Manual of Psychiatric Therapeutics: Practical Psychopharmacology and Psychiatry (Little, Browns Paperback Book Series)

Editors: Shader, Richard I.

Title: Manual of Psychiatric Therapeutics, 3rd Edition

Copyright 2003 Lippincott Williams & Wilkins

> Table of Contents > 11 - Alcoholism and Its Treatment

11

Alcoholism and Its Treatment

Domenic A. Ciraulo

Richard I. Shader

Ann Marie Ciraulo

Alcoholism remains a major public health problem in the United States. An estimated 14 million Americans meet the diagnostic criteria for alcohol abuse or alcoholism, resulting in economic costs of over 184 billion dollars annually according to the Tenth Special Report to the United States Congress on Alcohol and Health (2000). Using a sampling of adults from five metropolitan areas, the Epidemiologic Catchment Area survey estimated that the lifetime prevalence of alcohol-related disorders is 13.5%, with consistently higher rates for men than for women (for lifetime, 1-year, and 1-month prevalence). Somewhat higher rates were found in the National Comorbidity Survey, which sampled a relatively younger population and found a lifetime prevalence of alcohol dependence of 20.1% for men and 8.2% for women. The Joint Committee of the National Council on Alcoholism and Drug Dependence and the American Society of Addiction Medicine defines alcoholism as a primary, chronic, often progressive and fatal disease having genetic, psychosocial, and environmental factors that influence its development and manifestations. Impaired control over drinking; preoccupation with alcohol; use of alcohol despite adverse consequences; or cognitive distortions, such as denial, may be continuous or periodic. Although per capita alcohol consumption in the United States has declined somewhat since 1981, alcohol is the most abused substance in this country, and the lifetime risk for alcohol abuse is between 13% and 20%, with men at greater risk than women. For perspective, one should remember that alcohol, at the brain concentrations experienced during intoxication, has both specific and nonspecific effects on many cellular processes, including both excitatory and inhibitory transmission. The alcohol withdrawal (or abstinence) syndrome (see Chapter 12) is a state of overactivity of the central nervous system that is marked by increased firing of sympathetic neurons; enhanced production of norepinephrine and cortisol; and increased activity of excitatory amino acids, such as glutamate.

This chapter presents an overall treatment approach to the patient who misuses or abuses or who is dependent on alcohol. In Chapter 12, the recognition and treatment of the alcohol withdrawal syndrome and its complications are reviewed. The approach taken throughout this chapter is based on the view that alcoholism is a multidetermined social and medical phenomenon requiring careful diagnosis and evaluation, as well as individualized treatment. The primary clinician must be familiar with, and open to, a variety of applicable techniques, ranging from individual and group psychotherapy to Alcoholics Anonymous (AA), family therapy, pharmacotherapy, or behavioral treatments, and he or she must be prepared to use consultants in these fields when this becomes necessary. Although the first goal is to have the patient stop drinking, understanding a patient's feelings, conflicts, relationships, experiences, relevant family interactions, expectations, and history is essential in planning a treatment program. Secondary diagnosis (e.g., anxiety, familial tremor, depression, schizophrenia) is necessary to determine whether and when pharmacologic intervention is appropriate.

I. Diagnosis

Table 11.1 lists the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV), criteria for the diagnosis of alcohol dependence. From a clinical standpoint, an affirmative answer to the question, Did you ever think or did anyone ever tell you that you had a problem with alcohol? is usually enough to make a presumptive diagnosis of alcohol abuse or dependence. Finding out how many drinks a person must have to feel high and whether this amount has changed can also be helpful as an indication of tolerance development, in which increasing amounts of alcohol are needed to produce the desired effect. More detailed questioning should focus on social disruptions (e.g., problems

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Another useful screening tool is the CAGE system (see Additional Reading). CAGE is a mnemonic for the following four questions that are easily included in a clinical interview:

• C: Have you ever felt you should cut down on your drinking?

• A: Have people annoyed you by criticizing your drinking?

• G: Have you ever felt bad or guilty about your drinking?

• E: Have you ever had a drink first thing in the morning to steady your nerves or to get rid of a hangover (an eye opener )?

If a patient answers yes to two or three of these questions, a presumptive diagnosis of alcoholism can be made in about 90% of patients.

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Another commonly used assessment scale is the Michigan Alcohol Screening Test, a 25-item questionnaire that covers the psychosocial complications of alcoholism. (Note: Briefer 13-item and 10-item forms are also available.) The MacAndrew Alcoholism Scale, a 49-item scale derived from the Minnesota Multiphasic Personality Inventory, is another commonly used self-report screening instrument.

A. Alcoholism as a Disease

Alcoholism is a complex disease with biologic, psychologic, and social components. The concept of alcoholism as a disease is useful from a variety of perspectives. Having the patient focus on this concrete issue facilitates engagement in psychotherapy and helps to reduce the overwhelming and sometimes obsessive feelings of guilt. This approach also allows the clinician to address the problem drinking directly. The disease concept, however, should not connote that alcoholism is a unitary phenomenon with a single etiology or treatment, any more than the term psychosis connotes a single disease with one specific treatment. Also consistent with the disease concept are data suggesting a genetic vulnerability to alcoholism in some individuals, particularly in males who show an earlier onset of alcohol use, develop tolerance and physical dependence, and exhibit marked antisocial behavior in childhood and adolescence.

The disease concept should not imply that a person has no control of his or her drinking and behavior. As with most medical illnesses, a person's behavior influences the course of the illness (e.g., diabetes mellitus and hypertension). Even when excessive drinking is a symptom of an underlying psychiatric illness, if the problem drinking persists long enough, it takes on a life of its own; and, almost invariably, ending the drinking must become the focus of any initial therapy.

B. Genetics and Alcoholism

Early twin studies had suggested that the heritability of alcoholism was approximately 50% in men, although a genetic link in women was not established. More recently, a study of adult Australian twins suggested that about two-thirds of the risk is genetically mediated in both men and women, with the remainder being determined by environmental factors.

The mechanism of genetic risk is unknown. The strongest evidence linking genes to alcoholism is the finding of specific polymorphisms of the alcohol dehydrogenase genes, ADH2 and ADH3. Alcohol is first metabolized to acetaldehyde by the hepatic enzyme alcohol dehydrogenase (Fig. 11.1). Acetaldehyde in turn is metabolized to acetic acid by aldehyde dehydrogenase. Alleles of ADH2 and ADH3 encode forms of alcohol dehydrogenase that metabolize the alcohol to acetaldehyde more rapidly than do other forms of the enzyme. As a consequence, acetaldehyde accumulates and produces toxicity. The alleles are common in Asian populations, in which they provide a partial protective effect against the development of alcoholism. Other genes may also be involved in the development of alcoholism. Although early studies suggested that dopamine receptor gene DRD2 polymorphisms were associated with the risk for alcoholism, later studies have not confirmed this relationship. Other studies have linked genes coding for serotonin 5-hydroxtryptamine 1B [5-HT_1B] receptors (and the serotonin transporter) to certain subtypes of alcoholism. Additional studies have found an association between alcoholism and the allele of the tyrosine hydroxylase gene. Further studies are required to validate these findings.

C. Associated Psychiatric Illnesses

A careful differential diagnosis must always include consideration of concomitant or underlying psychiatric illnesses. Depressive symptoms (see Chapters 18 and 19) are found in many alcoholic patients, either as a consequence of chronic drinking or, less commonly, as a predisposing factor to alcohol abuse. Transient symptoms of depression frequently occur after the cessation of drinking. Some epidemiologic evidence suggests a connection between depression and alcoholism. However, other studies note that the

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D. Multidisciplinary Approach

Ideally, diagnosis and treatment of the alcoholic patient are pursued in a multidisciplinary setting. A physician and nurse familiar with the medical problems associated with acute withdrawal and chronic alcohol consumption should be part of the diagnostic and treatment team. Often the alcoholic patient's presenting complaint is medical, and the diagnosis of alcoholism is made only by an alert clinician with a high index of suspicion. Commonly associated conditions are hypertension, pneumonia, gastrointestinal problems, impotence, insomnia, and neuropathies. Among patients on general medical wards (depending on the type of institution and the population served), between 12% and 60% will have an alcohol problem. Thus, the importance of an alert medical practitioner can hardly be overemphasized.

Serum -glutamyl transferase (SGGT) or transpeptidase is a sensitive indicator of the effects of alcohol on the liver. In a person who has been drinking heavily, this enzyme typically remains elevated (i.e., over 30 U per L) for 4 to 5 weeks after the cessation of drinking. If no confounding explanation for an elevation in SGGT is present, this test can be used to aid in the diagnosis of alcoholism or in monitoring abstinence. SGGT may also be elevated in liver disease from other causes, as well as in obesity, inflammatory bowel or thyroid disease, diabetes, pancreatitis, acute renal insufficiency, trauma, or other illnesses. (Note: SGGT levels may also be increased from the use of high doses of benzodiazepines or phenytoin.) Elevated SGGT, especially in the presence of macrocytic anemia, should alert the clinician to the potential of alcohol abuse. Although several other biologic markers or combinations of markers have been used to identify alcoholic patients in general hospitals, none are commonly used in clinical practice. Carbohydrate deficient transferrin, a widely used marker for heavy drinking in research studies, may also have clinical utility. This test is not widely available at present, and it does not have adequate sensitivity in women unless it is used in conjunction with SGGT.

To ensure a comprehensive diagnostic and treatment evaluation, a psychiatrist should be a member of the treatment team. In addition, social workers should be available for family evaluations and therapy and to aid in community and aftercare placement. Finally, an alcohol counselor (often a recovering alcoholic) who is familiar with AA is an invaluable asset to the treatment team. He or she also provides concrete evidence that recovery is possible. The counselor can also be a valuable link to community and aftercare resources.

Most office-based psychiatric physicians find the team approach impractical. In such instances, the psychiatrist must be prepared to fill several roles, including inquiry about medical problems and referral to appropriate treatment alternatives when necessary. Evaluating available family members and, on occasion, engaging in family therapy may also be valuable. Most importantly, the psychiatrist must be cognizant of the importance of the support and group involvement provided by programs such as AA to many alcoholic patients, and he or she should encourage such patients to attend meetings regularly and to participate actively. Although the comments in this paragraph target the office-based psychiatrist, they apply to many other physicians and mental health clinicians as well.

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II. Therapeutic Modalities for Alcoholism

A. Psychosocial and Behavioral Treatments

These are the primary forms of therapy for alcoholism. Although the efficacy of many types of behavioral treatments is well established, no specific type is superior. In a large sample study, the following three treatments were compared: 12-step facilitation therapy, which was modeled on the principles of AA; cognitive-behavior therapy (CBT); and motivational enhancement therapy (National Institute on Alcohol Abuse and Alcoholism [NIAAA], Project MATCH, 1998). All the treatments were effective; however, 12-step facilitation therapy was slightly more effective than the other therapies in one particular subgroup in which the subjects were recruited from outpatient settings as opposed to those recruited from aftercare programs. A follow-up study of the Project MATCH sample found that all of the therapies were also associated with lower medical costs (comparison of pretreatment and posttreatment), although the motivational enhancement therapy did not fare as well in certain subgroups (e.g., patients with a diagnosis of alcohol dependence, high psychiatric severity, or low social support). In clinical practice, psychotherapy for alcohol dependence is usually based on one of two conceptual models, social learning theory or psychodynamic theory. Both approaches often include aspects of motivational enhancement therapy, community reinforcement, contingency contracting, pharmacotherapy, and network therapy (i.e., involvement of the patient's social network).

B. Individual Psychotherapy

CBT is based on social learning theory (see Bandura, 1977; Marlatt and Gordon, 1985), but it may also incorporate aspects of motivational (see Miller and Rollnick, 1991) and change theories (see DiClemente and Prochaska, 1982). An example of this approach is the COMBINE Behavioral Intervention, which was designed by an expert panel participating in the NIAAA study Combining Medications and Behavioral Interventions. It incorporates many of the therapeutic interventions used in Project MATCH. COMBINE Behavioral Intervention is based on the principles that people pass through a series of stages in the course of modifying behavior and that different therapeutic interventions should be used depending on the stage of change. These stages are as follows:

• Precontemplation, in which the person is not considering a change;

• Contemplation, in which the individual realizes that a problem exists but has ambivalence about change;

• Action, in which the person engages in efforts to change the behavior;

• Maintenance, in which strategies are used to support the change and to prevent relapse.

COMBINE Behavioral Intervention consists of four phases that correspond to the stages of change. In the first phase, techniques of motivational interviewing are used to enhance a person's readiness for change. In the second phase, a shift from building motivation for change to development of a plan for change occurs. Early in the second phase, the therapist examines the common antecedents and consequences of drinking and assesses psychosocial functioning. Later in the second phase, a treatment plan is negotiated with the individual. In the third phase, the plan is implemented using various coping skills modules (e.g., assertiveness training, mood and craving management, relationship skills training, social or recreational counseling, job finding training). After the modules are completed, the fourth phase, which focuses on the maintenance of abstinence and the psychosocial gains achieved in prior phases, begins. When relapse occurs, the treatment is modified by repeating or adding the appropriate modules from the earlier treatment phases.

Although many clinicians treating alcoholism have embraced CBT as a first-line psychotherapy, others favor a psychodynamically oriented approach. An inherent disadvantage of the psychodynamic approach is the extensive training that is needed to acquire adequate skills. This approach cannot be

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Individual psychodynamic psychotherapy may be helpful to many alcoholic patients; however, some modifications of technique are necessary. The initial phases of psychotherapy need a here and now focus to help the patient deal with the problems that have arisen from alcohol abuse and to suggest practical techniques for avoiding relapse. This first phase is crucial in establishing rapport; general agreement is found on the principle that an active, nurturing therapist is more likely to be effective than one who is not. Therapist empathy, a positive therapeutic alliance, and a nonconfrontational style, which are sometimes referred to as a client-centered approach, correlate with positive outcomes.

Often, one of the earliest issues in therapy is establishing whether total abstinence is the only acceptable treatment goal. The authors' recommendation is that total abstinence is the goal of treatment. Although the ability of some alcoholic patients to return to controlled drinking has been documented, predicting who can return to moderate drinking and who will lose control is impossible. Some research suggests that the patients with more severe alcohol problems are less likely to achieve controlled drinking.

With regard to drinking episodes that occur during the course of treatment, the authors' approach is flexible. Even though the first goal of treatment is to stop drinking, expecting an alcoholic patient to stop drinking as soon as he or she enters treatment is unrealistic. Occasional drinking episodes are not, in and of themselves, sufficient reason for hospitalization. If the patient slips during the course of treatment, psychotherapy should explore the circumstances surrounding the episode; this can result in the patient's greater awareness of high-risk situations and mood states that lead to drinking. The clinician must accept that alcoholism is a chronic disease and that relapses are common.

In general, when the patient is intoxicated at a treatment session, an evaluation of safety and of the need for hospitalization should be made, along with reasonable efforts to ensure safe transportation home when inpatient treatment is not indicated. Although, on occasion, the intoxicated state may provide useful information about the alcoholic patient's behavior while drunk, typically very little can be accomplished and these sessions are canceled.

An initial task in treatment involves confronting the patient's denial of a problem with alcohol. Admitting one is an alcoholic can be a narcissistic injury, implying loss of control and powerlessness. Empathic confrontations, family meetings, and participation in AA are often helpful in confronting denial. The authors discourage large group interventions to coerce patients into treatment; however, carefully selected family members or friends, working in collaboration with clinicians, can help motivate patients for treatment. The authors find that two clinicians and one person with close personal ties to the patient provide a workable, and perhaps optimal, group composition. The selected friend or family member should meet with

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AA should also be discussed in the early stages of treatment. The clinician should introduce AA in a general way and should explore the patient's feelings about it. The more first-hand knowledge of AA the clinician has, the more effective he or she will be in confronting the patient's rationalizations and negative impressions about AA. AA Facilitation, a therapeutic intervention that encourages AA participation and reinforces AA principles, was established as an effective psychosocial intervention in Project MATCH.

At an early stage in treatment, addressing the issue of a balanced life-style is also important. Although a balance between work and recreational activities has never been directly linked to substance abuse problems, many authorities believe that achieving this balance is important to avoid chronic resentments about overworking. Brooding resentment is one of the negative emotional states that often leads to drinking.

Many clinicians believe that spirituality has a key place in the treatment of some patients and that it should be addressed early on. That conversion experiences facilitate abstinence has long been recognized, and religious reform groups have been successful in helping some alcoholic patients achieve and maintain abstinence.

In later stages of treatment, the focus shifts from an emphasis on supportive and directive techniques to the development of self-understanding, insight, and mastery. In practice, these progress concurrently, although as the length of time in recovery increases, the proportion of the effort focused on self-understanding, insight, and mastery increases.

Readers interested in a detailed discussion of psychosocial treatment approaches should refer to the Additional Reading section.

C. Group Psychotherapy

Groups are a useful treatment modality for alcoholic patients; however, no specific type of group therapy is consistently superior to others. Group work is especially useful in this population because of the difficulties that some alcoholic patients have in tolerating the intense feelings toward the treating clinician that they develop in individual therapy. Some clinicians also believe that confrontation of the alcoholic patient's denial and rationalization by the group is a more powerful and less-threatening intervention than when this is done by an individual clinician.

Other benefits may result from the positive effects that a group experience can have on the alcoholic patient's self-esteem and self-image. In the group setting, the patient helps others by listening and sharing and by offering advice and insights. By being with people who have recovered and maintained abstinence and with those who relapse but recover, the group experience can also instill hope. In addition, it provides an opportunity to discuss fears of intimacy and to acquire useful interpersonal skills. Finally, many groups fulfill an important educational function the patient can learn about alcoholism, its treatment, and the availability of other resources.

D. Family Therapy

Whenever an evaluation of the alcoholic patient's family is possible, this should be conducted. Experienced clinicians may also use family therapy as a primary or adjunctive treatment. Family therapy may take many forms, including meeting with the entire family in therapy sessions, seeing only the marital dyad, or encouraging group therapy for couples or spouses. For the clinician practicing outside of an alcoholism treatment center, making an initial family evaluation and, on that basis, coming to a decision about the value and extent of family involvement seems reasonable.

Al-Anon, Ala-Teen, and Adult Children of Alcoholics are specialized self-help groups that address family issues. They arose as parallel, but separate, groups from AA, and they bear much similarity to AA. They stress a caring detachment from the alcoholic patient, emphasizing that the family member is powerless over both alcohol and the patient; and they work to establish

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E. Alcoholics Anonymous

AA is a worldwide fellowship of an estimated 1.6 million recovering alcoholics who are dedicated to helping others recover from alcoholism. The foundation of the program is the Twelve Steps (Table 11.2). The steps help the recovering alcoholic to accept the diagnosis of alcoholism, to make abstinence his or her goal, to develop humility, and to learn reliance on others. The Twelve Steps encourage self-examination, absolve guilt, and promote altruism by helping other persons struggling with their use of alcohol.

AA has speaker meetings, discussion meetings, and step meetings. Speaker meetings are often open (i.e., nonalcoholics may attend). Small group discussions are closed, and these provide a forum for a more intimate exchange among recovering people. Special meetings address the needs of the newcomer. Step meetings are also usually closed and structured; each meeting focuses on one of the Twelve Steps. In these sessions, sometimes a chapter is read from the Twelve Steps and Twelve Traditions and then the members discuss it; other step meetings may be less structured. In addition to these types of meetings, informal networks develop for socialization, outreach, and spiritual renewal.

New members are encouraged to choose a sponsor, an AA member with long-term abstinence. The roles of the sponsor include staying in close contact with the new member, clarifying the tenets of the AA program, offering practical advice on maintaining abstinence, sharing his or her experiences in early recovery, and being a role model for the newcomer. Sponsorship is

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The AA program is one of the most powerful treatment programs for alcoholism, although AA does not view itself as treatment. The steps provide a guide for recovery, and they bear much similarity to the stages of psychotherapy that are often recommended for alcoholic patients. The early steps encourage the confrontation of denial and the admission of loss of control, whereas the later steps encourage self-examination. The goal is to replace dysfunctional defense mechanisms with more mature coping styles.

AA offers much practical advice that the clinician can and should reinforce. Alcoholic patients in early recovery are told to avoid major life changes and new intimate relationships. The plan for recovery is simple do not drink, go to meetings, and get a sponsor. AA stresses the role of negative emotional states in provoking relapse. The acronym HALT warns members that they should not get hungry, angry, lonely, or tired, because these states are triggers or cues to drinking. As the length of sobriety increases, the focus of the program shifts to character change.

AA is an invaluable resource for both alcoholic patients and treatment programs. Clinicians who treat alcoholic patients should be familiar with AA and the types and locations of meetings in their area. They differ in membership (e.g., educational background, socioeconomic status), dogmatism, and the acceptance of various forms of therapies and in their inclusion of patients with dual diagnoses, especially those who may require treatment with psychotropic medications. Knowledge of the availability of focused AA meetings (e.g., for physicians, women, youth, gays, or lesbians) is also important.

Some clinicians provide their alcoholic patients with a directory of available meetings. These can be obtained by contacting the local AA chapter listed in the telephone directory. The referring clinician should be aware of the difficulty that many patients have with going to their first meeting. In some cases, arranging telephone or personal contact between an active AA member and the patient may be necessary. Recovering physicians are often helpful in arranging such meetings.

F. Alternative Support Groups

Several alternative mutual support groups that reject some of the basic tenets of AA or that integrate other therapies, such as cognitive-behavioral techniques or medication, have developed. The major areas of divergence from AA philosophy are rejection of several key AA beliefs, including the disease concept of alcoholism, the spiritual component of AA, the labeling of participants as alcoholics, the need to identify with the culture of recovery, and the concept of a person's powerlessness over alcohol. Alternative groups may provide opportunities for treatment for individuals who refuse to attend AA because they do not accept the AA philosophy. The clinician must explore with the patient whether the reluctance to attend AA is related to philosophic differences or whether it is instead a reflection of ambivalence about entering treatment. Access to alternative groups may be limited in some areas of the country, and clinicians should become familiar with the more common programs, such as Rational Recovery and Self Management and Recovery Training (SMART), to determine their availability and their compatibility with other therapeutic interventions.

G. Community Reinforcement Approach

The community reinforcement approach (CRA) is a therapeutic approach to alcoholism and drug abuse that uses a variety of techniques to make abstinence more rewarding than drinking. The initial phases of treatment attempt to remove barriers to treatment, such as legal, financial, or other social problems. Treatment may include individual and group psychotherapy, family therapy, social clubs, vocational rehabilitation, housing assistance, or medication. CRA is often linked with contingency contracting to enhance treatment adherence and to decrease drinking directly. Although

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H. Pharmacotherapy for Alcoholism

Pharmacotherapy for abstinent alcoholic patients falls into the following two broad categories: relapse prevention and treatment of psychiatric comorbidity. Drugs for relapse prevention may decrease alcohol craving, treat persistent withdrawal symptoms or alcohol-induced toxicity, or block alcohol's reinforcing effects. Psychopharmacologic agents are valuable in the treatment of coexisting psychiatric disorders. In the presence of alcoholism, however, psychotropic drugs must be carefully selected. Attention must be paid to abuse liability, overdose risk, toxicity, and any potential for interaction with alcohol. In alcoholic patients, monitoring plasma levels may be crucial for evaluating the effectiveness and safety of some drugs, such as tricyclic antidepressants or other oxidatively metabolized drugs. Chronic exposure to alcohol may induce some metabolic pathways. The following subsections are guidelines that are intended to enhance the effective and safe use of specific drug classes that may be prescribed to alcoholic patients.

• Naltrexone. Naltrexone is a nonspecific opioid antagonist that has efficacy in the treatment of alcoholism. Agonist effects are minimal, but they may include miosis and dysphoria. In clinical practice, this does not pose limitations to its use. Some patients experience nausea and headaches, especially during the initiation of therapy, but this can be minimized by beginning with a 25 mg per day dose or by delaying drug therapy until the most severe symptoms of alcohol withdrawal have passed.

  The usual therapeutic dose is 50 mg per day, but some clinicians prescribe higher doses of 150 to 200 mg per day. These higher doses (i.e., those greater than 50 mg) are usually reserved for treatment-resistant cases, and they are mainly used by clinicians with extensive experience in the treatment of alcoholism. Although these higher doses are approved by the United States Food and Drug Administration for the treatment of opioid dependence, the rationale for higher doses in alcoholism derives from animal models that suggest a dose response relationship to alcohol consumption. Craving for alcohol, although this has not been studied rigorously, may predict drug response.

  Variability in the metabolism of naltrexone is observed, with levels of 6- -naltrexol, the major metabolite, being approximately 10 times higher than those of naltrexone (with great intersubject variability). Oral bioavailability ranges from 5% to 40%. Peak concentrations of naltrexone and its major metabolite occur within 1 hour of oral administration. The potency of 6- -naltrexol is less than that of naltrexone (in animal models, potency ratios of from 1 to 12 to 1 to 53 have been reported), but some preliminary studies in humans suggest that both the efficacy and adverse effects correlate with higher levels of 6- -naltrexol. Elimination half-lives range from 1 to 10 hours for naltrexone, with no accumulation after customary multiple dosing regimens.

  Clinical trials in alcoholic patients have produced a consistent profile of adverse effects, with nausea and headache being the most commonly reported. The most serious adverse effect is hepatotoxicity; hepatotoxicity was reported in studies of obesity at doses of 300 mg per day. In fact, a long-term tolerability study indicated that the liver enzymes decline with time in alcoholics who are treated with naltrexone. Nevertheless, monitoring of liver function tests is recommended, especially because most alcoholics achieve a reduction in the amount consumed rather than total abstinence. Furthermore, cases of hepatotoxicity in patients taking naltrexone do occur, and these require immediate discontinuation of

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  the drug. Other adverse effects include neuroendocrine changes, including increased serum cortisol, luteinizing hormone, and -endorphin with no change in corticotropin or follicle-stimulating hormone. Some studies have reported an increase in prolactin and testosterone. The clinical significance of these changes is unknown.

  Precipitated opioid withdrawal is a potential effect of naltrexone administration to alcoholic patients who are also using opioids. This can be avoided by obtaining a urine screen, although certain assays may not be sensitive to low opioid levels. The authors recommend that clinicians know the limits of sensitivity of the drug assay screens that they are ordering so that adverse interactions can be avoided. Alternatively, some treatment programs use a naloxone challenge when opioid dependence is suspected. This is done before administration of naltrexone. For the challenge procedure, naloxone is administered either intravenously or subcutaneously. For the intravenous challenge, 0.8 mg of naloxone is drawn into the syringe. After the injection of one-fourth of the syringe contents (0.2 mg), the patient is observed for 30 seconds for evidence of precipitated withdrawal. If no symptoms are noted, the remainder is injected and the observation period is extended for another 20 minutes. When symptoms do occur after either step, the patient is considered ineligible for naltrexone until he or she is opioid free. The subcutaneous challenge is conducted with the whole 0.8 mg and an observation period of 20 minutes. Usually, when either test method has been positive for opioids, a 24-hour interval is imposed before the challenge is repeated.

  Patients taking naltrexone may not achieve analgesia from typical doses of opioids for as long as 72 hours after the last dose. The duration of opioid antagonism is related to dosage, with the general guideline that 50, 100, and 150 mg produce antagonism for 24, 48, and 72 hours, respectively. Therefore, emergency situations require the use of opioid analgesias with respirator monitoring.

  Naltrexone is currently being tested in depot formulations, as is nalmefene, another opioid antagonist that may have efficacy in the treatment of alcohol dependence. Nalmefene (a -opioid and -opioid antagonist), when administered at 40 mg per day in one clinical study, was more effective in inducing abstinence than was the 10 mg per day dose or the placebo (see Chapter 10).

• Acamprosate (calcium acetylhomotaurinate). This synthetic drug shows structural similarity to -aminobutyric acid and taurine. Many clinical trials in Europe and the United States have established its efficacy in the treatment of alcohol dependence. It is typically administered in three divided doses totaling 2 to 3 g per day. Titrating the dosage is not necessary. The formulations that have been tested to date are poorly absorbed, with oral bioavailability of approximately 11% and peak concentrations after oral dose occurring at 1 to 2.5 hours. Mean elimination half-life after oral dosing has been reported to be about 33 hours. One should note, however, that the pharmacokinetic properties of the preparation available in the United States are proprietary at the present time. Despite its limited clinical use in the United States, some general clinical principles can be derived from its use abroad. Because the drug is not metabolized and because it is cleared entirely by renal elimination, disturbed hepatic function, with the exception of hepatic failure, should not affect the dosing. Steady-state levels are reached within 5 days. Neither gender nor age appears to affect the elimination unless the renal function is impaired. Data regarding drug interactions are inadequate; however, bioavailability may be decreased when the drug is taken with food. No evidence of an interaction with alcohol, diazepam, imipramine, or disulfiram has been observed. Common adverse effects include diarrhea and headache. Some patients also report pruritus

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  and a rash. Acamprosate by itself does not affect the electroencephalogram, although it may affect the sleep architecture changes induced by alcohol. No sedative effects, abuse, or impairments of psychomotor performance have been reported. The mechanism of action of acamprosate is uncertain; however, current research suggests that the drug may normalize glutamate hyperexcitability during withdrawal. A similar mechanism may be responsible for its putative effect in reducing cue-induced craving.

• Disulfiram (Antabuse). This drug may be a useful adjunct in the treatment of chronic alcoholism. When combined with alcohol, disulfiram causes a reaction that ranges from mild discomfort to a severe reaction consisting of flushing, throbbing in the head, respiratory difficulty, nausea and vomiting, sweating, chest pain, palpitations, dyspnea, hypotension, syncope, vertigo, confusion, and blurred vision. In severe cases, unconsciousness, respiratory arrest, cardiovascular collapse, convulsions, and death can occur.

  Either disulfiram or its metabolites interferes with the normal metabolism of alcohol (Fig. 11.1). Aldehyde dehydrogenase is inhibited, and, as a result, acetaldehyde accumulates and causes many of the symptoms of the alcohol-disulfiram reaction. Inhibition of dopamine -hydroxylase, xanthine oxidase, succinic dehydrogenase, and catalase activity may also account for parts of the syndrome.

  Disulfiram is given to the alcoholic patient as a deterrent to further drinking. Once the individual is aware that even small amounts of alcohol may precipitate an unpleasant reaction, he or she is less likely to drink impulsively. The decision not to drink is made once a day when the pill is taken, instead of each time a craving is experienced. Because the patient is aware that the duration of action of disulfiram is as long as 5 to 14 days, he or she must wait before resuming drinking, which further decreases the likelihood of an impulsive drinking binge. Disulfiram, when it is ingested as part of a total treatment plan, can be extremely effective in decreasing drinking relapses in some chronic alcoholic patients. Placebo-controlled studies are difficult to conduct with a drug whose effectiveness depends on anticipated actions. Even after so many years of use and study, no placebo-controlled studies of disulfiram have unequivocally established its efficacy. Nevertheless, for some patients, disulfiram use is worthwhile, especially early in treatment. Studies using the monitored administration of disulfiram have generally produced superior results to those that have not used monitors. Thus, many programs suggest that patients who are prescribed disulfiram should take their daily doses under the supervision of a monitor, preferably a person who has a strong investment in the patient's abstinence and who is willing to attend some therapy sessions.

  Disulfiram use is contraindicated in the presence of severe myocardial disease and certain psychoses. It has the ability to exacerbate schizophrenia, mania, or depressions, possibly as a result of its action on the enzymes involved with catecholamine synthesis and degradation. Disulfiram inhibits dopamine -hydroxylase, the enzyme that converts dopamine to norepinephrine, and low pretreatment levels of this enzyme may be associated with psychotic reactions to the drug. Preexisting differences in the biogenic amine enzyme systems may predispose certain patients to behavioral toxicity.

  Before starting any patient on disulfiram, the rationale for its use should be fully explained. The patient must be reliable enough for the physician to be assured that alcohol has not been consumed during the previous 12 hours. The patient should be warned to avoid alcohol in disguised forms, such as sauces, vinegars, cough and cold mixtures, mouthwashes, aftershave lotions, sunscreens, back rubs, or fumes.

  Patients should also be told that certain medications, when taken with alcohol, may cause a disulfiram-like reaction. These include the

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  genitourinary tract antiinfective agent metronidazole (Flagyl), some additional antifungal and antibiotic agents (e.g., chloramphenicol [Chloromycetin]), and some oral hypoglycemic agents (e.g., chlorpropamide [Diabinase], tolbutamide [Orinase]).

  When patients are well selected and well motivated, socially stable, obsessively careful, and not depressed or suicidal and low doses of disulfiram (e.g., 250 mg) are used, severe alcohol-disulfiram reactions will be minimized. If they occur, supportive measures to restore blood pressure and treatment of any signs or symptoms of shock should be initiated. One gram of vitamin C (as ascorbic acid) administered intravenously may act as an antioxidant and may reduce acetaldehyde production, thereby promoting the excretion of unmetabolized alcohol. Intravenous ephedrine sulfate and antihistamines (e.g., diphenhydramine, 25 to 50 mg) may also be administered, although the rationale for this is not well-established. The potassium levels should be monitored because hypokalemia sometimes occurs.

  Side effects from disulfiram are usually minor; they include a garlic or metallic aftertaste during the first few weeks of therapy, dermatitis, headache, drowsiness, and impotence. More serious adverse reactions include hepatotoxicity, optic neuritis, peripheral neuropathy, and polyneuritis. Liver function tests should be monitored for several weeks after disulfiram is started. Disulfiram may inhibit the metabolism of concomitantly administered oxidatively metabolized medications.

• Ondansetron. This drug, which is a 5-HT₃ receptor antagonist, may reduce drinking in early-onset alcoholic patients; however, additional studies are required.

• Antianxiety (sedative-hypnotic) agents. Benzodiazepines are clearly useful and effective for treating the alcohol abstinence syndrome (see Chapter 12). Less clear, however, is their role in chronic alcoholism. A growing body of evidence seems to suggest that many types of anxiety antedate the onset of alcoholism. From these observations, one can infer that symptomatic anxiety may have etiologic significance in alcohol abuse and dependence. Once alcohol-induced withdrawal anxiety has been ruled out, anxiolytics may be prescribed. In general, agents with a lower abuse potential should be used first. -Adrenergic receptor antagonists or buspirone can be good first choices. However, their efficacy in panic disorder and some forms of social phobia may be limited or inconsistent.

  The benzodiazepines have considerable abuse liability for alcoholics, but some patients may nevertheless benefit from them. Among the benzodiazepines, a spectrum of abuse potential exists. Those agents with a rapid onset of euphoric effect and a short duration of action may present the greatest risk. Diazepam and alprazolam, for example, may produce a rapid initial euphoric effect and may increase the craving for alcohol in abstinent alcoholics. Chlordiazepoxide and oxazepam, as benzodiazepines that have a slower onset of action and less intense initial subjective effects, may present a lower risk for abuse. No matter which benzodiazepine is chosen, only single-source dispensing of limited supplies should be permitted, and frequent patient contact is essential.

  Antidepressants may also be of value in some forms of anxiety. However, the clinician must remember that, in the alcoholic patient, an overdose with a tricyclic antidepressant or even with other antidepressants, such as bupropion, which may lower seizure threshold, may lead to serious morbidity or death. Monoamine oxidase inhibitors, selective serotonin reuptake inhibitors (e.g., fluoxetine, sertraline, paroxetine, citalopram), and mixed-action agents (e.g., venlafaxine) may be helpful when anxiety, phobic symptoms (e.g., social phobia), and panic attacks accompany a depressed or dysphoric mood. Monoamine oxidase inhibitors should be used cautiously and only by physicians who are experienced in

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  their use. Sedating antidepressants, such as mirtazapine, nefazodone, or doxepin, are also commonly prescribed for these patients.

• Antidepressants. Depression in alcoholic patients is a serious problem requiring vigorous treatment. Although many alcoholic patients undergo a time-limited withdrawal depression lasting 2 to 3 weeks, some depression may persist. In a small proportion of patients, depression that lasts may represent persistent withdrawal-related depression. More likely, however, enduring depressive symptoms indicate the presence of a major depression, they are the consequence of chronic residual effects of alcohol on the brain, or they are a reflection of the psychologic and social disruptions caused by alcoholism (e.g., loss of relationships, jobs, or self-esteem; demoralization). Suicide is a serious problem, with 6% to 21% of alcoholic patients committing suicide, compared with an estimated 1% of the general population (see Chapter 17).

  The authors' practice is to observe a depressed alcoholic patient without an established diagnosis of major depression for 3 weeks after the discontinuation of alcohol. When the patient's depressive symptoms persist, an antidepressant is started. In patients showing a clinical picture consistent with major depressive disorder that antedates the onset of alcoholism or that was present in periods of prolonged abstinence, an antidepressant may be started sooner than 3 weeks. No specific antidepressant has been shown to be superior in the treatment of depression in alcoholics, although serotonergic agents, such as selective serotonin reuptake inhibitors, are often tried first because some studies suggest that they may decrease alcohol consumption in problem drinkers and that they may increase the days of abstinence.

• Lithium. Although some evidence has suggested that lithium use may reduce relapse in alcoholics and may block the euphoric effects of alcohol, this use of lithium has not gained wide clinical acceptance for this population. Lithium is most often prescribed for alcoholic patients with bipolar disorder, major depression, or a family history of mood disorder and for highly impulsive episodic drinkers. It is also occasionally used to treat patients with impulsive angry outbursts. Carbamazepine, oxcarbazine, or valproate may also be useful in certain impulsive alcoholic patients (see also Chapter 13).

• Antipsychotic agents. These agents offer an advantage over benzodiazepines for the relief of agitation and anxiety in some patients because they have little intrinsic abuse potential. This potential benefit must be weighed against the risk of tardive dyskinesia from conventional antipsychotic agents (e.g., chlorpromazine) and the discomfort from other side effects. Studies that compared the two classes of drugs and that found several of the conventional antipsychotic agents to be superior have used low doses of benzodiazepines, thus obscuring findings due to problems of cross-tolerance (i.e., benzodiazepines are cross-tolerant with alcohol; antipsychotic agents are not).

  The authors do not recommend the use of conventional antipsychotic agents for alcoholic patients unless the patient has an accompanying psychiatric illness for which this class is more clearly indicated (e.g., in a patient with schizophrenia who has a concomitant alcohol problem). Even in these cases, atypical antipsychotic agents are preferred over conventional agents. Clozapine, for example, may reduce alcohol consumption in patients with schizophrenia and schizoaffective disorder. Similarly, tiapride, a dopamine-2 (D₂) receptor antagonist, is used in the treatment of alcohol withdrawal and relapse prevention in Europe.

III. Comment

Outcome results are influenced by a variety of factors, including motivation to stop drinking, amount and duration of alcohol use, and availability of treatment resources and personal supports. The highest recovery rates (approximating 75%) are found in those who acknowledge their drinking problem and have adequate financial and emotional (e.g., family) support.

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