FOR ALCOHOL ABUSE. Richard Saitz, MD, MPH, and Stephanie S. O Malley, PhD

Transcription

1 ALCOHOL AND OTHER SUBSTANCE ABUSE /97 $ PHARMACOTHERAPIES FOR ALCOHOL ABUSE Withdrawal and Treatment Richard Saitz, MD, MPH, and Stephanie S. O Malley, PhD Approximately 11 to 15 million persons in the United States report current heavy use of alcohol or alcohol abuse and dependence, costing almost $100 billion each year.47,58,113 Almost one half of these persons meet Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria for alcohol dependence, and almost 400,000 persons are in treatment for alcoholism at any one time.4, 47, *07 The lifetime prevalence of alcohol abuse is 14% and of alcohol dependence is 870, and there are more than 1 million discharges with an alcohol-related diagnosis, mostly alcohol dependence, from U.S. short-stay hospitals each year.37, lzy The prevalence of alcohol use disorders is high in the general population and is higher in general hospitals and in outpatient medical practices , 158 Clearly, physicians are in frequent contact with persons with alcohol problems. Physicians have the opportunity to intervene in a variety of ways, including prevention, recognition of the diagnosis, brief intervention, appropriate referral, management of withdrawal, and relapse prevention. This article focuses on the pharmacologic management of alcohol withdrawal and dependence. Dr. Saitz was supported in this work as a Faculty Fellow by the Center for Substance Abuse Prevention Faculty Development Program, grant number 1 T From the Clinical Addiction Research and Education Unit, Section of General Internal Medicine, Boston Medical Center, Boston University School of Medicine, Boston, Massachusetts (RS); and the Department of Psychiatry, Substance Abuse Treatment Unit, Yale University School of Medicine, New Haven, Connecticut (SSO) MEDICAL CLINICS OF NORTH AMERICA VOLUME 81 NUMBER 4 * JULY

2 882 SAITZ & OMALLEY PHARMACOTHERAPIES FOR ALCOHOL PROBLEMS Pharmacologic Effects and Goals of Pharmacotherapy Pharmacologic Effects of Alcohol Acutely, alcohol produces intoxication, and with repeated use, tolerance and dependence develop. Although alcohol at high doses results in cell membrane alterations that may be responsible for general anesthetic effects, coma, and respiratory depression, many of the effects of alcohol intoxication seen clinically are likely to be explained by more specific Io6 Alcohol affects endogenous opiates and several neurotransmitter systems in the brain, including y-aminobutyric acid (GABA), glutamate, and dopamine. Alcohol intake results in an increase in endogenous ~pioids.~~ These opioids may produce the euphoria experienced with alcohol consumption and play a role in reinforcing further consumption. Activation of inhibitory chloride influx mediated by the GABA A-type receptor during exposure to alcohol contributes to the anxiolytic and sedative effects and the impairment of motor coordination seen in intoxication.ioh Chronic alcohol exposure leads to decreases in GABA A-type receptor function, which may be involved in tolerance and withdrawal symptoms.' In addition to potentiating inhibitory neurotransmission, alcohol inhibits the function of the receptor for the excitatory neurotransmitter glutamate. The attenuating effect of alcohol on the N-methyl-D-aspartate (NMDA) type of glutamate receptor contributes to intoxication, impaired cognition and learning, and blackouts. Chronic alcohol intake also results in up-regulation of the NMDAtype glutamate receptor and excitotoxicity or neuronal cell death as a result of excessive glutamate receptor activation. These chronic changes are likely involved in blackouts, amnesia (and the Wernicke-Korsakoff syndrome), cerebellar degeneration, and susceptibility to withdrawal seizures.io6, 156 Finally, alcohol interacts with both serotonin and dopamine receptors, resulting in increases in dopamine in brain reward centers. These effects on monoamine neurotransmitters likely play a role in the rewarding and reinforcing effects of alcohol.1oh Currently, there are no clinically useful agents that can reverse all of the pharmacologic effects of alcohol. A compound known as RO partially antagonizes alcohol's effects at the GABA A-type receptor, thereby decreasing the sedative, anxiolytic, and motor impairment effects of alcohol but not the intoxicating lethal 79, 80, 93 Although the utility of an alcohol antagonist is unknown, its most likely role would be in reversing overdoses. Use of RO is currently limited by toxicities, including proconvulsant and anxiogenic effects. It is clear that alcohol has specific pharmacologic effects. Many mediators appear to be involved, and alcohol's clinical and biochemical effects cannot be explained by invoking only one mechanism. Knowledge of the several known pharmacologic mechanisms can be used to explain alcohol's clinical effects and to guide an understanding of effective and potential pharmacotherapies for alcohol abuse and dependence. Goals of Pharmacotherapy for Alcohol Problems The goals of pharmacotherapy for alcohol abuse or dependence include (1) the reversal of the pharmacologic effects of alcohol, (2) treatment and prevention of withdrawal symptoms and complications, (3) maintenance of abstinence and

3 PHARMACOTHERAPIES FOR ALCOHOL ABUSE 883 the prevention of relapse with agents that decrease craving for alcohol or the loss of control over drinking or make it unpleasant to ingest alcohol, and (4) treatment of coexisting psychiatric disorders that complicate recovery. This article focuses on the treatment of withdrawal and treatments to achieve abstinence and prevent relapse. More than 100 different medications have been reported as treatments for alcohol ~ithdrawa1.l~~ The best evidence for efficacy lies with the benzodia~epines.~~, lol Other agents such as the P-blockers may be useful adjuncts in certain situations. With benzodiazepines, however, the symptoms, signs, and complications of withdrawal can be prevented and treated. Once through the detoxification phase, medications can play a role in decreasing subsequent harmful alcohol intake. Agents such as naltrexone (ReVia), an opiate antagonist, and disulfiram (Antabuse), an alcohol-sensitizing drug, are approved for use in the treatment of alcoholism and have shown success in its treatment. Finally, other psychotropic agents have roles in treating psychiatric disorders that frequently coexist in patients with alcohol use disorders. These medications not only affect the comorbid psychiatric disorder, but also appear to reduce alcohol intake in such persons. PHARMACOLOGIC MANAGEMENT OF ALCOHOL WITHDRAWAL Incidence of Symptomatic Alcohol Withdrawal Between 13% and 71% of persons presenting for alcohol detoxification develop significant symptoms of alcohol withdrawal.hz, 13s, Is9, lh5 This wide-ranging incidence depends on the population studied and the severity of dependence in the subjects. In one series of more than 1000 ambulatory patients at a nonmedical detoxification program, one third developed tremors, but only 0.6% developed seizures or delirium tremens.'6x In patients hospitalized for alcohol withdrawal receiving no specific pharmacologic treatments, 15% developed seizures, and 15% developed delirium tremens.62, 159 The development of symptomatic withdrawal is dose dependent, as evidenced by the observations of 10 subjects consuming between 286 and 458 ml/ day of 95% ethanol (17 to 27 standard 1.5 ounce shots of 80 proof liquor) for 7 to 87 days.59 On sudden abstinence, all subjects developed weakness, anorexia, diaphoresis, and tremor. Six subjects who had been drinking the larger amounts for the longest period of time all developed nausea, vomiting, hyperreflexia, diarrhea, fever, and hypertension. Five of these developed hallucinations and seizures or delirium tremens. Mechanism of Alcohol Withdrawal The central nervous system adapts to the overall inhibitory effects of longterm alcohol exposure on inhibitory GABA A-type and excitatory NMDA-type glutamate receptor transmission by adjustments in receptor number and function. When alcohol is no longer present, these adaptations result in greater central nervous system excitability.

4 884 SAITZ & OMALLEY Symptoms of Alcohol Withdrawal The DSM-IV definition of alcohol withdrawal includes two main component~.~ The first component is a history of cessation or reduction in heavy and prolonged alcohol use. The second component includes the presence of symptoms of alcohol withdrawal (two or more): autonomic hyperactivity (sweating or tachycardia); increased hand tremor; insomnia; nausea or vomiting; transient tactile, visual, or auditory hallucinations; psychomotor agitation; anxiety; and grand ma1 seizures. The best validated tool for the measurement of symptom severity in alcohol withdrawal is the Clinical Institute Withdrawal Assessment Scale for Alcohol, revised (CIWA-Ar) (Table l).152 This tool, applied only after the diagnosis of alcohol withdrawal is made, is helpful for assessment of severity and guidance in treatment and allows clinicians to communicate more objectively regarding the severity of withdrawal. The scale should be used one to three times daily, more frequently when patients are symptomatic, and as frequently as hourly when making medication dosing decisions based on symptoms. Because the symptoms measured by the CIWA-Ar are nonspecific, caution must be used in its interpretation when the scale is applied to patients with other acute illnesses that may mimic alcohol withdrawal (eg, sepsis). The delirium tremens are a later complication of alcohol withdrawal defined by the presence of disorientation and hyperautonomic signs, often preceded by gradually worsening autonomic symptoms. Seizures and hallucinations, however, may occur in the absence of significant additional symptoms. Goals of Pharmacotherapy for Alcohol Withdrawal Goals for alcohol-dependent persons decreasing or discontinuing alcohol intake include (Table 2) the prevention and treatment of symptoms, seizures, delirium tremens, and medical or psychiatric complications; long-term abstinence after detoxification, and entry into ongoing medical and alcohol-dependence treatment. Long-term complications that might be affected by pharmacologic intervention include the propensity to have seizures during future withdrawal episodes, known as kindling, and the development of Korsakoff s psychosis.*, 2 1 There is substantial evidence that pharmacologic management of alcohol withdrawal can treat and prevent symptoms of withdrawal, seizures, and delirium tremens. The impact of pharmacologic management on other manifestations of the alcohol withdrawal syndrome remains less clear. Pharmacotherapies for Alcohol Withdrawal Benzodiazepines Benzodiazepines are the drugs of choice for the management of alcohol withdrawal. The best evidence for efficacy exists for the long-acting benzodiazepines. Benzodiazepines have been shown not only to ameliorate the symptoms of alcohol withdrawal, but also to prevent seizures and delirium tremens., 24, 14, 176 In a randomized trial in 537 symptomatic hospitalized patients, those receiving chlordiazepoxide had a combined rate of seizures or delirium tremens of 2% compared with 10% to 16% for patients receiving chlorpromazine

5 PHARMACOTHERAPIES FOR ALCOHOL ABUSE 885 Table 1. CLINICAL INSTITUTE WITHDRAWAL ASSESSMENT SCALE FOR ALCOHOL, REVISED (CIWA-Ar) Nausea and vomitinpask Do you feel sick to your stomach? Have you vomited? Observation 0 no nausea with no vomiting intermittent nausea with dry heaves constant nausea, frequent dry heaves and vomiting Paroxysmal sweats-observation 0 no sweats visible 1 barely perceptible sweating, palms moist n L 3 4 beads of sweat obvious on forehead drenching sweats Agitation-Observation 0 normal activity 1 somewhat more than normal activity moderately fidgety and restless paces back and forth during most of the interview or constantly thrashes aboui Tremor-Arms extended and fingers spread apart. Observation 0 no tremor 1 not visible, but can be felt fingertip to fingertip moderate, with patient s arms extended severe, even with arms not extended Visual disturbances-ask Does the light appear to be too bright? Is its color different? Does it hurt your eyes? Are you seeing anything that is disturbing to you? Are you seeing things you know are not there? Observation 0 not present 1 very mild sensitivity 2 mild sensitivity 3 moderate sensitivity 4 moderately severe hallucinations 5 severe hallucinations 6 extremely severe hallucinations 7 continuous hallucinations Tactile disturbances-ask Have you any itching, pins and needles sensations, any burning, any numbness or do you feel bugs crawling on or under your skin? Observation none very mild itching, pins and needles, burning, or numbness mild itching, pins and needles, burning, or numbness moderate itching, pins and needles, burning, or numbness 4 moderately severe hallucinations 5 severe hallucinations 6 extremely severe hallucinations 7 continuous hallucinations Headache, fullness in bead-ask Does your head feel different? Does it feel like there is a band around your head? Do not rate for dizziness or lightheadedness. Otherwise rate severity 0 not present 1 very mild 2 mild 3 moderate Auditory disturbancesask Are you more aware of sounds around you? Are they harsh? Do they frighten you? Are you hearing anything that is 4 moderately severe disturbing to you? Are you hearing things you know 5 severe are not there? Observation 6 verysevere 0 not present 7 extremely severe I very mild harshness or ability to frighten 2 mild harshness or ability to frighten Anxietj-Ask Do you feel nervous? Observation 3 moderate harshness or ability to frighten 4 moderately severe hallucinations no anxiety, at ease 5 severe hallucinations mildly anxious 6 extremely severe hallucinations 7 continuous hallucinations moderately anxious, or guarded, so Orientation and clouding of sensorium-ask What day anxiety is inferred is this? Where are you? Who am I? 0 oriented and can do serial additions 1 cannot do serial additions 2 disoriented for date by no more than 2 calendar equivalent to acute panic states as seen in severe delirium or acute days schizophrenic reactions 3 disoriented for date by more than 2 calendar days 4 disoriented for Place and/or person Total score is a simple sum of each item score (maximum score = 67) Adapted from Sullivan JT, Sykora K, Schneiderman J, et al: Assessment of alcohol withdrawal: The revised clinical institute withdrawal assessment for alcohol scale (CIWA-Ar). Br J Addict 84:1353, 1987; with permission. (The scale is not copyrighted and may be used freely.)

6 886 SAlTZ & OMALLEY Table 2. GOALS OF PHARMACOTHERAPY FOR ALCOHOL WITHDRAWAL Goals for which substantial evidence of effectiveness exists Treatment of alcohol withdrawal symptoms Prevention of initial and recurrent seizures Prevention and treatment of delirium tremens Other goals Prevention of medical and psychiatric complications of alcohol withdrawal Prevention of kindling effect Prevention of Korsakoff's psychosis Improvement in the likelihood of abstinence Minimization of adverse drug effects Entry into ongoing medical and addictions treatment Cost-effective treatment (Thorazine), thiamine, hydroxyzine (Atarax), or placebo.62 Although one study has found that diazepam (Valium) was more effective for the management of withdrawal symptoms than lorazepam (Ativan), resulting in a smoother course of withdrawal and less chance of recurrent symptoms, few clinically significant differences between the benzodiazepines used in the treatment of alcohol withdrawal have been found.9, 17, y2, yh, 11", Iz8, 144, 173 The best evidence for efficacy in preventing the serious complications of seizures and delirium tremens, however, lies with chlordiazepoxide (Librium) and diazepam.h2, 137 Furthermore, shorteracting benzodiazepines such as alprazolam (Xanax) or oxazepam (Serax) may be less effective in the prevention of seizures and are associated with a higher risk of the development of seizures during alcohol withdrawal.*y, 14'. 17' Benzodiazepines have been compared with other medications for the management of alcohol withdrawal. Although phenothiazines, clonidine (Catapres), and carbamazepine (Tegretol) may reduce symptoms, no evidence supports their ability to prevent seizures or delirium tremens.", 84, lso In fact, seizures are more common when phenothiazines are used, and delirium is more common when P-blockers are used as monotherapy for alcohol withdrawal.25, 62, 17b The benzodiazepines are generally safe.4x,141 There is a small risk of excessive sedation, particularly in inadequately monitored patients, the elderly, or patients with significant liver disease.s4 In such cases (e.g., hepatic synthetic dysfunction with hypoalbuminemia or elevated prothrombin time or severe lung disease with carbon dioxide retention), oxazepam or lorazepam may be preferable. There are no controlled data to guide pharmacotherapy of alcohol withdrawal in pregnancy. Although both chlordiazepoxide and diazepam are category D drugs, meaning that there is evidence of human fetal risk, the benefit of using a proven effective therapy for a brief course of therapy to prevent serious maternal and fetal complications likely outweighs the risks.1o, 61, y7, lss When there is concern that medication may be diverted or that the diagnosis of alcohol withdrawal is in question, the use of benzodiazepines with lower abuse potential, such as the slower onset of action agents for oral use, chlordiazepoxide or oxazepam, should be considered in preference to those with more rapid onset, such as diazepam, lorazepam, or alprazolam.5, 4y, 141 Lastly, when cost is a consideration, the inexpensive oral chlordiazepoxide, diazepam, or lorazepam could be chosen.iz7 The use of the costly parenteral lorazepam and the short-acting intravenous agents (i.e., midazolam [Versed]) has no advantage over the use of the longer-acting drugs and produces similar Parenteral agents should be used only when medications cannot be given orally and for the delirium tremens.

7 PHARMACOTHERAPIES FOR ALCOHOL ABUSE 887 Other Drugs and Adjunctive Pharmacologic Therapies Other drugs that have been used in the management of alcohol withdrawal include barbiturates, alcohol (ethanol), sympatholytics, carbamazepine, neuroleptics, magnesium, and thiamine. Barbiturates. Barbiturates are the second most common drug class used to treat alcohol withdrawal in the United Although there is clinical experience suggesting efficacy, and anticonvulsant properties are well known, there is only one controlled trial of barbiturate use for alcohol withdrawal. Patients received either oral barbital or intramuscular diazepam for symptoms as needed.h6 Although a subgroup of patients receiving barbital was more likely to achieve a satisfactory effect, overall there was no difference in either time to sedation or clinical condition. This single study supports the clinical experience that notes the ability of a long-acting barbiturate to alleviate the symptoms of alcohol withdrawal. The barbiturates, particularly the long-acting ones, are also more likely to result in respiratory depression and have a worse toxic-to-therapeutic index compared with the benzodiazepine~.~~ Furthermore, there are no controlled trials comparing barbiturates to placebo, and there are no data on the efficacy of barbiturates in the treatment or prevention of seizures or delirium tremens. Although evidence is lacking, favorable clinical experience and consensus suggest that phenobarbital is an acceptable alternative for the management of alcohol withdrawal in pregnant women.i0, 61, 97, Is5 Alcohol. Because alcohol relieves the symptoms of alcohol withdrawal and continued alcohol intake prevents the development of alcohol withdrawal, it might appear that alcohol would be useful in the management of alcohol withdrawal. In the only interpretable controlled study, alcohol did not prevent the development of seizures and delirium tremen~.~~ Furthermore, alcohol has known toxicities (pancreatitis, hepatitis, bone marrow suppression), has a short half-life, has no known advantages to its use, and requires the monitoring of blood levels when used intravenously. Also, its use may appear to condone alcohol intake to the alcoholic who may be beginning recovery. Sympatholytics. Because the symptoms of alcohol withdrawal are at least in part due to increased sympathetic outflow, sympatholytics would appear to be logical treatments. In patients withdrawing from alcohol and receiving oxazepam as needed, vital signs became normal more rapidly in patients randomized to atenolol (Tenormin) rather than placebo.69 In a subgroup of subjects symptomatic at baseline, atenolol improved withdrawal symptoms. Clonidine has been shown to be as effective as chlordiazepoxide and more effective than placebo in treating the signs and symptoms of alcohol withdrawal.", l4 Although sympatholytics improve some symptoms and signs of alcohol withdrawal, the sympathetic nervous system is not solely responsible for the manifestations of alcohol withdrawal. Clonidine, other central a-adrenergic agonists, and P-blockers have not been shown to have any favorable impact on seizures or delirium. In fact, propranolol (Inderal) has been associated with a higher incidence of delirium.'76 Additionally, P-blockers may provide a false sense of security by correcting some of the autonomic manifestations of withdrawal, such as tachycardia or hypertension, thereby clouding the clinical picture in a patient who may nevertheless be progressing to delirium tremens or seizures. Thus, sympatholytics are not appropriate monotherapy for alcohol withdrawal. The main role of P-blockers in the management of alcohol withdrawal is when additional pharmacologic control of autonomic signs and symptoms is

8 888 SAITZ & OMALLEY desired, for example, in cases of angina or marked anxiety. Clonidine may have a role in the management of coexisting severe hypertension or in cases of combined opiate and alcohol ~ithdrawal.~~ Carbamazepine. This anticonvulsant is as effective as oxazepam and more effective than placebo in treating the minor signs and symptoms of alcohol withdrawal.'" 84 Although at higher doses nausea and ataxia may limit use, potential advantages of carbamazepine include the lack of a dependence syndrome, lack of an interaction with alcohol, its safety when used in the shortterm for alcohol withdrawal, and its potential to prevent alcohol withdrawal seizures and kindling8, 27, 125 Currently, however, there is no evidence regarding treatment or prevention of delirium and insufficient evidence in humans to permit safety and efficacy conclusions regarding the use of carbamazepine to treat alcohol withdrawal. Neuroleptics. Neuroleptics can reduce the symptoms of alcohol withdrawal, but they (particularly the phenothiazines) are less efficacious in preventing delirium and may increase the risk of seizures during alcohol withdrawal.", I4O Therefore, they should not be used as monotherapy for alcohol withdrawal. Neuroleptics, however, particularly the butyrophenones such as haloperidol (Haldol), are useful as adjunctive therapy to treat agitation and hallucinations. Thiamine and Magnesium. Neither thiamine nor magnesium has been shown to have any impact on the signs or symptoms of alcohol withdrawal or the incidence of seizures or delirium during alcohol withdrawal.62, 172 Both thiamine and magnesium, however, have a role in the pharmacologic management of alcohol withdrawal. Although relatively uncommon as part of the acute presentation of alcohol withdrawal, Wernicke's encephalopathy (confusion, ataxia, and ophthalmoplegia) and Korsakoff's syndrome are disastrous complications if they deve10p.l~~ Acute Wernicke's encephalopathy may go undiagnosed initially but can be prevented by administration of thiamine before glucose administrati~n.~~, 157 Therefore, an initial dose of parenteral thiamine followed by daily oral doses should be administered to patients withdrawing from alcoh01.'~~~ 174 Hypomagnesemia is common in patients withdrawing from 131 Hypomagnesemic patients can develop many nonspecific signs and symptoms, including hyperactive reflexes, weakness, tremor, reversible hypoparathyroidism with hypocalcemia, refractory hypokalemia, and cardiac dy~rhythmias.~~, 157, 167 Serum magnesium levels are unhelpful and can be misleading in that total body stores may be depleted in the face of a normal serum level. Also, initially low serum levels often return to normal spontaneously even though total body magnesium deficiency persists. The signs and symptoms of clinical magnesium deficiency are nonspecific and may go unrecognized, complications can be catastrophic, and magnesium administration is safe in the absence of renal impairment. Therefore, magnesium should be given to all persons with signs of deficiency and should be routinely considered for all patients withdrawing from alcohol.y' In severe magnesium deficiency, the deficit is approximately 1 to 2 meq/kg of body weight; greater than 50% of a dose given intravenously is excreted when renal function is normal. The goal is to replete half of the deficit on the first day, then the remaining deficit on the following 4 days9' For example, for a 70-kg person, administer 32 to 48 meq (4 to 6 ampules) of magnesium sulfate in each of 2 L of intravenous fluid on the first day followed by half that amount daily for 4 days. Oral repletion with magnesium-containing antacids can be effective but may be limited by diarrhea.

9 PHARMACOTHERAPIES FOR ALCOHOL ABUSE 889 Selecting Patients for Pharmacotherapy of Alcohol Withdrawal The decision to manage alcohol withdrawal with or without medications should be based on the risk of developing severe symptoms, delirium tremens and seizures, side effects of medications, patient comfort, and the presence of concomitant conditions such as coronary artery disease or pregnancy, which may themselves be complicated by symptomatic alcohol withdrawal. Large numbers of patients can safely detoxify from alcohol with no medications.iz, 146, 168 Unfortunately, no known clinical features or combination of features absolutely predicts the development of the complications of withdrawal or rules out their occurrence. Time abstinent can be helpful in deciding on the need for pharmacologic intervention. In one large study, no patient who was asymptomatic at 36 hours of abstinence developed symptoms requiring medication.12 Other clinical features help to identify a greater likelihood of development of alcohol withdrawal symptoms, more severe symptoms, and seizures or delirium (Table 3). Duration of alcohol abuse for 6 or more years increases the odds of developing any withdrawal symptoms 15 times. In one study, 73% of those who abused alcohol for 6 or more years developed withdrawal symptoms, whereas 86% of those who abused alcohol for a shorter period of time did not develop symptoms.8 Higher breath or blood alcohol at the beginning of detoxification is associated with a greater requirement for medication, worse tremor, and worse overall withdrawal severity.29, I5l, Although consuming larger amounts of alcohol is associated with more severe withdrawal symptoms, other patient characteristics, such as older age, duration of alcoholism, and severity of alcohol dependence, are more predictive of withdrawal severity in multivariable analyses.8, 19, 78, Iz4, 149 Gastrointestinal illness and elevation in serum aspartate aminotransferase levels have also been associated with more severe withdrawal, although these may simply be markers reflecting severity of alcoholism.im, I5l, I6l More severe craving and withdrawal symptoms at baseline have been associated with longer duration of alcohol withdrawal symptoms."' Although prediction of symptoms can be helpful, it would be more useful to be able to predict the occurrence of seizures or delirium. A higher alcohol Table 3. RISK FACTORS FOR MORE SEVERE ALCOHOL WITHDRAWAL SYMPTOMS, SEIZURES, AND DELIRIUM TREMENS Concomitant medical or surgical illness Moderate-to-severe withdrawal symptoms at baseline Older age Prior delirium tremens Prior detoxification@) Prior seizures Time since last drink Severity of alcohol dependence Elevated aspartate aminotransferase Greater degree of craving Greater quantity and frequency of alcohol intake Higher blood or breath alcohol Longer duration of alcoholism More symptoms of alcohol dependence Presence of alcohol-associated gastrointestinal illness

10 890 SAlTZ & OMALLEY level on admission, coexisting drug abuse, more prior detoxifications or hospitalizations, and a history of prior alcohol withdrawal seizures have been associated with the Occurrence of seizures during alcohol withdrawal (Table 3).16, 33, 71, loo, 145 Earlier age of onset of alcoholism, duration of alcoholism, a history of prior delirium, days since last drink, serum electrolyte and liver function test abnormalities, and comorbid medical or surgical illness have been associated with the occurrence of delirium or confusion during alcohol withdrawal.8, 13, 38, 39, 72, Ih6 The presence of moderate to severe withdrawal symptoms (similar to a CIWA-Arzl5) left untreated is one of the strongest predictors of confusion and seizures.3y Who should receive specific medication cross-tolerant with alcohol (eg, benzodiazepines) to manage withdrawal? There are no known factors or combinations of factors that predict with sufficient accuracy who will suffer the serious complications of alcohol withdrawal. All persons with a history of alcohol withdrawal seizures should receive medication during detoxification from alcohol. Seizures are more likely to occur in those who have previously had them and may not be preceded by warning autonomic symptoms or signs. All persons with moderate to severe symptoms and signs of alcohol withdrawal (i.e., a CIWA-Ar of 215) should receive medications. These patients are at substantial risk of developing the preventable complications of seizures and delirium tremens. Serious consideration should be given to choosing pharmacologic management of withdrawal in patients with longer duration and greater severity of alcoholism in those with mild to moderate symptoms (CIWA-Ar 8 to 14), in those with multiple prior detoxification episodes, in those with concomitant acute medical or surgical illness, and in pregnant patients. In addition to being at higher risk for seizures, patients with multiple detoxification derive theoretic benefit from prevention of kindling8 Patients with acute medical or surgical illness are not only at higher risk for complicated withdrawal, but also they may go on to seizures or confusion even if withdrawal symptoms and signs are minimal at pre~entation.~~ In pregnancy, although the risk of developing seizures or delirium tremens may not be increased, the consequences of the occurrence of these complications for the mother and fetus are serious. If pharmacologic therapy is not instituted, close monitoring for the development or worsening of symptoms or signs of withdrawal is required to identify failures of nonpharmacologic treatment in whom medications should be started. Persons with minimal or no symptoms at 36 hours after the last drink can safely be managed without pharmacologic therapy. Treatment Settings for the Management of Alcohol Withdrawal Given a comparison of the prevalence of alcohol dependence and the number of persons in treatment each year, it is likely that much detoxification from alcohol occurs outside the health care system. Within the health care system, alcohol withdrawal treatment occurs in outpatient settings, inpatient detoxification units, or hospitals. There is successful clinical experience with selected patients for home and outpatient detoxification, and one randomized trial compared inpatient and outpatient treatment for mild to moderate withdrawal. This comparison revealed that costs and duration of treatment were lower in the outpatient group at the expense of worse treatment completion rates and short-term abstinence rates (although 6-month abstinence rates were not

11 PHARMACOTHERAPIES FOR ALCOHOL ABUSE 891 A controlled case series showed similar outcomes in selected patient~.'~~ In another study of outpatient detoxification, symptom severity and craving but not socioeconomic status or homelessness were associated with treatment failure."' Selected patients can be safely detoxified as outpatients (Table 4). A detailed evaluation should be done looking for coexisting acute or chronic medical, surgical, or psychiatric conditions (including pregnancy) that would complicate alcohol withdrawal and indicate inpatient treatment. Candidates for outpatient treatment should have only mild to moderate symptoms, no significant concurrent other drug use, and little alcohol craving and should be reassessed frequently (i.e., daily) to decide on the benzodiazepine prescription. It is helpful to have a responsible sober person available to help the patient monitor symptoms and administer medications. A history of seizures or delirium tremens makes outpatient management more risky and should be considered when the triage decision is made. Although socioeconomic status and homelessness may make outpatient treatment more challenging, they are not associated with treatment failure and therefore do not contraindicate outpatient treatment of withdrawal. Treatment Regimens Treatment of Symptoms and Prevention of Complications Fixed-Schedule Therapy. Benzodiazepines given regularly at a fixed dosing interval are the gold standard therapy for alcohol withdrawal. This type of regimen, for example, chlordiazepoxide 50 to 100 mg orally every 6 hours for 1 day followed by 2 days at 25 to 50 mg per dose (Table 5), is known to prevent delirium and seizures.62 Patients should be monitored and given additional medication when indicated by symptoms. This type of regimen is useful in patients who require medications regardless of symptoms, including those with a history of seizures. It also may be preferable for pregnant women, patients with acute medical or surgical illness, or patients with a history of delirium tremens. Front-Loading. The advantage of front-loading is that the regimen delivers high doses of medication early in the course of ~ithdrawa1.l~~ Diazepam is given in 20-mg doses every 2 hours until resolution of withdrawal symptoms. On average, three medication doses are required. This regimen has also been shown to decrease rates of seizures. Advantages of front-loading are that medication administration and intensive monitoring are limited to the early symptomatic Table 4. SELECTING PATIENTS FOR OUTPATIENT TREATMENT FOR ALCOHOL WITHDRAWAL Contraindications to outpatient withdrawal management Severe alcohol withdrawal symptoms Delirium tremens Coexisting acute or chronic illness necessitating inpatient treatment Pregnancy Follow-up not feasible Relative contraindications to outpatient withdrawal management History of seizures History of delirium tremens Significant craving

12 892 SAITZ & OMALLEY Table 5. TREATMENT REGIMENS FOR ALCOHOL WITHDRAWAL Fixed-schedule dosing Chlordiazepoxide orally every 6 h for 3 d ( mg per dose day 1, then mg per dose). Additional mg every 1-2 h as needed Front-loading Diazepam 20 mg orally every 2 h while symptomatic until resolution Symptom-triggered therapy Chlordiazepoxide mg orally hourly whenever symptomatic (CIWA-Ar 28) For delirium tremens Diazepam 10 mg intravenously, then 5 mg every 5 min until calm but awake If unable to take oral medication or in the presence of hepatic synthetic dysfunction (hypoalbuminemia, elevated prothrombin time), intramuscular, sublingual, oral, or intravenous (for delirium tremens only) lorazepam 1-4 mg may be substituted Oral oxazepam mg or lorazepam may be substituted in the elderly and those at risk of excessive sedation or its complications All patients should receive thiamine mg daily, first dose parenterally. Consider magnesium administration (intravenously) 2-4 meqlkg on day 1, meqlkg daily on days 2-4 (see text) CIWA-Ar = Clinical Institute Withdrawal Assessment-Alcohol, revised scale. period of withdrawal, and the long-acting medications and their metabolites provide a self-tapering effect over time. The period of medication treatment is substantially shorter than the fixed-schedule regimen. Front-loading is appropriate for the same symptomatic patients eligible to receive fixed-schedule medications. If used in asymptomatic patients with concomitant acute medical disorders or a history of seizures, at least one dose should be administered. Symptom-Triggered Therapy. This regimen delivers medication only when the patient is symptomatic (i.e., CIWA-Ar 28).135, 151, 165 The advantage of this regimen is that treatment with medications is shorter, potentially avoiding oversedation and allowing the patient to proceed with treatment for alcohol dependence. Because it has been rigorously studied only in patients without seizures or acute comorbid medical illness, use of the regimen should be restricted to these groups. Choice of Appropriate Regimens. The main consideration in choosing a treatment regimen is whether medication must be delivered regardless of withdrawal symptoms (i.e., seizure history, acute medical illness) or if medication administration can be safely guided by symptoms. Regardless of regimen chosen, the key is frequent patient reevaluation, particularly early on, with attention to the symptoms and signs of alcohol withdrawal and to excessive sedation from medications. A cookbook regimen does not obviate this requirement; therapy should be individualized. Sedative medications should not be given to somnolent or sleeping patients. Significant symptoms and signs should be treated with more medication. The tendency to declare a particular benzodiazepine a treatment failure when symptoms persist should be resisted. This failure is usually due to inadequate dosing. Rather than switching specific drugs, larger additional doses usually treat all persistent alcohol withdrawal symptoms. Treatment of Alcohol Withdrawal Seizures Alcohol withdrawal seizures are generalized, occur early in the course of withdrawal (first 24 to 48 hours), and usually are single or recur only once or

13 PHARMACOTHERAPIES FOR ALCOHOL ABUSE 893 twice.lm The seizures generally resolve spontaneously. Benzodiazepines, carbamazepine, and probably phenobarbital prevent seizures, but phenytoin is ineffective and therefore not indicated for prophylaxis or treatment of seizure^.^, 26, lz6, 136, 147 If the seizure is not typical for alcohol withdrawal (eg, focal seizures, focal neurologic examination, head trauma, suspected intracranial bleeding, meningitis or encephalitis, or status epilepticus), however, the use of phenytoin is reasonable? The mainstay of treatment for alcohol withdrawal seizures is administration of benzodiazepines as in the regimens previously described, preferably diazepam, chlordiazepoxide, or lorazepam, all shown to prevent initial and recurrent seizures.%, Treatment of Delirium Tremens The long-acting benzodiazepines are known to prevent the delirium tremens.62 The most effective and safest treatment regimen for established delirium tremens is intravenous diazepam. When such patients were randomized to either paraldehyde or diazepam 10 mg followed by 5 mg every 5 minutes, the diazepam group achieved a calm but awake state more rapidly and suffered fewer complications including death.154 To deliver this treatment safely, constant observation is necessary. PHARMACOLOGIC MANAGEMENT OF ALCOHOL DEPENDENCE Mechanism of Alcohol Dependence Pharmacotherapy has played an important, if not central, role in helping patients safely initiate abstinence. Historically, however, pharmacotherapies have not been used to help maintain abstinence following cessation of drinking. In recent years, there have been extensive efforts to identify medications to assist in the rehabilitation of the person with alcohol dependence. The core feature of the alcohol dependence syndrome is loss of control over drinking.99 The person with alcohol dependence is preoccupied with thoughts about drinking and finds it difficult to abstain from alcohol despite negative consequences. In addition, once drinking begins, the patient drinks more than he or she intended. In this regard, initial alcohol consumption appears to prime further drinking.35, 82 These aspects of alcohol dependence, craving for alcohol and loss of control over drinking, have been the targets of pharmacologic interventions for primary alcohol dependence. Two medications, disulfiram and naltrexone, are currently marketed for the treatment of alcohol dependence in the United States. Disulfiram is intended to prevent impulsive resumption of drinking in response to craving or other cues because the patient knows that disulfiram in combination with ethanol results in an aversive rea~tion.~" Naltrexone is a competitive opioid antagonist that has been shown to reduce craving for alcohol and increase abstinence rates when combined with psychosocial treatment.ll6< In addition, naltrexone reduces the risk of continued drinking if a lapse in abstinence occurs, possibly because it blocks some of the reinforcing effects of alcohol that prime further drinking.119, ls3, lm Finally, serotonin reuptake inhibitors and serotonin agonists are currently under investigation as agents that may reduce the amount of alcohol consumed by patients in alcohol treatment.67

14 894 SAITZ & OMALLEY Pharmacotherapies for Alcohol Dependence Alcohol Sensitizing Drugs Alcohol sensitizing drugs, including disulfiram and calcium carbimide (Temposil, Abstem, available in Canada only), are used to deter a patient from drinking by producing an aversive reaction if the patient drinks. These drugs inhibit the liver enzyme aldehyde-nicotinamide-adenine dinucleotide (NAD) oxireductase (aldehyde dehydrogenase [ALDH]), which catalyzes the oxidation of acetaldehyde, a toxic by-product of alcohol metabolism, to acetate. The resulting increase in acetaldehyde produces an aversive reaction characterized by facial flushing, throbbing headache, nausea and vomiting, chest pain, palpitations, tachycardia, weakness, dizziness, blurred vision, confusion, and hypotension. Severe reactions can occur, particularly in vulnerable individuals, including myocardial infarction, congestive heart failure, cardiac arrhythmia, respiratory depression, convulsions, and death. Disulfiram can provoke an adverse interaction with alcohol for up to 2 weeks after it has been discontinued, but the time of risk for occurrence of an aversive reaction is usually up to 4 to 7 days. With calcium carbimide, this effect lasts only 24 hours. Calcium carbimide has fewer side effects and fewer drug interactions than dis~lfiram.~~, R5 Patients should be advised to avoid all sources of alcohol (eg., mouthwash and vinegars). When first developed in the 1940s, disulfiram was used as an aversive agent; the patient was exposed to ethanol while on the medication. Because this exposure can be dangerous, disulfiram should be prescribed as a tool to support the patient's decision to abstain. By taking disulfiram once a day, knowledge of the disulfiram-ethanol interaction can prevent drinking later in the day. Although disulfiram appeared to be effective in a series of small-scale studies, these were largely un~ontrolled.8~ Since then, a well-designed, largescale cooperative study of 605 male veterans treated for 1 year found 250 mg of disulfiram to be no better than an inert dose or no pill in helping patients remain ab~tinent.~' A subset of patients who relapsed, however, drank significantly less frequently during the year of treatment if they had received 250 mg disulfiram compared to those who did not. This subset of patients tended to be older and more socially stable. Contraindications. There are a number of contraindications to disulfiram use (Table 6).," Because of the potential adverse effects of the disulfiram-ethanol interaction, patients with cerebrovascular, cardiovascular, or severe pulmonary disease or chronic renal failure are not candidates for disulfiram. The use of disulfiram in patients who may have occult vascular disease, such as those over 60 years of age and patients with diabetes, should also be avoided.40, 138 Because of the danger of vomiting during the aversive reaction and the potential for variceal hemorrhage, disulfiram is contraindicated in cirrhosis with portal hypertension. The severity of the disulfiram-ethanol interaction may also be increased by drugs that impair blood pressure regulation such as a-adrenergic and p- adrenergic receptor antagonists and vasodilators. Patients with organic brain syndromes are not candidates because they may not understand or remember the risks associated with the disulfiram-ethanol reaction, a prerequisite to effective treatment. Disulfiram can worsen psychiatric symptoms, lower the seizure threshold, and cause peripheral neuropathy and should be avoided in patients with these conditions (with the exception of patients with prior alcohol withdrawal seizures). Disulfiram is also contraindicated in pregnancy because of an association with birth defects. Disulfiram can cause drowsiness, and so it should not be used in patients whose occupations require alertness to avoid safety problems. To evaluate the severity of this side

15 PHARMACOTHERAPIES FOR ALCOHOL ABUSE 895 Table 6. CONTRAINDICATIONS TO THE USE OF DlSULFlRAM AND NALTREXONE Conditions resulting in increased risk associated with the disulfiram-ethanol reaction Cerebrovascular disease Cardiovascular disease Severe pulmonary disease Renal failure Cirrhosis with portal hypertension Occult atherosclerosis (i.e., >age 60, diabetes) Conditions that may be exacerbated by disulfiram Psychosis Significant depressive illness Idiopathic seizure disorder Peripheral neuropathy Other contraindications to disulfiram Organic brain syndrome: limited ability to understand risks of disulfiram-ethanol reactions Pregnancy: associated with birth defects Precautions for the use of disulfiram Concurrent use of a-adrenergic or p-adrenergic receptor antagonists Concurrent use of vasodilators Absolute contraindications to naltrexone Acute hepatitis or liver failure Current dependence on opiate or opiate withdrawal Need for opiate medication Relative contraindications to naltrexone Pregnancy Adolescence effect, disulfiram should be taken first on the weekend at bedtime and discontinued if the patient continues to be drowsy on awakening after 2 to 3 days of medi~ation.~~ A rare but potentially fatal idiosyncratic hepatotoxicity can occur with disulfiram. As a result, baseline liver function tests (serum bilirubin, transaminases, alkaline phosphatase) should be obtained and the patient monitored for hepatotoxicity by symptoms and by repeating the blood tests at 2 weeks, 3 months, 6 months, then twice yearly while on disulfiram. Hepatotoxicity typically occurs within the first 3 months of treatment. Drug Interactions. Disulfiram has the potential to interfere with the biotransformation of several drugs, including warfarin, phenytoin, isoniazid, rifampin, diazepam, chlordiazepoxide, imipramine, and desipramine leading to toxic levels. As a result, drug levels or the prothrombin time (warfarin) should be used to monitor dosage levels if these drugs are needed. Dosage. The usual dose of disulfiram is 250 mg daily, which should not be begun until at least 24 hours after the last drink. The 250-mg dose is generally preferred because it is associated with fewer side effects than 500 mg, although some investigators have suggested that the lower dose does not reliably produce an aversive reaction if the patient drinks.18, 70 Although alcohol sensitizing agents are generally prescribed to be taken on a daily basis, an alternative strategy that has been proposed is that they could be taken in anticipation of specific high- risk situations.6, lz8, Iz1 Patient Selection. Disulfiram is a modest benefit to selected patients with alcohol dependence. Disulfiram appears to work primarily through the psychological knowledge of the potential ethanol-disulfiram interaction and does not

16 896 SAITZ & OMALLEY appear to have a primary effect on craving or the urge to drink. Perhaps as a result, disulfiram s utility is limited not only by contraindications, but also by problems with compliance and patient acceptability. In the large cooperative trial of veterans, for example, only 20% were compliant, and they had similar outcomes regardless of whether they took placebo or disulfiram. Disulfiram, however, may provide some assistance to the highly motivated patient with a stable home environment or to the patient participating in a treatment program that uses strategies to enhance compliance with di~ulfiram.~, 41 Women have been rarely studied, and so these conclusions are drawn primarily for male alcoholics. Disulfiram has beneficial effects on drinking in subsets of patients, and although it is not first-line therapy for alcohol dependence, it can be helpful in selected patients. Opiate Antagonists Naltrexone, an opiate antagonist, was approved by the Food and Drug Administration in 1994 for use in the treatment of alcohol dependence. Nalmefene, an experimental opiate antagonist derived from naltrexone, also shows promise for this indication.88 Naltrexone was originally developed for the treatment of opiate addiction and effectively blocks the effects of exogenous In contrast to disulfiram, naltrexone does not cause severe adverse reactions to alcohol. Instead, naltrexone is thought to attenuate the reinforcing effects but not the negative aspects of alcohol consumption, such as cognitive impairment and ~edati0n.i~~ Among alcoholics in treatment, those who consumed alcohol reported feeling less intoxicated and less craving for The efficacy of naltrexone for use in alcohol dependence has been investigated in two placebo-controlled clinical trials.118, In a combined analysis of the data from the 186 alcohol-dependent patients in these two studies, patients randomized to receive 50 mg of naltrexone for 12 weeks were more likely to remain abstinent and to avoid relapse to heavy drinking; 31% of placebo patients remained abstinent compared to 54% of patients on naltrexone; 48% of placebo patients avoided heavy drinking, whereas 75% of naltrexone patients successfully avoided drinking to excess. Craving for alcohol was also significantly lower for patients on naltrexone. In a follow-up study, two thirds of patients originally treated for 12 weeks with naltrexone remained predominantly free of alcohol-related problems during the 6 months following discontinuation of the medication; in contrast, only one third of the placebo-treated patients remained free of problem^."^ The maintenance of abstinence during treatment was a strong predictor of outcome 6 months later. As a result, abstinence should be the goal of treatment. The decision regarding the continuation of naltrexone beyond 12 weeks is based on clinical judgment. In making this decision, the physician considers whether the patient has made changes that could support continued abstinence, the patient s previous history of response to treatment, and the patient s interest in continuing. When used to treat opiate addiction, naltrexone is generally used for at least 6 months.36 Although the previous studies examined naltrexone as an adjunct to traditional alcoholism treatment approaches, a primary care-based treatment of alcohol dependence with adjunctive naltrexone may be feasible.112 Patients receive naltrexone and supportive counseling provided by a nurse practitioner or a physician s assistant weekly for 4 weeks and biweekly for 6 weeks under the supervision of a physician. In preliminary analyses, 20 of 30 patients successfully completed treatment, and the majority reported significant reductions

17 PHARMACOTHERAPIES FOR ALCOHOL ABUSE 897 in drinking and had lower gamma glutamyltransferase (GGT) levels.11z Data comparing the effectiveness of this model to the effectiveness of naltrexone provided within a specialized alcoholism treatment program are needed. Contraindications and Side Effects. Naltrexone can precipitate a severe withdrawal syndrome in patients currently dependent on opiates and is therefore contraindicated in such patients (see Table 6). At doses substantially higher than the 50 mg daily recommended for the treatment of alcoholism, naltrexone has been shown to have dose-related hepatotoxicity.izz As a result, naltrexone is contraindicated in patients with acute hepatitis or liver failure. The mild transaminitis often seen in alcoholism is not a contraindication to naltrexone; however, baseline bilirubin and serum transaminases and periodic monitoring of transaminases are indicated monthly for the first 3 months, then every 3 months. More frequent monitoring may be indicated if transaminases are elevated. Naltrexone should be discontinued if persistent elevations in liver enzymes occur, unless mild (less than three times normal) elevations are attributable to ongoing alcohol use. In the clinical trials of naltrexone, patients on naltrexone had lower serum transaminase levels at termination than patients on placebo, presumably because they were drinking less.11s, 16* Finally, the safety of naltrexone has not been evaluated in pregnant women or in adolescents. The most common side effect of naltrexone is nausea, often coinciding with peak drug levels within 90 minutes of administration, which was reported by 10% of patients who participated in a large multisite safety st~dy.~~,~~ Other common side effects that occurred in more than 2% of patients were headache, dizziness, nervousness, fatigue, insomnia, vomiting, anxiety, and somnolence. Drug Interactions. Because disulfiram and naltrexone are both potential hepatotoxins, their combined use is not recommended. The combined use of naltrexone in combination with thioridazine may result in increased lethargy and somnolence. The incidence of adverse events does not appear to be elevated in patients receiving antidepressants and naltre~one.~~ Naltrexone precipitates withdrawal in opiate-dependent persons. Pain Management. Because naltrexone blocks the effects of opiates, nonopioid pain medications or approaches should be tried, including nonsteroidal antiinflammatory agents. When opioids are necessary for the treatment of severe pain, the blockade can be overridden with a rapidly acting analgesic, but treatment must be monitored in a setting staffed and equipped for cardiopulmonary resuscitation because the resulting respiratory depression may be deeper and more prolonged. Patients needing elective surgery and opioid-containing analgesics should be advised to discontinue naltrexone at least 72 hours before the scheduled procedure. Dosage. The recommended dosage of naltrexone is 50 mg daily. To minimize the severity of side effects, some investigators recommend 25 mg daily for the first 2 days, then increasing to 50 mg daily if tolerated. At 50 mg daily, naltrexone effectively blocks p,-opioid receptors. Although not yet documented, doses up to 100 mg daily may be more effective in the treatment of alcohol dependence. Medication compliance is likely to be enhanced by recommending morning dosing as part of the patient's usual routine (e.g., with breakfast). Morning routines are better established for most people, and this may be particularly true for alcohol-dependent patients who are more likely to drink in the evenings. In addition, the risk of nausea appears to be lower with longer duration of ab~tinence."~ Patient Selection. The potential benefits of naltrexone outweigh the risks for many patients. Because studies of addictions treatment have found that medication alone is not adequate treatment, naltrexone should be provided as

18 898 SAITZ & OMALLEY part of an overall treatment plan that includes co~nseling.~" Compliant patients have better outcomes when taking naltrexone than when taking placebo and are therefore likely to be better treatment candidates.io0, lo* To minimize risks, naltrexone should be prescribed only after patients have been stabilized from acute withdrawal from alcohol. For patients with a history of opiate abuse, a 7-day period of abstinence from short-acting opiates (e.g., heroin) is required to avoid precipitating withdrawal, whereas 10 to 14 days may be needed for patients who have been using long-acting opiates (e.g., methadone). In an effort to identify whether there is a subset of patients who particularly benefit from the addition of naltrexone to psychotherapy, the following characteristics have been identified: (1) high levels of craving for alcohol; (2) poorer educational attainment or poor cognitive skills; and (3) a history of alcoholism in first-degree relatives6", 115, 163 These predictors can be considered potential guides only, however, because the subjects studied were primarily male alcoholics without substantial comorbid psychiatric or drug abuse problems. Other Medications for Alcohol Dependence Several investigators have examined the potential utility of selective serotonin reuptake inhibitors, including ritanserin, ondansetron, and fluoxetone, for reducing alcohol consumption. These drugs can produce decreases in alcohol consumption in heavy drinkers.y8, IU2, lu4, lo5 Placebo-controlled studies in alcoholdependent patients have found no differences in any measures of drinking outcomes,6k, 13y although fluoxetine was effective in reducing depressive symptoms among depressed patients.68 Although their safety and effectiveness make the selective serotonin reuptake inhibitors reasonable choices for the treatment of depression in alcoholics, their use cannot be recommended for the treatment of nondepressed alcoholics without further study. Acamprosate, calcium acetylhomotaurinate, is approved for use for the treatment of alcoholism in several European countries. In contrast to naltrexone, which is thought to reduce positive reinforcement from alcohol, acamprosate is hypothesized to reduce the craving associated with conditioned alcohol withdrawal, by reducing glutamate activity and stimulating inhibitory GABA transmission.32, 175 Acamprosate appears to be well tolerated; diarrhea is the major side effect.12" Several large, multisite, 3- to 12-month, placebo-controlled trials in Europe have found improvements in abstinence rates favoring acamprosate (18% versus 7% continuously abstinent at 1 year in one 75, 76, 12", 169 Additional study is needed to determine whether acamprosate can affect other outcomes, such as drinking amounts when patients experience a lapse in abstinence. Furthermore, study has been primarily in severely alcohol-dependent patients. Although it remains unclear which patients benefit the most from acamprosate, further study may show it to be an important addition to the options for the pharmacologic treatment of alcohol dependence. Adjunctive Treatment for Alcohol Dependence None of the pharmacologic treatments for alcoholism represent cures but rather tools for helping the patient be more successful in efforts toward recovery. Patients need more than a prescription and advice to call if there are any problems. Provision of frequent supportive counseling or other psychosocial treatment is essential and is a key to insuring medication compliance. In addition, these visits can provide an opportunity to address partial response to

19 PHARMACOTHERAPIES FOR ALCOHOL ABUSE 899 Table 7. STRATEGIES TO ADDRESS PARTIAL RESPONSE TO PHARMACOTHERAPY OF ALCOHOL DEPENDENCE Review the need for pharmacologically assisted or inpatient detoxification Evaluate medication compliance and institute strategies to increase compliance Intensify the level of psychosocial intervention Involve a significant other in treatment Evaluate for and treat comorbid psychopathology, such as anxiety or depression Evaluate whether an alternative medication would be more effective treatment (Table 7), to revise the treatment plan, and to continue evaluation of the need for more intensive or more specialized treatment. Alcoholism is associated with high rates of comorbid psychiatric disorders, especially depression and anxiety disorders.53, 64 The effective management of depression and anxiety in alcoholics with pharmacotherapy can lead to improvements in affective symptoms and may be associated with reductions in drinking and alcohol-related problems.28, 30, 87, Io8, 142 Effective management of these psychiatric problems is important because these patients may relapse in response to the ongoing stress associated with anxiety or depre~sion.~, The provision of psychosocial support and treatment of comorbid psychiatric illness by the primary care provider or by more specialized alcohol treatment services augments the effectiveness of pharmacologic treatments for alcoholism (described elsewhere in this issue). This comprehensive multimodality approach to treatment is effective for helping many patients make substantial strides in recovery from alcoholism. SUMMARY Pharmacologic management of alcoholism is only one part of the management of both alcohol dependence and withdrawal, which also includes the provision of a calm, quiet environment; reassurance; ongoing reassessment; attention to fluid and electrolyte disorders; treatment of coexisting addictions and common medical, surgical, and psychiatric comorbidities; and referral for ongoing psychosocial and medical treatment. 03, 143, ls7, I7O For further discussion of these topics, the reader is referred to previously published s0urces.9~, 13*, 15*, I7I A survey of alcoholism treatment programs revealed that although benzodiazepines were the most commonly used drugs, standardized monitoring of patients withdrawal severity was not common practice, and a significant minority of clinicians were using a variety of other drugs, some not known to prevent or treat the complications of withdra~a1.i~~ Treatment should be based on the available evidence (Working Group on Pharmacological Management of Alcohol Withdrawal: American Society of Addiction Medicine Committee on Practice Guidelines: Pharmacological management of alcohol withdrawal: An evidencebased practice guideline. Unpublished draft, 1997).57 Patients with significant symptoms, patients with complications such as seizures or delirium tremens, and patients at higher risk for complications of alcohol withdrawal should receive benzodiazepines, particularly chlordiazepoxide, diazepam, or lorazepam, because of their safety and documented efficacy in preventing and treating the most serious complications of alcohol withdrawal. These drugs may be dosed on a fixed schedule for a predetermined number of doses on a tapering schedule over several days, or they may be administered

20 900 SAITZ & OMALLEY by front-loading. An alternative approach for selected patients without seizures or acute comorbidity is symptom-triggered therapy, which individualizes treatment and decreases the duration and dose of medication administration. With either of the regimens, patients should have their withdrawal severity monitored until symptoms are resolving. Once withdrawal from alcohol is safely completed, the focus should turn to helping to prevent relapse. Disulfiram may be useful in highly motivated subsets of patients and when compliance-enhancing strategies are used. Naltrexone is useful in the broader population of patients entering treatment for alcohol dependence. These pharmacologic interventions should be given in the context of ongoing psychosocial support. There is substantial evidence that pharmacologic management of alcohol abuse and dependence is effective. As would be predicted from alcohol s myriad cellular effects, no panacea exists for alcoholism. For alcohol withdrawal, however, although treatment regimens have only recently been refined, evidence for effective treatment of symptoms and prevention of complications with benzodiazepines has been available for decades. Within the last decade, effective treatments, including naltrexone, have been shown to reduce alcohol intake in alcohol-dependent persons. Given the prevalence and cost of alcohol-related problems, all effective therapies (including pharmacologic treatments) should be considered to treat alcohol abuse and dependence. References 1. Allan AM, Harris RA: Involvement of neuronal chloride channels in ethanol intoxication, tolerance, and dependence: In Galanter M (ed): Recent Developments in Alcoholism. New York, Plenum, 1987, p Alldredge BK, Lowenstein DH: Status epilepticus related to alcohol abuse. Epilepsia 34:1033, Alldredge BK, Lowenstein DH, Simon RP: Placebo-controlled trial of intravenous diphenylhydantoin for short-term treatment of alcohol withdrawal seizures. Am J Med 87645, American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, ed 4. Washington, DC, American Psychiatric Association, American Psychiatric Association: Task Force on Benzodiazepine Dependency: Benzodiazepine Dependence, Toxicity and Abuse. Washington, DC, American Psychiatric Association, Annis HM: A cognitive-social learning approach to relapse: Pharmacotherapy and relapse prevention counseling. Alcohol Alcohol (suppl 1):527, Baekeland F, Lundwall L, Kissin B, et al: Correlates of outcome in disulfiram treatment of alcoholism. J Nerv Ment Dis 153:1, Ballenger JC, Post RM: Kindling as a model for alcohol withdrawal syndromes. Br J Psychiatry 133:1, Banki CM: Comparative study with grandaxin and diazepam in alcohol withdrawal syndrome and gerontopsychiatric diseases. Ther Hung 31:120, Barron WM, Lindheimer MD (eds): Medical Disorders During Pregnancy, ed 2. St. Louis, Mosby, Baumgartner GR, Rowen AC: Clonidine versus chlordiazepoxide in the management of the acute alcohol withdrawal syndrome. Arch Intern Med , Benzer DG: Quantification of the alcohol withdrawal syndrome in 487 alcoholic patients. J Subst Abuse Treat 7117, Bezzegh A, Nyuli L, Kovacs GL: Alpha-atrial natriuretic peptide, aldosterone secretion and plasma renin activity during alcohol withdrawal: A correlation with the onset of delirium tremens? Alcohol 8:333, 1991