comparison with placebo (n = 209) (58). Monthly intramuscular injections of active drug combined with 12 low-intensity psychosocial intervention sessions were superior to placebo in terms of number of heavy drinking days (380 mg, 25% decrease, p = 0.03; 190 mg, 17% decrease, p = 0.07). Further, a post hoc analysis indicated a rapid rate onset of therapeutic effect in the first 2 days (59). There is also evidence that in early problem drinkers, naltrexone dosing targeted to high-risk situations may be an alternate strategy to daily oral dosing (60).

Typical starting doses are 25 to 50 mg/day orally. A large multicenter usage study reported that in 570 patients on naltrexone, the most common adverse effects were nausea (9.8%) and headache (6.6%), with 15% of patients dropping out because of nausea (61). Although no deaths occurred, a single case report has raised the question of a possible association between naltrexone and rhabdomyolysis (62).

One double-blind, placebo-controlled trial with another opioid antagonist, nalmefene (20 or 80 mg/day), found that this agent had a significant benefit over placebo in preventing relapse to heavy drinking (63). A second controlled trial, however, did not demonstrate superiority over placebo (64).

The possible benefits of opiate antagonists in treating symptoms of schizophrenia or bipolar disorder without alcohol dependence or comorbid alcohol and cocaine dependence may warrant studies in these difficult-to-treat populations (65,66,67 and 68). Furthermore, some data support a synergistic therapeutic effect when naltrexone is combined with CBT (69).

In summary, naltrexone and perhaps other opioid antagonists are promising agents in the pharmacotherapy of alcohol dependence with or without coexisting psychiatric and addictive disorders (63). However, the duration and severity of illness, adequacy of support systems, and patient adherence may be important modifiers of efficacy.

Acamprosate (calcium acetylhomotaurine) has a chemical structure similar to the endogenous amino acid homotaurine and GABA. It appears to normalize N-methyl-D-aspartate (NMDA) receptor tone in the glutamate system, possibly restoring GABA/glutamate balance. It is a recipient of FDA approval for maintenance of abstinence in alcohol dependence.

Results from animal studies indicating a decrease in voluntary alcohol intake led to a number of double-blind, placebo-controlled trials involving more than 4,500 patients with alcohol dependence (70). In a review of these data, Mason and Ownby (70) found that 13 of 16 studies demonstrated a significant benefit from acamprosate versus placebo in terms of

One randomized trial in 160 subjects indicated that the combination of acamprosate plus naltrexone was superior to placebo (p = 0.008) and acamprosate monotherapy (p = 0.04) but not to naltrexone monotherapy. Subjects also received group psychotherapy (71).

The Combining Medications and Behavioral Interventions (COMBINE) Study is an NIAAAsponsored controlled trial of pharmacotherapy for alcoholism (43). In the largest trial of its kind to date (n = 1,383), patients were randomized to a variety of medication treatment groups or behavioral counseling only for 16 weeks with up to 16 months of follow-up (72). Those who received naltrexone with medical follow-up were the least likely to relapse to a heavy drinking day. In contrast to earlier results, however, there appeared to be no advantage in adding acamprosate. Differences in patient populations and the higher dropout rates in this trial are possible explanations for the different outcome from previous studies.

Dose-response data indicate that 2 g daily (666 mg three times a day) is optimal. Of note, this agent is not metabolized by the liver but is excreted via the kidneys. In addition, it demonstrates an excellent safety profile, with loose stools or diarrhea being the only adverse effects reported more often than with placebo. Acamprosate does not inhibit or induce cytochrome P450 (CYP) isoenzymes. Other data indicate that this agent can be safely administered concurrently with disulfiram or naltrexone.

Ondansetron is a 5-HT₃ antagonist approved by the FDA as an antiemetic. Controlled trials with this agent as monotherapy or in combination with naltrexone indicate a potential role for alcohol dependence (73,74 and 75).

When considering the role of antidepressants in the treatment of alcohol dependence, ample evidence shows that alcoholism and depression are often associated, but they may also present as distinct entities (76). In this context, Schuckit et al. (77) addressed the issue of induced versus independent major depressive disorder (MDD) in 2,945 alcoholics. These authors concluded that it was possible to distinguish between substance-induced and -independent episodes. Symptoms often overlap, however, at times making proper diagnosis difficult.

Clinical studies of depressed alcoholics give some suggestions of the course of treatments. Brown et al. (78) demonstrated that those male patients in their sample with dual diagnoses of alcohol dependence and a mood disorder did not demonstrate more severe depressive symptoms or a slower recovery than their counterparts with either diagnosis alone. Evidence from another study shows that depression in schizophrenic alcoholics on acute inpatient admission resolves within the same time frame as does depression in nondually diagnosed alcoholics (79). If supported and broadened by further investigation, this finding would simplify treatment strategies by including patients with a dual diagnosis in mainstream addiction programs.

Tricyclic Antidepressants. The role of tricyclic antidepressants (TCAs) for depressed alcoholics has usually been limited to the period of acute withdrawal and not for longer-term maintenance. Methodological problems with studies in this area include (80)

Despite these design flaws, many of the studies support the beneficial effects of TCAs in the treatment of depression associated with alcohol withdrawal. These benefits, however, do not exceed those of placebo after 3 weeks and thus may have only limited application in clinical practice.

Of the available antidepressants, imipramine is the most extensively studied. A trial assessing the effectiveness of this agent for alcoholism with comorbid depression had certain advantages over its predecessors, including (81)

Although criteria for response are incomplete, the investigators reported that of 60 alcoholics who had major depression and who completed an initial 12-week open-label trial of imipramine, 27 (45%) responded, showing improvement in both mood (posttreatment Hamilton Depression Rating Scale [HDRS] score, 3; SD±3) and drinking behavior (30% achieving abstinence and another 15% a “much reduced level”). These response rates were further enhanced after dose increases or treatment with disulfiram. Patients who improved with imipramine in the initial open trial were then randomized into a subsequent 6-month, double-blind maintenance phase. During this phase, 7 of 10 (70%) suffered a relapse on placebo, in contrast to only 4 of 13 (31%) on imipramine. Although the sample sizes were small, the investigators believed that this represented a significant improvement for those on medication in a common dual-diagnosis scenario.

Selective Serotonin Reuptake Inhibitors. New possibilities emerged with the introduction of the selective serotonin reuptake inhibitors (SSRIs). Basic studies using these agents in animals demonstrated a decrease in alcohol preference and consumption, whereas nonspecific monoamine uptake blockers (e.g., amitriptyline, doxepin) did not (82). Using animal models of spontaneous alcohol consumption, Gorelick (82) reported evidence that increased brain serotonin activity tended to decrease alcohol preference and consumption. Extrapolating these results from the laboratory to the clinical arena, Gorelick and
Paredes (83) then studied the effect of fluoxetine (up to 80 mg/day) on alcohol consumption in 20 men with chronic dependence. After a 28-day, double-blind, placebo-controlled period, these investigators found that the fluoxetine group had a 14% lower alcohol intake, primarily during the first week. The beneficial effect was associated with a lower proportion of requests as well as less craving for alcohol. As in the imipramine outcomes, however, these investigators did not find a significant effect in later weeks (i.e., virtually no differences in scores on the Hamilton Depression and Anxiety Scales or the abridged Hopkins Symptom Checklist). A second 12-week, placebocontrolled trial of fluoxetine (up to 60 mg/day) did not find this SSRI different from placebo (84). A subsequent 14-week, placebo-controlled trial in 100 patients with alcohol dependence found that sertraline (maximum dose, 200 mg/day) was superior to placebo but only in type A alcoholics (i.e., 53.3% on sertraline abstained vs. 16.0% on placebo; p < 0.04) (85).

Although the mechanism of action of SSRIs in treating alcohol dependence remains unclear, Gorelick and Paredes (83) postulate that it is not due to motor inhibition or general sedation. Rather, they believe that it may be “related to decreased appetite and food intake or a conditioned taste aversion mediated by increased brain serotonin activity.” Other competing theories summarized by Thomas (86) include

Garbutt et al. (46) reviewed the existing evidence for the usefulness of SSRIs in the management of alcoholic patients with and without significant depression or anxiety. The studies varied in design and outcome, but overall, these investigators believed the data were limited and not promising (87,88,89,90 and 91). The results of some trials, however, may be confounded by high rates of comorbid mood and anxiety symptoms.

Lithium, however, has not fulfilled its initial promise for the treatment of primary alcoholism with and without a concurrent affective disorder. Dorus et al. (92) studied 457 male alcoholics in a Veterans Administration collaborative study and found that lithium did not alter the use of alcohol in either depressed or nondepressed alcoholics. Specifically, they reported abstinence in 38% of lithium-treated nondepressed alcoholics (compared with 28% of placebocontrolled subjects) and 32% of lithium-treated depressed alcoholics (compared with 37% of their placebo-controlled subjects). Fawcett et al. (93) reported beneficial effects of lithium in 104 alcoholics studied in a double-blind, placebocontrolled design. They found, however, that 19 of 51 patients (37%) given lithium and 22 of 53 patients (42%) given placebo were abstinent at the 6-month follow-up, with the numbers even more similar at 12-month follow-up.

Although lithium no longer appears promising to treat alcohol dependence itself, it may have a place in pharmacotherapy of the overall syndrome. A small pilot study (n = 12) by Nagel et al. (94) assessed lithium in a double-blind, placebo-controlled design focusing on recently (3 to 7 days before entry into study) detoxified alcoholics who manifested a syndrome resembling hypomania. Symptoms consisted of elevated psychomotor activity, grandiosity, irritability, a heightened desire for social contact, loquaciousness, and sexual preoccupation. The severity of symptoms was significantly decreased by treatment with low-dose lithium carbonate (serum levels 0.3 to 0.5 mEq/L) but was not affected by placebo treatment.

As noted earlier, anticonvulsants such as VPA and CBZ may be useful in withdrawal states from alcohol and for relapse prevention (32,95,96,97 and 98). Topiramate appears to indirectly decrease mesocortical dopamine by facilitating GABAergic activity on a non-BZD receptor and by antagonizing amino-5-methyl-3-hydroxy-4-isoxazolepropionic acid and kainate glutamatergic receptors (99). Two placebo-controlled trials demonstrated benefit with topiramate for alcohol dependence (100,101).