Chapter 9 Clinical Management of Alcohol Abuse and Dependence

 

Chapter 9. Clinical Management of Alcohol Abuse and Dependence

CLINICAL MANAGEMENT OF ALCOHOL ABUSE AND DEPENDENCE:

INTRODUCTION

Alcohol abuse and dependence are prevalent and costly problems in the United States today. Data

from the Epidemiologic Catchment Area Study indicate that the lifetime prevalence of alcohol

dependence is 14.7% (Regier et al. 1990). More strikingly, approximately 100,000 Americans die

each year from alcohol-related disease or injury (McGinnis and Foege 1999). It has been estimated

that alcohol-related problems account for at least 15% of health care expenditures and cost the

U.S. economy an excess of $185 billion in medical costs, loss of life and property, and reduced

productivity (Harwood 2000). Unfortunately, alcohol dependence is underdiagnosed and difficult to

treat. In as few as 1–2 years following treatment, only about 20%–30% of treated patients have

maintained abstinence, with most returning to heavy drinking. Clearly, there is a critical need for

the development of more effective therapies for the treatment of alcoholism.

DIAGNOSTIC ISSUES

Intoxication

Depending on the individual, effects of alcohol may be observed after as little as one standard

drink. Most states in this country have designated a blood alcohol level of 0.08 g/dL as the legal

limit of intoxication. Table 9–1 lists diagnostic criteria for alcohol intoxication as defined by the

DSM-IV-TR (American Psychiatric Association 2000). In nonalcoholics, a blood alcohol level of 0.40

g/dL is associated with a 50% risk of mortality. In determining how quickly a person’s blood

alcohol level will decrease, one can use the rule of thumb that the body metabolizes approximately

1 drink (approximately 0.015 g/dL) per hour.

TABLE 9–1. DSM-IV-TR criteria for alcohol intoxication

1. Recent ingestion of alcohol.
2. Clinically significant maladaptive behavioral or psychological changes (e.g., inappropriate sexual or

aggressive behavior, mood lability, impaired judgment, impaired social or occupational functioning) that

developed during, or shortly after, alcohol ingestion.

1. One (or more) of the following signs, developing during, or shortly after, alcohol use:

(1) slurred speech

(2) incoordination

(3) unsteady gait

(4) nystagmus

(5) impairment in attention or memory

(6) stupor or coma

1. The symptoms are not due to a general medical condition and are not better accounted for by another

mental disorder.

Abuse

Alcohol abuse is diagnosed in individuals who have repetitive problems in interpersonal, legal, or

psychosocial domains within a 12-month period, but do not meet criteria for alcohol dependence.

Table 9–2 presents the DSM-IV-TR criteria used to diagnose alcohol abuse.Print: Chapter 9. Clinical Management of Alcohol Abuse and Dependence http://www.psychiatryonline.com/popup.aspx?aID=346216&print=yes…

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TABLE 9–2. DSM-IV-TR criteria for substance abuse

1. A maladaptive pattern of substance use leading to clinically significant impairment or distress, as

manifested by one (or more) of the following, occurring within a 12-month period:

(1) recurrent substance use resulting in a failure to fulfill major role obligations at work, school, or home

(e.g., repeated absences or poor work performance related to substance use; substance-related absences,

suspensions, or expulsions from school; neglect of children or household)

(2) recurrent substance use in situations in which it is physically hazardous (e.g., driving an automobile or

operating a machine when impaired by substance use)

(3) recurrent substance-related legal problems (e.g., arrests for substance-related disorderly conduct)

(4) continued substance use despite having persistent or recurrent social or interpersonal problems caused

or exacerbated by the effects of the substance (e.g., arguments with spouse about consequences of

intoxication, physical fights)

1. The symptoms have never met the criteria for Substance Dependence for this class of substance.

Dependence

The diagnosis of alcohol dependence is met when an individual continues to drink despite

significant alcohol-related problems. There is a pattern of repeated alcohol consumption that can

result in tolerance, withdrawal, and compulsive drinking behavior in which the person cannot stop

drinking, despite attempts to do so. Although tolerance and withdrawal symptoms are not

necessary for the diagnosis of alcohol dependence, some studies indicate a more severe clinical

course for patients with histories of either of these physiological components, especially

withdrawal (Schuckit et al. 1998). Table 9–3 outlines the DSM-IV-TR criteria used to diagnose

alcohol dependence.

TABLE 9–3. DSM-IV-TR criteria for substance dependence

A maladaptive pattern of substance use, leading to clinically significant impairment or distress, as manifested

by three (or more) of the following, occurring at any time in the same 12-month period:

(1) tolerance, as defined by either of the following:

(a) a need for markedly increased amounts of the substance to achieve intoxication or desired effect

(b) markedly diminished effect with continued use of the same amount of the substance

(2) withdrawal, as manifested by either of the following:

(a) the characteristic withdrawal syndrome for the substance (refer to Criteria A and B of the criteria sets for

Withdrawal from the specific substances)

(b) the same (or a closely related) substance is taken to relieve or avoid withdrawal symptoms

(3) the substance is often taken in larger amounts or over a longer period than was intended

(4) there is a persistent desire or unsuccessful efforts to cut down or control substance use

(5) a great deal of time is spent in activities necessary to obtain the substance (e.g., visiting multiple doctors

or driving long distances), use the substance (e.g., chain-smoking), or recover from its effects

(6) important social, occupational, or recreational activities are given up or reduced because of substance use

(7) the substance use is continued despite knowledge of having a persistent or recurrent physical or

psychological problem that is likely to have been caused or exacerbated by the substance (e.g., current

cocaine use despite recognition of cocaine-induced depression, or continued drinking despite recognition that

an ulcer was made worse by alcohol consumption)

Specify if:

With Physiological Dependence: evidence of tolerance or withdrawal (i.e., either Item 1 or 2 is present)Print: Chapter 9. Clinical Management of Alcohol Abuse and Dependence http://www.psychiatryonline.com/popup.aspx?aID=346216&print=yes…

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Without Physiological Dependence: no evidence of tolerance or withdrawal (i.e., neither Item 1 nor 2 is

present)

Course specifiers (see text for definitions):

Early Full Remission

Early Partial Remission

Sustained Full Remission

Sustained Partial Remission

On Agonist Therapy

In a Controlled Environment

Withdrawal

Alcohol withdrawal typically begins 6–8 hours after the last drink, peaks 24–28 hours after the last

drink, and generally resolves within 7 days (Myrick and Anton 2004). The manifestation of alcohol

withdrawal varies widely, and possible manifestations are outlined in Table 9–4. Only about 5% of

individuals with alcohol dependence will develop more than mild to moderate withdrawal

symptoms. Chronic medical conditions, nutritional deficiencies, and electrolyte abnormalities often

contribute to and complicate the picture of alcohol withdrawal.

TABLE 9–4. DSM-IV-TR criteria for alcohol withdrawal

1. Cessation of (or reduction in) alcohol use that has been heavy and prolonged.
2. Two (or more) of the following, developing within several hours to a few days after Criterion A:

(1) autonomic hyperactivity (e.g., sweating or pulse rate greater than 100)

(2) increased hand tremor

(3) insomnia

(4) nausea or vomiting

(5) transient visual, tactile, or auditory hallucinations or illusions

(6) psychomotor agitation

(7) anxiety

(8) grand mal seizures

1. The symptoms in Criterion B cause clinically significant distress or impairment in social, occupational, or

other important areas of functioning.

1. The symptoms are not due to a general medical condition and are not better accounted for by another

mental disorder.

Specify if:

With Perceptual Disturbances

Alcohol withdrawal seizures, usually grand mal in type, are estimated to occur in 5%–15% of

patients. An individual with a history of alcohol withdrawal seizures is considered to be at

significant risk for seizures during subsequent withdrawal periods. Although it is not life

threatening, alcohol hallucinosis occurs in 3%–10% of patients with severe alcohol withdrawal.

Hallucinations can be auditory, visual, or tactile in the presence of a clear sensorium. Delirium

tremens (DTs), or alcohol withdrawal delirium, are characterized by agitation, tremulousness,

autonomic instability, fevers, auditory and visual hallucinations, and disorientation, and are the

most severe complication of alcohol withdrawal. DTs are estimated to occur in 5% of patients

admitted for alcohol withdrawal (Mayo-Smith et al. 2004) and must be considered a medical

emergency, given that without prompt and adequate treatment the mortality rate of this conditionPrint: Chapter 9. Clinical Management of Alcohol Abuse and Dependence http://www.psychiatryonline.com/popup.aspx?aID=346216&print=yes…

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can be as high as 20%.

IDENTIFICATION

Essential steps in identifying individuals with alcohol use disorders include understanding the high

prevalence of these disorders and the generally low rate at which they are identified and treated. It

has been reported that only 20% of people with significant alcohol use disorders are identified as

having such, and only 20% of those identified individuals will actually receive treatment (Kaner et

1. 1999).

Several questionnaires are available for the detection of drinking-related problems. A positive

response to any of the questions on the CAGE (named for its four questions; Ewing 1984) should

lead the clinician to further investigate problem drinking with the patient. The Alcohol Use

Disorders Identification Test (AUDIT) (Saunders et al. 1993), a 10-item questionnaire, and the 10-

and 25-item Michigan Alcohol Screening Test (MAST) (Conley 2001) are also frequently used to

indicate potential alcohol problems.

Because patients may underreport their drinking, biomarkers of heavy alcohol use can play an

important role in identifying individuals at risk for alcohol use disorders. Table 9–5 outlines

biological markers that may be indicative of heavy drinking. -Glutamyltransferase (GGT) has

typically been recognized as a liver enzyme whose elevation may be indicative of alcohol use. The

sensitivity of GGT in detecting alcohol abuse is 40%–60%, with a specificity of about 80%. A

limitation of GGT is that it may not be particularly sensitive to relapse. The carbohydrate-deficient

transferrin test (%CDT), which is a newer tool for identifying heavy alcohol use, measures the

relative percentage in serum of the carbohydrate-deficient form of an iron transport protein. The

diagnostic specificity of the %CDT for recent heavy drinking is approximately 70% in patients with

non-alcohol-induced liver cirrhosis, 88.2% in hepatitis patients, and 93.5% in patients with a

nonspecific elevation of GGT (Hock et al. 2005), making it a more sensitive and specific indicator of

alcohol consumption. The combination of a %CDT and GGT measurement further enhances the

detection of problem drinking.

TABLE 9–5. Values of biological markers suggesting heavy drinking

Marker

Men Women Accuracy

% Carbohydrate-deficient transferrin (%CDT) >2.0 U/L >2.6 U/L Very good

-Glutamyltransferase (GGT) >35 U/L >30 U/L Very good

Mean corpuscular volume (MCV)

>91 m3

>91 m3

Good

Aspartate aminotransferase (AST) >40 U/L >33 U/L Fair

Alanine aminotransferase (ALT) >46 U/L >35 U/L Fair

Uric acid

>8.0 mg/dL >6.2 mg/dL Fair

5-Hydroxytryptophol to 5-hydroxyindoleacetic acid ratio >20 pmol/nmol >20 pmol/nmol Fair

Source. Adapted from Schuckit and Tapert 2004.

MEDICAL COMPLICATIONS

Alcohol was identified as the third leading actual cause of death in the United States in 2000,

contributing to 85,000 deaths, or 3.5% of all deaths in that year (Mokdad et al. 2004). The

mortality risk is calculated to be 33% higher for hazardous drinkers (four to six drinks daily for

men and two to four drinks daily for women) and 47% higher for harmful drinkers (more than six

drinks daily for men and more than four drinks daily for women) compared with abstainers or

lower-level drinkers.

A major cause of early mortality among alcoholic individuals is heart disease, occurring at an

earlier age and at a higher rate in these individuals than in their nonalcoholic counterparts.

Although light-to-moderate alcohol consumption has been associated with a lower risk ofPrint: Chapter 9. Clinical Management of Alcohol Abuse and Dependence http://www.psychiatryonline.com/popup.aspx?aID=346216&print=yes…

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myocardial infarction or cardiac death in men and postmenopausal women, heavier alcohol

consumption has been associated with a significantly increased risk of cardiac diseases, including

cardiomyopathy, dysrhythmias, and hypertension.

The consequences of heavy alcohol consumption on the liver are well documented and can occur as

a progression from steatosis (“fatty liver”) to alcoholic hepatitis and cirrhosis. Steatosis, marked by

an excessive buildup of fat inside liver cells, is the earliest stage of alcoholic liver disease and can

occur with heavy drinking for as little as a few days. Steatosis can be reversed with abstinence.

Alcoholic hepatitis, acute inflammation of the liver caused by excessive alcohol intake, can be

accompanied by nausea, lack of appetite, vomiting, fever, abdominal pain and tenderness, jaundice,

and, sometimes, mental confusion. Up to 70% of all alcoholic hepatitis patients may eventually go

on to develop permanent scarring of the liver (cirrhosis). In addition, the combination of alcohol

use and infection with hepatitis C virus can be particularly dangerous. It has been estimated that

patients infected with hepatitis C who consume alcohol are 31 times more likely to develop

cirrhosis than those who abstain from alcohol use (Henry et al. 2002). A substantial proportion of

individuals with cirrhosis will progress to liver cancer.

Another leading cause of death among alcoholic patients is cancer. A large meta-analysis found that

alcohol consumption particularly increases the risks for cancers of the oral cavity, pharynx,

esophagus, and larynx. Statistically significant increases in risk also exist for cancers of the

stomach, colon, rectum, liver, female breast, and ovaries (Bagnardi et al. 2001). The authors found

that concurrent tobacco use, which is common among drinkers, enhances alcohol’s effects on the

risk for cancers of the upper digestive and respiratory tract.

TREATMENT OF ALCOHOLISM

Alcohol Withdrawal

Patients being treated for alcohol withdrawal often need adjunctive management of a variety of

medical conditions. A physical examination should be performed with particular emphasis placed on

assessing for cardiac conditions such as arrhythmia or heart failure, liver disease, pancreatic

disease, gastrointestinal bleeding, infections, or neurological impairment. Vital signs should be

stabilized while electrolyte and nutritional disturbances are corrected.

Nutritional deficits are common in persons with chronic alcohol use. These deficits include

hypomagnesemia, hypophosphatemia, and hypokalemia. Deficits are secondary to dietary habits

and alcohol-related changes in the digestive tract. Most individuals with alcoholism are vitamin

deficient and therefore could benefit from oral multivitamin preparations containing folic acid for a

few weeks. The replacement of thiamine is particularly important, given its role in Wernicke’s

encephalopathy. All patients being treated for alcohol withdrawal should immediately be given 100

mg/day of thiamine and throughout the withdrawal period. It is important to also remember that

thiamine should be provided prior to glucose administration in order to prevent precipitation of

Wernicke’s encephalopathy by depletion of thiamine reserves.

Inpatient versus outpatient treatment

Alcohol detoxification can be safely and effectively accomplished on both an outpatient and

inpatient basis. Although there have been studies evaluating inpatient versus outpatient

detoxification, no specific criteria have been rigorously tested.

Inpatient treatment

Inpatient treatment of alcohol withdrawal provides the safest setting for detoxification. Trained

staff can ensure that patients will be carefully monitored and appropriately supported. The use of

an inpatient facility may also be of greater benefit in providing continuity of care, given that

individuals often begin the process of rehabilitation while in the hospital. In addition, inpatient

detoxification offers the patient a separation from the environmental stimulation for alcohol and/or

other drug use during the treatment period.Print: Chapter 9. Clinical Management of Alcohol Abuse and Dependence http://www.psychiatryonline.com/popup.aspx?aID=346216&print=yes…

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Despite the lack of research-based criteria, certain patients are more likely to respond favorably to

inpatient treatment. Individuals with an established history of significant withdrawal symptoms,

patients who have recently been drinking at very high levels, or patients with a history of

withdrawal seizures or DTs are better served by inpatient treatment. A serious concomitant medical

illness or psychiatric illness also favors the need for inpatient treatment. In addition, patients who

have already experienced multiple detoxification treatments may be at an increased risk of

complications and should therefore be considered for inpatient detoxification (Brown et al. 1988).

Outpatient treatment

An increasing number of alcohol detoxification treatments are taking place outside the hospital

setting. The shift from inpatient to outpatient treatment may in some ways reflect the changing

health care environment, which has limited access to inpatient settings. As a result, increased

attention is being focused on the efficacy and safety of outpatient detoxification. In a review of the

literature on ambulatory detoxification, Abbott et al. (1995) found that less than 10%–20% of

patients required admission to an inpatient unit. The completion rates for ambulatory detoxification

programs ranged from 35% to 95% with most programs showing completion rates above 70%. In

most studies reviewed, 50% of patients continued in alcohol rehabilitation treatment. Most

importantly, this review found no reports of mortality or serious medical complications during

outpatient treatment, except for one program that reported a seizure occurring after the start of

detoxification.

Although no specific criteria have been formulated to determine patient selection for outpatient

alcohol detoxification, there are important factors about candidates’ suitability for outpatient

treatment that should be assessed (Table 9–6). Candidates for outpatient detoxification should

have only mild to moderate withdrawal symptoms, no concomitant medical or severe psychiatric

illnesses that could interfere with the withdrawal process, and no history of withdrawal seizures or

DTs; potential outpatient candidates should also have a sober significant other to serve as a

reliable support person. Patients should be seen daily to reassess withdrawal symptoms, the

occurrence of medical complications, and to monitor the treatment regime.

TABLE 9–6. Relative indications for outpatient alcohol detoxification

Mild to moderate withdrawal symptoms

No medical or neurological illness

No infection

Psychiatrically stable

No history of seizures or delirium tremens

Reliable support person (for care and vehicular transport)

Need to re-assess in 24 hours

Pharmacological treatment

Benzodiazepines are considered by research studies and consensus reports to be the drugs of

choice to treat alcohol withdrawal (Anton and Becker 1995; Institute of Medicine 1990). More

specifically, in North America, benzodiazepines are the mainstay of alcohol withdrawal treatment

and are considered the standard of care, as judged by multiple reviews on this topic (Mayo-Smith

MF et al. 2004; Ntais et al. 2005).

In general, there are two dosing strategies for treating alcohol withdrawal. The first option entails

using a fixed dosing schedule. A loading procedure is recommended for inpatients in severe alcohol

withdrawal. In this treatment strategy, 10 mg or more of diazepam or another long half-life

benzodiazepine is administered every hour until either symptoms are suppressed or the patient

becomes oversedated. Often, only 1–2 days of medication is used and tapering is not required. In

the most recent trials (Myrick et al. 2005; Ntais et al. 2005), symptom-triggered treatment isPrint: Chapter 9. Clinical Management of Alcohol Abuse and Dependence http://www.psychiatryonline.com/popup.aspx?aID=346216&print=yes…

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employed, as measured by the Clinical Institute of Withdrawal Assessment for Alcohol Scale,

Revised (CIWA-Ar) to indicate the need for a benzodiazepine (Saitz et al. 1994).

Symptom-triggered treatment allows for reduced total doses of benzodiazepines. With lower doses

of benzodiazepines, patients display less sedation and are able to more readily engage in other

treatment activities. The CIWA-Ar appears to be a useful instrument for quantifying alcohol

withdrawal and an effective guide for determining the need for ancillary “rescue” medication

dosing.

Based on reviews and meta-analyses, no one single benzodiazepine appears to be superior to

others in the treatment of alcohol withdrawal (Mayo-Smith 1997). The selection of a specific

benzodiazepine should be made on the basis of clinical factors such as age, status of liver function,

and the presence or absence of a history of seizures. An agent’s kinetic profile, in terms of half-life

and simplicity of liver metabolism, has been used as the rationale to promote one benzodiazepine

over another. Longer half-life agents may cause problems ranging from oversedation to

coordination difficulties and confusion in individuals with liver impairment. Many alcoholic patients

present with liver dysfunction, which indicates that the use of shorter half-life agents such as

oxazepam and lorazepam is favored. Because lorazepam is available in multiple methods of

administration, including oral, sublingual, and intramuscular, all of which have good absorption, it

may be a particularly effective agent, in contrast to chlordiazepoxide or diazepam.

Treatment of complicated withdrawal

More severe complications of alcohol withdrawal include withdrawal seizures and DTs. Primary

alcohol withdrawal seizures are self-limited and usually require only supportive treatment.

However, benzodiazepines are considered the treatment of choice. The issue of what method

should be used in the treatment of DTs is somewhat controversial. Benzodiazepines are often

prescribed to decrease both autonomic hyperactivity and the risk of alcohol withdrawal seizures

and to control agitation. Despite these beneficial effects, benzodiazepines may contribute to the

behavioral dyscontrol and confusion that accompanies DTs. Low doses of antipsychotic agents such

as haloperidol are also used for the treatment of DTs.

Relapse Prevention

Disulfiram

Disulfiram is an alcohol deterrent drug that has been in use for over 50 years. It interrupts the

metabolism of alcohol by irreversibly inhibiting aldehyde dehydrogenase, thereby blocking the

breakdown of acetaldehyde to acetate. When a patient taking disulfiram drinks alcohol, the

accumulation of acetaldehyde results in facial flushing, nausea and vomiting, headache, and

changes in blood pressure. The patient’s fear of this disulfiram-alcohol reaction, particularly after

experiencing it, is presumed to serve as a strong reinforcement for abstinence.

A large placebo-controlled trial of disulfiram treatment found no significant differences in rates of

abstinence or time to first drinking day (Fuller et al. 1986). Patient nonadherence was likely a main

contributor of the negative finding, considering that only 20% of 577 subjects who completed the

study were compliant with disulfiram treatment. However, among patients who drank and had a

complete set of assessment interviews, those in the 250-mg disulfiram group reported significantly

fewer drinking days than those in the 1-mg or no-disulfiram groups. A significant relationship

between adherence to drug regimen and complete abstinence was found in all groups. Fuller et al.

(1986) concluded from their findings that disulfiram may help reduce drinking frequency after

relapse, but it does not enhance counseling in aiding alcoholic patients to sustain continuous

abstinence or delay the resumption of drinking. They also suggested that older, more motivated

men seemed to be more compliant and to do better with disulfiram.

Adherence is an obstacle in determining the generalization of disulfiram’s effectiveness. Wright and

Moore (1990) have shown that supervised disulfiram treatment and incentive-driven interventions

are associated with decreased alcohol consumption and increased rates of abstinence. A detailedPrint: Chapter 9. Clinical Management of Alcohol Abuse and Dependence http://www.psychiatryonline.com/popup.aspx?aID=346216&print=yes…

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meta-analysis revealed that evidence for the efficacy of disulfiram is lacking overall, but that some

evidence is available for disulfiram being effective when given under supervision (Berglund et al.

2003).

Naltrexone

After it was shown to reduce drinking frequency and the likelihood of relapse to heavy drinking,

naltrexone was approved by the U.S. Food and Drug Administration (FDA) in 1994 for the treatment

of alcohol dependence (O’Malley et al. 1992; Volpicelli et al. 1992). Although its mechanism of

action is not fully understood, naltrexone’s competitive antagonism at the opioid receptor is

hypothesized to block the release of dopamine induced by the consumption of alcohol and therefore

reduces alcohol craving and loss of control by reducing the rewarding effects of alcohol.

A large meta-analysis including 27 randomized, controlled trials of naltrexone revealed that

short-term treatment with naltrexone decreased relapse with a risk ratio of 0.64, with the number

needed to treat (NNT; i.e., the number of patients treated to achieve a better outcome over placebo

response) being 7 (Srisurapanont and Jarusuraisin 2005). The analysis also showed that, in a

comparison with the placebo group, naltrexone lowered the risk of treatment withdrawal in

alcohol-dependent patients by 28% (NNT = 13).

The efficacy of naltrexone was recently supported by the Combining Medications and Behavioral

Interventions for Alcoholism (COMBINE) trial, a federally funded, randomized, controlled trial

involving 1,383 recently abstinent alcoholics from 11 U.S. academic sites and that evaluated the

efficacy of naltrexone, acamprosate, or both, in comparison with each other and placebo, with

health care provider–delivered medical management, and with or without a specialized alcohol

counselor, delivered combined behavioral intervention (Anton et al. 2006). In this trial, individuals

that were given naltrexone plus medical management; or naltrexone, medical management, and

combined behavioral intervention; had a higher percentage of days abstinent than those receiving

placebo and medical management only. Naltrexone also reduced the risk over time of heavy

drinking days.

Not all studies of naltrexone have revealed positive results (Gastpar et al. 2002; Krystal et al.

2001), which suggests there may be subtypes of individuals who are more likely to respond to

naltrexone. The drug may be preferentially effective among alcoholics whose disease is mostly

characterized by reward craving, given that it is believed to work by blocking endogenous opioids,

thereby diminishing the pleasant effects of alcohol consumption. King et al. (1997) investigated the

effects of naltrexone on subjective response to alcohol in a double-blind, placebo-controlled trial.

They found a differential response to naltrexone, based on subjects’ paternal history of alcoholism

and levels of stimulation experienced during alcohol drinking.

Work recently conducted by researchers reveals that variants of the opioid receptor, which may

alter the affinity of the receptor for endogenous ligands, may also affect response to naltrexone. In

a post-hoc study that combined three previously collected data sets, subjects of European descent

with one or two copies of the 118G variant allele and who were treated with naltrexone had

significantly lower rates of relapse and took a longer time to return to heavy drinking than those

homozygous for this allele (Oslin et al. 2003). These differences were not found among subjects

assigned to placebo. Given potential genetic variabilities in the response to naltrexone,

meta-analyses may underestimate the effect size for naltrexone because of the heterogeneity of

patients (Heilig and Egli 2006).

Because compliance is clearly critical in the success of naltrexone, a long-acting injectable

naltrexone is also available. Garbutt et al. (2005) performed a randomized, double-blind,

placebo-controlled trial of extended-release, injectable naltrexone in 624 actively drinking,

alcohol-dependent adults who received either a monthly intramuscular injection of 380 mg of

long-acting naltrexone, 190 mg of long-acting naltrexone, or a matching volume of placebo

combined with 12 sessions of low-intensity psychosocial intervention. Compared with placebo, 380

mg of long-acting naltrexone resulted in a 25% decrease in the event rate of heavy drinking days,Print: Chapter 9. Clinical Management of Alcohol Abuse and Dependence http://www.psychiatryonline.com/popup.aspx?aID=346216&print=yes…

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and 190 mg of naltrexone resulted in a 17% decrease. The same study also revealed that men more

than women and those with lead-in abstinence exhibited greater treatment effects.

A crucial consideration for the clinician and the patient is that naltrexone is an opioid antagonist

and can therefore induce withdrawal in an opioid-dependent individual. Special consideration must

also be taken with pain control, because naltrexone will block the effects of opioid analgesics. In a

supervised hospital setting, the antagonist properties of naltrexone can be overridden with

increased doses of opioid analgesics.

Acamprosate

Acamprosate was approved by the FDA in 2004 for the treatment of alcohol dependence but has

been available by prescription in France since 1989. It is reported to assist in the maintenance of

abstinence and decrease negative symptoms associated with the acute postwithdrawal period in

recently detoxified alcohol-dependent individuals. Acamprosate is structurally similar to

-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system,

and is thought to exert its therapeutic effect by modulating the excitatory glutamate amino acid

system (N-methyl-D-aspartic acid; NMDA) in the brain. By functioning to increase GABAergic

activity and/or inhibiting glutamatergic activity via modulation of the NMDA receptor, acamprosate

may ameliorate alcohol withdrawal symptomatology (Boeijinga et al. 2004).

Multiple trials performed in Europe and elsewhere support the efficacy and safety of acamprosate.

Mann et al. (2004) performed a large meta-analysis, involving 4,087 individuals, of 17 randomized,

placebo-controlled trials of acamprosate. They found that continuous abstinence rates at 6 months

were significantly higher in the acamprosate-treated patients. At 12 months, the overall pooled

difference for continued abstinence between subjects treated with acamprosate and those given

placebo was 13.3%. The effect sizes in abstinence rates at 3, 6, and 12 months were 1.33, 1.50,

and 1.95, respectively. Bouza et al. (2004) also performed a meta-analysis comprising 13 studies of

acamprosate and 19 studies of naltrexone. They too found that acamprosate helped maintain

abstinence in alcohol-dependent individuals who had stopped drinking.

Not all studies of acamprosate have shown efficacy over placebo. Findings of the COMBINE study,

mentioned earlier (Anton et al. 2006), did not support the efficacy of acamprosate under

intent-to-treat analyses. There has been much speculation about the reasons for this discrepancy in

results. Differences in study populations and designs may be contributing factors. For instance, in

many of the European clinical trials, acamprosate was initiated while the patients were hospitalized

for alcohol detoxification and many patients had lengthy hospital stays for rehabilitation. In

contrast, the COMBINE patients were initiated on study drugs as outpatients, after attaining a

minimal 4 days of abstinence (Anton et al. 2006). However, over 50% of participants had more

than 4 days of reported abstinence prior to randomization. Additionally, a combined analysis of

many studies conducted in Europe did not find predictors of response, including alcohol withdrawal

symptoms or severity of alcohol problems (Verheul et al. 2005). In summary, at present, it is

unclear which alcoholic individuals will be more likely to respond to acamprosate, but the weight of

the data does suggest that those with a strong commitment to abstinence who take the medication

for several weeks while abstaining might have better outcomes in the long run than those who are

not given acamprosate.

Because acamprosate is poorly absorbed, it is generally given in high doses of approximately 2

g/day, in three doses. Acamprosate has been found to be generally well tolerated by patients in all

of the clinical trials to date. Diarrhea is the most common side effect noted, but headache,

dizziness, and pruritis have also been reported, to a much lesser degree.

Combination therapy

Attention has recently focused on the use of naltrexone and acamprosate in combination. Although

studies have shown that the two medications are safe and well tolerated in combination, the results

supporting the combination’s superior efficacy over naltrexone alone are mixed. Some trials have

shown superior efficacy (Feeney et al. 2006; Kiefer and Wiedemann 2004), but the COMBINE trialPrint: Chapter 9. Clinical Management of Alcohol Abuse and Dependence http://www.psychiatryonline.com/popup.aspx?aID=346216&print=yes…

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did not show a superior effect of naltrexone and acamprosate over naltrexone alone (Anton et al.

2006).

Nonpharmacological treatment options

Treatment modalities that have been used for alcohol use disorders include psychodynamic

psychotherapy, cognitive-behavioral therapy (CBT), motivational enhancement therapy, 12-step

facilitation (TSF), contingency management, network therapy, group therapy, and family therapy.

Motivational interviewing, or motivational enhancement therapy (MET), is a brief, time-limited

intervention and therapeutic approach, in which the clinician works with the patient to build trust

by showing empathy. Areas of resistance to change are noted, and the patient is encouraged to

discuss why altering drinking patterns might be beneficial. Modifications of motivational

enhancement have been used in brief physician interventions. The clinician asks about drinking

behavior, reviews alcohol-related problems, and emphasizes the adverse effects of alcohol. One

paradigm incorporates two 15-minute physician visits separated by a month. These interventions

are followed by two 5-minute telephone conversations with a nurse to reinforce the lessons

learned. In addition, the patient keeps a diary of his or her drinking pattern and establishes

realistic goals that are set in a contract. Evaluation of this approach revealed that more than

two-thirds of the drinking patients agreed to participate in therapy, and excellent outcomes of

reduced drinking and alcohol problems were maintained over a 4-year period (Fleming et al. 2002).

Project MATCH (Matching Alcoholism Treatments to Client Heterogeneity) was a multisite clinical

trial designed to investigate if patient–treatment matching improved treatment outcomes. Over a

12-week period, 1,726 subjects were randomly assigned to TSF, CBT, or MET. Interaction effects

with selected patient characteristics were studied, including severity of alcohol involvement,

cognitive impairment, psychiatric severity, conceptual level, gender, meaning seeking, motivational

readiness to change, social support for drinking versus abstinence, sociopathy, and typology of

alcoholism. Subjects were recruited from two parallel study arms: one with alcohol-dependent

patients who received outpatient therapy and one with patients who received aftercare therapy

following inpatient or day hospital treatment. Overall, study subjects showed significant and

sustained improvement in increased percentage of abstinent days and decreased number of drinks

per drinking days, with few clinically significant outcome differences among the three treatments

in either treatment arm. There was no difference in sustained abstinence among treatments in the

aftercare arm. However, outpatients who received TSF were more likely to remain completely

abstinent in the year following treatment than outpatients who received the other treatments. With

regard to matching patient characteristics with specific treatments, client anger demonstrated the

most consistent interaction in the trial, with significant matching effects evident at both the 1-year

and 3-year follow-ups. Clients identified as having high levels of anger fared better in MET than in

CBT or TSF. Conversely, clients with low levels of anger performed better after treatment in CBT

and TSF than in MET. The overarching conclusion of this study appears to be that once patients

have reached a point at which they are willing to consider abstinence, their motivation and

characteristics are likely to be better predictors of outcome than any specific aspect of the

treatment program (Project MATCH Research Group 1997, 1998).

SPECIAL POPULATIONS

Comorbid Populations

The co-occurrence of substance abuse and psychiatric disorders is a complex and common

phenomenon. The National Institute of Mental Health Epidemiologic Catchment Area (ECA) study

and the National Comorbidity Study (NCS) are two large epidemiological surveys that have

evaluated the prevalence of comorbid psychiatric and substance use disorders in community

samples. In the ECA study, 45% of individuals with alcohol use disorders had at least one

co-occurring psychiatric disorder (Regier et al. 1990). Likewise, in the NCS, 78% of

alcohol-dependent men and 86% of alcohol-dependent women met lifetime criteria for another

psychiatric disorder, including drug dependence (Kessler et al. 1996). The co-occurrence of

psychiatric and alcohol use disorders is clinically important because comorbidity has a negativePrint: Chapter 9. Clinical Management of Alcohol Abuse and Dependence http://www.psychiatryonline.com/popup.aspx?aID=346216&print=yes…

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impact on the course, treatment outcome, and prognosis of both syndromes.

The accurate diagnosis and differentiation between substance-induced states and primary

psychiatric diagnoses are two of the more difficult tasks in assessing patients with co-occurring

psychiatric symptoms and substance use disorders. Clinicians often differentiate substance-induced

transient symptoms from psychiatric illness through observation during a period of abstinence.

However, the duration of abstinence necessary for accurate diagnosis should be based on both the

diagnosis being assessed and the substance used. Sustained psychiatric symptoms during lengthy

periods of abstinence, a family history of the particular psychiatric disorder, and the onset of

psychiatric symptoms before the onset of substance abuse and dependence all suggest a primary

psychiatric illness.

Although the treatments for psychiatric and substance use disorders have largely consisted of

separate clinical services, the integration of services is paramount to the optimal treatment of

individuals with comorbid conditions. Such programs often include a mix of group and individual

therapy. CBTs are among the most efficacious treatments for anxiety disorders and substance use

disorders (Anton et al. 1999). Brown et al. (1997) demonstrated that alcoholic persons with

depressive symptoms had improved outcomes at 3- and 6-month follow-up visits after treatment

with CBT for depression, compared with a control group given treatment in the form of relaxation

training. Individuals with comorbid psychiatric and substance use disorders can also benefit from

participation in 12-step groups such as Alcoholics Anonymous and Narcotics Anonymous.

The ideal approach to the pharmacological treatment of comorbid conditions is to use an agent that

has no abuse potential, is safe and well tolerated, and may be efficacious for both disorders. Data

support the use of selective serotonin reuptake inhibitor (SSRI) agents for the

pharmacotherapeutic treatment of comorbid alcohol dependence and major depression. Higher

doses of SSRIs and tricyclic antidepressants may be required because of the possibility that alcohol

use has induced hepatic microsomal activity. The use of SSRIs in the area of subtyping alcoholics

shows promise, but much work remains to be done (Kranzler et al. 1996; Pettinati et al. 2000).

Although lithium is accepted as the gold-standard agent in the treatment of bipolar disorder,

anticonvulsant agents have shown some promise in the treatment of substance use disorders and

comorbid bipolar and substance use disorders (Myrick et al. 2004). Research investigating the use

of psychiatric medications in combination with alcohol-treatment medications such as naltrexone

and acamprosate would be useful.

Adolescents

Alcohol is the most the common substance of abuse among adolescents. In 2005, 47% of twelfth

graders reported past-30-days drinking and 29.2% reported binge drinking (five or more drinks in

a row, per occasion) within the past 2 weeks (Johnston et al. 2006). Diagnostic criteria for alcohol

use disorders are based on adult symptom patterns, which may not fit for some heavy-drinking

teenagers. The diagnostic criteria of preoccupation, loss of control, and reckless behavior while

using can occur in teenagers, but medical problems and severe withdrawal are unlikely (Brown and

D’Amico 2001).

When evaluating adolescents with possible alcohol use disorders, educational status, family

functioning, peer relationships, legal status, and use of free time should be assessed, in addition to

direct questions about the use of alcohol and other drugs and possible psychiatric disorders.

Investigating areas of academic performance, school attendance, disciplinary problems, and any

history of abuse can be particularly important because it helps the practitioner ascertain the

adolescent’s risk of an alcohol use disorder. There is a high level of co-occurrence of substance use

and other psychiatric disorders in adolescents.

Psychosocial treatments for alcohol use disorders in adolescents should be adapted for this specific

population. If at all possible, family participation should be viewed as a prerequisite for successful

treatment for any adolescent with a substance use disorder. Motivational therapy, CBT, behavioral

therapies (including operant-conditioning methods as well as behavioral contingency contracts andPrint: Chapter 9. Clinical Management of Alcohol Abuse and Dependence http://www.psychiatryonline.com/popup.aspx?aID=346216&print=yes…

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parent management training), family therapy, and 12-step approaches may all be useful options. In

employing 12-step approaches, it is important to help the family identify a support group that is

geared specifically toward adolescents. Multisystemic therapy involves working with teenagers,

parents, schools, community resources, and peers to decrease problem behaviors (Henggeler et al.

1995). As with adults, the aim of pharmacotherapy in adolescents with substance use disorders

includes detoxification, interfering with the physiological and subjective effects of the substance,

and treatment of co-occurring psychiatric disorders. A small, open-label trial of naltrexone in

adolescents found that it was well tolerated and reduced craving and drinking among adolescents

who were dependent on alcohol (Deas et al. 2005).

Women

Differences have been identified in the incidence, development, and consequences of alcohol

dependence in women as compared with men; women more often drink alone, binge less, have

more regular drinking patterns, and drink smaller quantities. For women in relationships, drinking

patterns are more likely to match that of their significant others. After equivalent doses of alcohol,

women have been shown to have higher blood ethanol levels than men. Likely contributors to this

include lower levels of alcohol dehydrogenase in the gastric mucosa and livers of women compared

with men, as well as the lower adjusted total body water content and smaller volume of

distribution in women (Frezza et al. 1990).

The faster progression from first drink to significant problems with alcohol in women as compared

with men has been termed the telescoping effect (Frezza et al. 1990). Women reach criteria for

alcohol dependence from onset of drinking more quickly than men and progress to liver disease

with lower levels of drinking over a shorter period of time than do men. In addition, women who

develop cirrhosis from alcohol dependence have a higher rate of mortality than their male

counterparts. Women’s risk of breast cancer is also increased by moderate to heavy alcohol

consumption.

Alcohol use disorders in women can lead to sexual dysfunction, menstrual cycle abnormalities, and

amenorrhea (Blume and Russell 2001). Alcohol may also increase the risk of spontaneous abortion.

Fetal alcohol syndrome, resulting from heavy use of alcohol during pregnancy, is characterized by

growth deficiencies, facial abnormalities, and significant impairments in the neurodevelopment of

the fetus (Jones and Smith 1973). In addition, studies suggest that even low to moderate levels of

drinking during pregnancy are associated with alcohol-related birth defects.

Women with alcohol use disorders are more likely to present for treatment of other problems, such

as marital or relationship difficulties, physical illness, or emotional problems (Weisner and Schmidt

1992). Related to this, they are more likely to seek treatment in psychiatric or primary care

settings than in traditional substance disorders treatment programs (Beckman and Kocel 1982).

Estimates indicate that women make up approximately 25% of patients in traditional treatment

centers for alcohol dependence in the United States (U.S. Department of Health and Human

Services 1990). It is important to recognize potential gender-specific barriers that may have an

impact on treatment initiation and completion. Such barriers include lack of gender and cultural

appropriateness in program content, fear of legal consequences (particularly loss of child custody),

lack of child care and transportation, inadequate or no health insurance coverage, caretaker roles

for dependent family members, and societal intolerance and stigmatization of substance-dependent

women (Chasnoff 1991). Some evidence suggests that gender-specific services can improve

treatment retention, substance use outcomes, and possibly psychosocial functioning in women

when compared with traditional mixed-gender programs, but further research is warranted (Brady

and Ashley 2005; Greenfield et al. 2007).

Older Adults

According to the annual national survey on drug use and health sponsored by the Substance Abuse

and Mental Health Services Administration (SAMHSA 2004), 49.9% of individuals between the ages

of 60 and 64 years and 35.3% of individuals ages 65 years and older reported past-month alcoholPrint: Chapter 9. Clinical Management of Alcohol Abuse and Dependence http://www.psychiatryonline.com/popup.aspx?aID=346216&print=yes…

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use. In addition, 6.5% of people ages 65 years and older reported binge drinking (5 or more drinks

on one occasion, on at least 1 day in the past month) and 1.8% reported heavy drinking (5 or more

drinks on the same occasion, on each of 5 or more days in the past 30 days). Standard drinking

guidelines for adults 65 years and older state that individuals should not consume more than 1

standard drink per day or 7 standard drinks per week (National Institute for Alcohol Abuse and

Alcoholism 1995).

There are several barriers to diagnosing alcohol use disorders among older adults. Many problems

caused by alcohol can mimic other disorders common in this age group, such as dementia and

depression. Other barriers include patient reluctance to divulge this information and clinician

failure to adequately screen in this subset of the population. Identification and treatment are of

utmost importance because even relatively moderate amounts of alcohol can increase the risk for

health problems such as hypertension, sleep problems, and malnutrition (SAMHSA 1998). Other

consequences may include acute pancreatitis, alcohol-induced cirrhosis, or alcohol-related

cardiomyopathy, in addition to an increased risk of trauma from falls or motor vehicle accidents

(Oslin 2004). Because individuals generally take more prescription and over-the-counter

medications with increasing age, the risk for interactions with alcohol and drugs is certainly

heightened. Alcohol use is one of the leading risk factors for developing adverse drug reactions and

is known to interfere with the metabolism of many medications, such as digoxin and warfarin

(Fraser 1997).

CONCLUSION

Alcoholism is a devastating illness that leads to huge societal losses. Despite the fact that

alcoholism is underdiagnosed, effective identification strategies are available and need to be

further utilized in medical settings. Over the past decade, there have been exciting developments in

the treatment of alcohol withdrawal and relapse prevention. In particular, there have been

advancements not only in the treatment strategies for alcohol withdrawal but also the location in

which detoxification may occur. There has also been much progress made in the prevention of

relapse to alcohol use. Improvements include the approval of a new medication for alcohol

dependence, the use of combined treatments for alcohol dependence, and increased research in the

use of nonpharmacological treatment strategies. Despite these advances, more effective

interventions for individuals with alcohol use disorders are needed. An increased understanding of

the neurobiological underpinnings of alcohol dependence, including the role of pharmacogenetics,

may lead to enhanced effectiveness of future treatment strategies.

KEY POINTS

Detection and referral rates of alcoholic patients are low.

The biomarker carbohydrate-deficient transferrin test alone, or in combination with -glutamyltransferase,

may be used to identify heavy alcohol use and monitor drinking status during alcohol treatment.

Treatment of alcohol withdrawal has primarily become an outpatient procedure.

The Clinical Institute of Withdrawal Assessment for Alcohol Scale, Revised, appears to be a useful

instrument for quantifying alcohol withdrawal and guiding the need for ancillary rescue medication dosing.

U.S. Food and Drug Administration–approved medications for the treatment of alcohol dependence include

disulfiram, naltrexone, and acamprosate.

REFERENCES

Abbott JA, Quinn D, Knox L: Ambulatory medical detoxification for alcohol. Am J Drug Alcohol Abuse

21:549–563, 1995 [PubMed]

American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th

Edition, Text Revision. Washington, DC, American Psychiatric Association, 2000

Anton RF, Becker HC: Pharmacology and pathophysiology of alcohol withdrawal, in Handbook of

Experimental Pharmacology, the Pharmacology of Alcohol Abuse, Vol 114. Edited by Kranzler HR.Print: Chapter 9. Clinical Management of Alcohol Abuse and Dependence http://www.psychiatryonline.com/popup.aspx?aID=346216&print=yes…

14 of 17

18/10/2008 10:11

New York, Springer-Verlag, 1995, pp 315–367

Anton RF, Moak DH, Waid LR, et al: Naltrexone and cognitive behavioral therapy for the treatment

of outpatient alcoholics: results of a placebo-controlled trial. Am J Psychiatry 156:1758–1764, 1999

[Full Text] [PubMed]

Anton RF, O’Malley SS, Ciraulo DA, et al: Combined pharmacotherapies and behavioral interventions

for alcohol dependence: the COMBINE study: a randomized controlled trial. JAMA 295:2003–2017,

2006 [PubMed]

Bagnardi V, Blangiardo M, La Vecchia C, et al: Alcohol consumption and the risk of cancer: a

meta-analysis. Alcohol Res Health 25:263–270, 2001 [PubMed]

Beckman LJ, Kocel KM: The treatment delivery system and alcohol abuse in women: social policy

implications. J Soc Issues 18:139–151, 1982

Berglund M, Thelander S, Salaspuro M, et al: Treatment of alcohol abuse: an evidence-based

review. Alcohol Clin Exp Res 27:1645–1656, 2003 [PubMed]

Blume SB, Russell M: Alcohol and substance abuse in obstetrics and gynecology practice, in

Psychological Aspects of Women’s Health Care: The Interface Between Psychiatry and Obstetrics

and Gynecology, 2nd Edition. Edited by Stotland NL. Washington, DC, American Psychiatric Press,

2001, pp 421–439

Boeijinga PH, Parot P, Soufflet L, et al: Pharmacodynamic effects of acamprosate on markers of

cerebral function in alcohol-dependent subjects administered as pretreatment and during alcohol

abstinence. Neuropsychobiology 50:71–77, 2004 [PubMed]

Bouza C, Angeles M, Munoz A, et al: Efficacy and safety of naltrexone and acamprosate in the

treatment of alcohol dependence: a systematic review. Addiction 99:811–828, 2004 [PubMed]

Brady and Ashley OS: Women in substance abuse treatment: results from the alcohol and drug

services study (ADSS). 2005. Available at: http://www.oas.samhsa.gov/womenTX/womenTX.pdf.

Accessed July 22, 2007.

Brown ME, Anton RF, Malcolm R, et al: Alcohol detoxification and withdrawal seizures: Clinical

support for a kindling hypothesis. Biol Psychiatry 23:507–514, 1988 [PubMed]

Brown RA, Evans DM, Miller IW, et al: Cognitive-behavioral treatment for depression in alcoholism.

J Consult Clin Psychol 65:715–726, 1997 [PubMed]

Brown SA, D’Amico EJ: Outcomes of alcohol treatment for adolescents. Recent Dev Alcohol

15:307–327, 2001 [PubMed]

Chasnoff IJ: Drugs, alcohol, pregnancy, and the neonate. Pay now or pay later. JAMA

266:1567–1568, 1991 [PubMed]

Conley TB: Construct validity of the MAST and AUDIT with multiple offender drunk drivers. J Subst

Abuse Treat 20:287–295, 2001 [PubMed]

Deas D, May MP, Randall C, et al: Naltrexone treatment of adolescent alcoholics: an open-label pilot

study. J Child Adolesc Psychopharmacol 15:723–728, 2005 [PubMed]

Ewing JA: Detecting alcoholism. The CAGE questionnaire. JAMA 252:1905–1907, 1984 [PubMed]

Feeney GF, Connor JP, Young RM, et al: Combined acamprosate and naltrexone, with cognitive

behavioral therapy is superior to either medication alone for alcohol abstinence: a single centre’s

experience with pharmacotherapy. Alcohol Alcohol 41:321–327, 2006 [PubMed]

Fleming MF, Mundt MP, French MT, et al: Brief physician advice for problem drinkers: long-term

efficacy and benefit-cost analysis. Alcohol Clin Exp Res 26:36–43, 2002 [PubMed]

Fraser AG: Pharmacokinetic interactions between alcohol and other drugs. Clin PharmacokinetPrint: Chapter 9. Clinical Management of Alcohol Abuse and Dependence http://www.psychiatryonline.com/popup.aspx?aID=346216&print=yes…

15 of 17

18/10/2008 10:11

33:79–90, 1997 [PubMed]

Frezza M, di Padova C, Pozzato G, et al: High blood alcohol levels in women. The role of decreased

gastric alcohol dehydrogenase activity and first-pass metabolism. N Engl J Med 322:95–99, 1990

[PubMed]

Fuller RK, Branchey L, Brightwell DR, et al: Disulfiram treatment of alcoholism. A Veterans

Administration cooperative study. JAMA 256:1449–1455, 1986 [PubMed]

Garbutt JC, Kranzler HR, O’Malley SS, et al: Efficacy and tolerability of long-acting injectable

naltrexone for alcohol dependence: a randomized controlled trial. JAMA 293:1617–1625, 2005

[PubMed]

Gastpar M, Bonnet U, Böning J, et al: Lack of efficacy of naltrexone in the prevention of alcohol

relapse: results from a German multicenter study. J Clin Psychopharmacol 22:592–598, 2002

[PubMed]

Greenfield SF, Trucco EM, McHugh RK, et al: The Women’s Recovery Group Study: A Stage I trial of

women-focused group therapy for substance use disorders versus mixed-gender group drug

counseling. Drug Alcohol Depend 90:39–47, 2007 [PubMed]

Harwood H: Updating Estimate of the Economic Costs of Alcohol Abuse in the United States:

Estimates, Update Methods, and Data. Bethesda, MD, National Institute on Alcohol Abuse and

Alcoholism, 2000

Heilig M, Egli M: Pharmacological treatment of alcohol dependence: target symptoms and target

mechanisms. Pharmacol Ther 111:855–876, 2006 [PubMed]

Henggeler SW, Schoenwald SK, Pickrel SG: Multisystemic therapy: bridging the gap between

university- and community-based treatment. J Consult Clin Psychol 63:709–717, 1995 [PubMed]

Henry JA, Moloney C, Rivas C, et al: Increase in alcohol related deaths: is hepatitis C a factor? J Clin

Pathol 55:704–707, 2002 [PubMed]

Hock B, Schwarz M, Domke I, et al: Validity of carbohydrate-deficient transferrin (%CDT),

gamma-glutamyltransferase (gamma-GT) and mean corpuscular erythrocyte volume (MCV) as

biomarkers for chronic alcohol abuse: a study in patients with alcohol dependence and liver

disorders of non-alcoholic and alcoholic origin. Addiction 100:1477–1486, 2005 [PubMed]

Institute of Medicine: Prevention and Treatment of Alcohol Problems. Washington, DC, National

Academy Press, 1990, pp 268–269

Johnston JD, O’Malley PM, Bachman JG, et al: Monitoring the Future: National Results on

Adolescent Drug Use: Overview of Key Findings, 2005 (NIH Publ No 05-5726). Bethesda, MD,

National Institute on Drug Abuse, 2006

Jones KL, Smith DW: Recognition of the fetal alcohol syndrome in early infancy. Lancet

2(7836):999–1001, 1973 [PubMed]

Kaner E, Heather N, McAvoy B, et al: Interventions for excessive alcohol consumption in primary

health care: attitudes and practices of English general practitioners. Alcohol Alcohol 34:559–566,

1999 [PubMed]

Kessler RC, Nelson CB, McGonagle KA, et al: The epidemiology of co-occurring addictive and mental

disorders: implications for prevention and service utilization. Am J Orthopsychiatry 66:17–31, 1996

[PubMed]

Kiefer F, Wiedemann K: Combined therapy: what does acamprosate and naltrexone combination tell

us? Alcohol Alcohol 39:542–547, 2004 [PubMed]

King AC, Volpicelli JR, Frazer A, et al: Effect of naltrexone on subjective alcohol response in

subjects at high and low risk for future alcohol dependence. Psychopharmacology (Berl)Print: Chapter 9. Clinical Management of Alcohol Abuse and Dependence http://www.psychiatryonline.com/popup.aspx?aID=346216&print=yes…

16 of 17

18/10/2008 10:11

129:15–22, 1997 [PubMed]

Kranzler HR, Burleson JA, Brown J, et al: Fluoxetine treatment seems to reduce the beneficial

effects of cognitive-behavioral therapy in type B alcoholics. Alcohol Clin Exp Res 20:1534–1541,

1996 [PubMed]

Krystal JH, Cramer JA, Krol WF, et al: Naltrexone in the treatment of alcohol dependence. N Engl J

Med 345:1734–1739, 2001 [PubMed]

Mann K, Lehert P, Morgan MY: The efficacy of acamprosate in the maintenance of abstinence in

alcohol-dependent individuals: results of a meta-analysis. Alcohol Clin Exp Res 28:51–63, 2004

[PubMed]

Mayo-Smith MF: Pharmacological management of alcohol withdrawal. A meta-analysis and

evidence-based practice guideline. JAMA 278:144–151, 1997 [PubMed]

Mayo-Smith MF, Beecher LH, Fischer TL, et al: Management of alcohol withdrawal delirium. An

evidence-based practice guideline. Arch Intern Med 164:1405–1412, 2004 [PubMed]

McGinnis JM, Foege WH: Mortality and morbidity attributable to use of addictive substances in the

United States. Proc Assoc Am Physicians 111:109–118, 1999 [PubMed]

Mokdad AH, Marks JS, Stroup DF, et al: Actual causes of death in the United States, 2000. JAMA

291:1238–1245, 2004 [PubMed]

Myrick H, Anton RF: Recent advances in the pharmacotherapy of alcoholism. Curr Psychiatry Rep

6:332–338, 2004 [PubMed]

Myrick H, Taylor B, LaRowe S, et al: A retrospective chart review comparing tiagabine and

benzodiazepines for the treatment of alcohol withdrawal. J Psychoactive Drugs 37:409–414, 2005

[PubMed]

National Institute for Alcohol Abuse and Alcoholism: The physician’s guide to helping patients with

alcohol problems (NIH Publ No 95-3769). Rockville, MD, National Institute for Alcohol Abuse and

Alcoholism, 1995

Ntais C, Pakos E, Kyzas P, et al: Benzodiazepines for alcohol withdrawal. Cochrane Database of

Systematic Reviews, Issue 3, Article No: CD005063, 2005

O’Malley SS, Jaffe AJ, Chang G, et al: Naltrexone and coping skills therapy for alcohol dependence.

A controlled study. Arch Gen Psychiatry 49:881–887, 1992 [PubMed]

Oslin DW: Late-life alcoholism: issues relevant to the geriatric psychiatrist. Am J Geriatr Psychiatry

12:571–583, 2004 [PubMed]

Oslin DW, Berrettini W, Kranzler HR, et al: A functional polymorphism of the mu-opioid receptor

gene is associated with naltrexone response in alcohol-dependent patients.

Neuropsychopharmacology 28:1546–1552, 2003 [PubMed]

Pettinati HM, Volpicelli JR, Kranzler HR, et al: Sertraline treatment for alcohol dependence:

interactive effects of medication and alcoholic subtype. Alcohol Clin Exp Res 24:1041–1049, 2000

[PubMed]

Project MATCH Research Group: Project MATCH secondary a priori hypotheses. Addiction

92:1671–1698, 1997

Project MATCH Research Group: Matching alcoholism treatments to client heterogeneity: treatment

main effects and matching effects on drinking during treatment. J Stud Alcohol 59:631–639, 1998

Regier DA, Farmer ME, Rae DS, et al: Comorbidity of mental disorders with alcohol and other drug

abuse. JAMA 264:2511–2518, 1990 [PubMed]

Saitz R, Mayo-Smith MF, Roberts MS, et al: Individualized treatment for alcohol withdrawal: aPrint: Chapter 9. Clinical Management of Alcohol Abuse and Dependence http://www.psychiatryonline.com/popup.aspx?aID=346216&print=yes…

17 of 17

18/10/2008 10:11

randomized double-blind controlled trial. JAMA 272:519–523, 1994 [PubMed]

Saunders JB, Aasland OG, Babor TF, et al: Development of the Alcohol Use Disorders Identification

Test (AUDIT): WHO Collaborative Project on Early Detection of Persons with Harmful Alcohol

Consumption—II. Addiction 88:791–804, 1993 [PubMed]

Schuckit M, Tapert S: Alcohol, in American Psychiatric Publishing Textbook of Substance Abuse

Treatment, 3rd edition. Edited by Galanter M, Kleber HD. Washington, DC, American Psychiatric

Publishing, 2004, p 159

Shuckit MA, Tipp JE, Bergman M, et al: Comparison of induced and independent major depressive

disorders in 2,945 alcoholics. Am J Psychiatry 154:948–957, 1997

Schuckit MA, Smith TL, Daeppen JB, et al: Clinical relevance of the distinction between alcohol

dependence with and without a physiological component. Am J Psychiatry 155:733–740, 1998 [Full

Text] [PubMed]

Srisurapanont M, Jarusuraisin N: Opioid antagonists for alcohol dependence. Cochrane Database of

Systematic Reviews, Issue 25, Article No: CD001867, 2005

Substance Abuse and Mental Health Services Administration: Substance abuse among older adults:

treatment improvement protocol (TIP: Series #26). Rockville, MD, U.S. Department of Health and

Human Services, 1998

Substance Abuse and Mental Health Services Administration: 2004 National survey on drug use and

health. Rockville, MD, U.S. Department of Health and Human Services, 2004

U.S. Department of Health and Human Services: Highlights from the 1989 National Drug and

Alcoholism Treatment Unit Survey (NDATUS). Rockville, MD, National Institute on Drug Abuse,

1990

Verheul R, Lehert P, Geerlings PJ, et al: Predictors of acamprosate efficacy: results from a pooled

analysis of seven European trials including 1485 alcohol-dependent patients. Psychopharmacology

(Berl) 178:167–173, 2005 [PubMed]

Volpicelli JR, Alterman AI, Hayashida M, et al: Naltrexone in the treatment of alcohol dependence.

Arch Gen Psychiatry 49:876–880, 1992 [PubMed]

Weisner C, Schmidt L: Gender disparities in treatment for alcohol treatment problems. JAMA

268:1872–1876, 1992 [PubMed]

Wright C, Moore RD: Disulfiram treatment of alcoholism. Am J Med 88:647–655, 1990 [PubMed]

SUGGESTED READING

Anton RF: Carbohydrate-deficient transferrin for detection and monitoring of sustained heavy drinking. What

have we learned? Where do we go from here? Alcohol 25:185–188, 2001

Anton RF, Swift RM: Current pharmacotherapies of alcoholism: a U.S. perspective. Am J Addict 12 (suppl

1):S53–S68, 2003

Oslin DW, Berrettini W, Kranzler HR, et al: A functional polymorphism of the mu-opioid receptor gene is

associated with naltrexone response in alcohol-dependent patients. Neuropsychopharmacology 28:1546–1552,

2003

Pettinati HM, Volpicelli JR, Kranzler HR, et al: Sertraline treatment for alcohol dependence: interactive effects

of medication and alcoholic subtype. Alcohol Clin Exp Res 24:1041–1049, 2000

Smothers BA, Yahr HT, Ruhl CE: Detection of alcohol use disorders in general hospital admissions in the United

States. Arch Intern Med 164:749–756, 2004

Copyright © 2008 American Psychiatric Publishing, Inc. All Rights Reserved.