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Medications in
the Treatment of Alcohol Addiction
Joseph
R. Volpicelli MD, PhD *Dr. Volpicelli is Director, Recovery Options Research Center and Associate Professor of Medicine, Department of Psychiatry, University of Pennsylvania, Philadelphia. <Read This article On the AlcoholMD Website> Behavioral approaches to alcohol addiction are moderately effective, with about half the patients showing significant reductions in excessive alcohol drinking in the year after beginning treatment.1 The combined use of medications with behavioral treatments offers the promise of improving treatment response rates and making recovery easier. Contributions from 20 years of basic research have advanced our understanding of the biological factors associated with addiction to alcohol. Based on this scientific foundation, the rational use of medications has demonstrated improved treatment outcomes in several research studies. The purpose of this report is to: 
review medications to aid
alcohol withdrawal, and reduce
alcohol addiction relapse rates,
discuss the role of medications
combined with psychosocial treatments, and
Medical Treatments for Alcohol Detoxification Medications provide a safe and effective means to facilitate detoxification from alcohol. Increasingly, alcohol detoxification occurs in outpatient settings. Except for relatively rare cases of medical or psychiatric emergencies, the use of medications dramatically reduces withdrawal symptoms and makes alcohol detoxification in ambulatory settings a safe and effective alternative to inpatient treatments.2 The object of alcohol withdrawal treatment is to block autonomic hyperactivity. This can be safely accomplished by using 1 of several classes of medications (e.g., benzodiazepines, antihypertensives, and anticonvulsants). The autonomic hyperactivity associated with withdrawal from alcohol is thought related to low levels of gamma amino butyric acid (GABA) activity or excessively high levels of the excitatory amino acids. The net effect is that the sympathetic nervous system becomes hyperactive, leading to withdrawal symptoms such as rapid heart rate, sweating, tremor, and nausea. In addition to these peripheral signs of alcohol withdrawal, the central nervous system becomes hyperactive and can lead to symptoms of anxiety, convulsions, and in severe cases delirium. Benzodiazepines Benzodiazepines are the primary medications of choice to treat alcohol withdrawal symptoms. Benzodiazepines are GABA agonists and so attenuate any deficiency in GABAergic activity. The benzodiazepine class of medications is not only effective for the peripheral symptoms of sympathetic hyperactivity but can attenuate the central nervous system withdrawal effects and effectively reduce anxiety, seizure risk, and risk for delirium. The pharmacological half-life of benzodiazepines differs greatly among the many types available. Some clinicians recommend the use of long-acting benzodiazepines such as chlordiazepoxide since the dose can be given at the first visit and the benzodiazepine will gradually self-taper.3 An advantage of the loading technique is that the medication can be given in an outpatient office and thus insure good medication compliance. Antihypertensives Beta-adrenergic blockers. Beta-blockers such as propranolol can be helpful adjuncts for alcohol detoxification. Unlike benzodiazepines, beta-blockers are not habit forming and can thus be used without concern for an abuse potential. This class of medications is effective in blocking many of the peripheral symptoms of alcohol withdrawal such as tremors, rapid heart rate, and sweating. This class of medications is less effective than benzodiazepines in reducing central signs and symptoms of alcohol withdrawal including alcohol craving and withdrawal seizures. Alpha-2 Adrenergic Agonists. The alpha-2 adrenergic agonists such as clonidine represent another class of antihypertensive medications that can effectively block autonomic hyperactivity and treat alcohol withdrawal. The alpha-2 adrenergic agonists reduce sympathetic hyperactivity and, like the beta-blockers, reduce many of the peripheral signs of alcohol withdrawal. In addition to reducing heart rate, and sweating, this class of medications is particularly helpful when hypertension is a significant component of withdrawal. Anticonvulsants Since alcohol withdrawal seizures are a potential complication of alcohol withdrawal, the use of anticonvulsants such as carbamazepine can be considered. The prophylactic use of anticonvulsants may prevent kindling, which is the increased tendency for nervous instability following each episode of alcohol withdrawal. Medications to Reduce Relapse Rates Disulfiram (Antabuse) Disulfiram inhibits the liver enzyme, aldehyde dehydrogenase, and blocks the metabolism of alcohol leading to high levels of acetylaldehyde. Alcohol drinking thus causes a toxic reaction associated with nausea, vomiting, sweating, malaise, and cramps. These negative consequences of drinking in the presence of disulfiram thus cancel the positive effects of alcohol. Large multicenter studies and randomized controlled trials have indicated that disulfiram has limited clinical utility since patients are often non-compliant in taking the medication.4 However, with supervision and positive contingencies for taking disulfiram, the effectiveness of disulfiram is enhanced.5 In an attempt to improve compliance, disulfiram implants have been developed. However, the implants have not resulted in the desired outcome largely due to inability of the implants to deliver adequate dosages to effectively block aldehyde dehydrogenase.6,7 Opioid Antagonists (Naltrexone) Animal studies have consistently shown a role for alcohol in the activation of the endogenous opioid system. This activation helps account for many of the rewarding and pleasurable effects of alcohol.8,9,10 The animal studies show that alcohol stimulates the release of endogenous opioids (e.g., endorphins) and alcohol drinking is reduced when opioid antagonists (e.g., naltrexone) block opioid receptors. The endorphin release stimulated by alcohol is particularly enhanced in rats and humans with a genetic predisposition for excessive alcohol drinking.11,12 For example, Gianoulakis and colleagues have found that individuals with a positive family history of alcoholism will have an enhanced release of peripheral levels of beta-endorphin following a moderate dose of alcohol. In contrast, for social drinkers without a family history of alcoholism, there is no increase in beta-endorphin levels.11 Pharmacokinetics, and Pharmacodynamics. Naltrexone, an opioid antagonist, has a half-life of about 4 hours, and its major metabolite, 6-beta naltrexol has a half-life of approximately 12 hours. When taken orally, naltrexone is rapidly absorbed and will obtain peak plasma levels in about 60 to 90 minutes. Safety. Naltrexone undergoes extensive first pass liver metabolism and there is some evidence of dose-related hepatotoxicity at doses 4-5 times higher than the currently recommended 50 mg daily dosage. More than 2 percent of alcohol dependent patients participating in an open-label safety trial reported nausea (10%), headache (8%), dizziness, nervousness, and fatigue (4% each), insomnia and vomiting (3% each), and anxiety and somnolence (2% each).13 With the exception of opiate containing medications, naltrexone taken concomitantly with antidepressant therapy does not lead to increases in adverse events relative to those not on antidepressant therapy.13 Naltrexone is contraindicated in patients with opioid dependence, patients in acute opioid withdrawal, those who require opioid analgesics for management of pain, and those with acute hepatitis or liver failure. Since naltrexone is an opioid antagonist, special considerations are required for the management of medical emergencies requiring pain management. Efficacy. Naltrexone was originally approved for the treatment of opiate addiction in 1984 and subsequently was approved for the treatment of alcoholism in the United States in 1994. Naltrexone has since been approved for the treatment of alcoholism in many other counties including Canada, Australia, and many European and Asian countries. The efficacy of naltrexone has been tested in several double-blind, placebo-controlled trials. For example, Volpicelli, et al.14 found that daily naltrexone tablets combined with traditional psychosocial treatment dramatically decreased alcohol relapse in a population of male alcohol-dependent veterans. About half of the patients taking placebo tablets relapsed during the 12 week study, whereas less than 25 percent of the naltrexone treated subjects relapsed. Similar results were found by O'Malley, et al.15 using a large heterogeneous population including women. In general, these studies have been 12 weeks in duration; with 1 study15 reporting on a 6-month follow-up period. Samples have been comprised primarily of male subjects (ranging from 71-100%) without other complicating psychiatric or substance abuse problems. A few smaller studies have also included specialized populations, such as those who use cocaine and alcohol16 and older alcoholics.17 The behavioral interventions in these naltrexone studies include day hospital treatment, cognitive behavioral therapy, and supportive therapy. The efficacy of a 50 mg daily dose against placebo was the protocol for most of these studies. However, several studies in progress are evaluating higher doses (e.g., up to 100 mg daily) and for longer periods of time (9 and 12 months). In the studies of alcohol dependent subjects, the most consistent finding was that naltrexone decreased the risk of drinking at hazardous levels as well as the percentage of drinking days.14,15,19 The effectiveness of naltrexone was enhanced among subjects who consistently took the naltrexone.20 The optimal duration of therapy with naltrexone is unknown. While efficacy data are available for 12 weeks, data have been reported at scientific conferences suggesting that some patients benefit from longer-term naltrexone therapy. In a 12-week study, patients treated with naltrexone were less likely to experience heavy drinking during the 6-month follow-up period than those treated with placebo. However, there was evidence that the effects of naltrexone appeared to decline over time raising the question of whether longer-term therapy may indeed be needed. Thus, the potential for naltrexone taken for longer periods of time may be warranted and deserves further evaluation.20 Several small studies have been conducted evaluating the potential for naltrexone use in special populations of alcoholics. Individuals with comorbid alcohol and cocaine use disorders were evaluated in an open-label study using 150 mg of naltrexone per day.21 The report from this study showed a positive effect for naltrexone. In contrast, a double-blind placebo-controlled study using 50 mg of naltrexone per day in 64 subjects with comorbid alcohol and cocaine use reported a negative effect.17 Other special population studies include a small study in older alcohol dependent males that suggested naltrexone might be efficacious18 and an open-label trial of adolescents that reported a beneficial effect from naltrexone.22 A reduced risk of relapse following a lapse, has been reported with naltrexone use (Table 1). Double-blind placebo-controlled trials14,15,18,19,23,24 have shown that individuals in the naltrexone arm experienced significantly lower relapse rates. However, the mechanism for this effect is unknown. In the clinical trials, alcohol dependent subjects reported retrospectively that they felt less "high"27 and experienced lower levels of craving and incentive to continue drinking.28 Fixed alcohol dose administration studies in non-alcohol dependent social drinkers reported that naltrexone appeared to reduce some of the positive mood-altering effects (e.g., stimulation), but not the aversive effects of alcohol (e.g., cognitive impairment, sedation).29,30 Direct evidence that naltrexone treatment is associated with reduced speed of drinking and the number of drinks consumed has been obtained using free drinking situations.31 Finally, evidence that naltrexone reduces measures of craving or urge to drink has been shown in studies of heavy drinkers.31,32 Summary. Naltrexone, 50 mg daily, is efficacious in reducing the risk of heavy drinking and in increasing the percentage of days abstinent, as established by the clinical trials of this medication. The optimal duration of therapy and the efficacy of alternative doses have not been established, but clinical trials are in progress. Compliance with naltrexone has been linked to treatment outcome and is likely linked to adverse events. Although the side effect profile of naltrexone is clinically acceptable, efforts to minimize adverse events should be investigated. While the hypothesized effect of naltrexone on reduction of craving has been inconsistent, laboratory studies and anecdotal reports provide support for this hypothesis. Acamprosate The neurotransmitters, glutamate and gamma amino-butyric acid (GABA), are also modulated by alcohol. Alcohol has been shown to inhibit the function of the glutamatergic N-methyl-D-aspartate (NMDA) receptor in vitro. Preclinical studies of chronic alcohol adminis-tration demonstrate an upregulation of NMDA receptors. Furthermore, NMDA antagonists given during withdrawal from alcohol have been shown to suppress withdrawal seizures. Increased cerebrospinal fluid (CSF) levels of glutamate during ethanol withdrawal may be associated with development of seizures and repeated withdrawal episodes increase the risk for seizures. Alcohol has also been shown to modulate the GABA system. Chronic administration of alcohol results in decreased GABA activity. Likewise, GABA levels are reduced in the brain and CSF of recently detoxified alcoholics. Since chronic alcohol drinking leads to enhanced glutaminergic activity and reduced GABAergic activity, medications that directly affect these 2 neurotransmitters may reduce the risk for relapse. Acamprosate (calcium acetyl-homotaurine), is a structural analogue of GABA and an upper homologue of taurine. It displays high binding capacity with GABA receptors and demonstrates functional activity in direct and indirect tests of GABA activity.33 In more recent studies, acamprosate exhibited the ability to inhibit NMDA receptors.34,35 In addition, in preclinical studies, acamprosate produced dose-dependent decreases in alcohol consumption, as well as diminished reinstatement of alcohol drinking. Acamprosate has been approved for use in many European countries, Latin American countries, and in Australia, South Africa, and Hong Kong as a treatment for alcohol dependence. Pharmacodynamics, and Pharmacokinetics. Acamprosate has a low bioavailability (10%) and is not metabolized by the liver. Excretion is primarily through the kidney, with an excretion half-life of 18 hours.36,37 Safety. The most common adverse effect from acamprosate is diarrhea, with lesser effects as rash and libido changes. No apparent interactions with medications have been noted. A report on drug interactions with acamprosate in established alcohol dependent individuals indicated no interaction with a variety of concommitent medications (e.g., antidepressants, anxiolytics, disulfiram, hypnotics, or neuroleptics).36 Efficacy. Several placebo-controlled trials have demonstrated the efficacy of acamprosate. The treatment periods in these trials usually began after inpatient detoxification and range from 3 - 12 months with follow-up periods ranging from 0 - 12 months following the discontinuation of therapy. Dosing was typically adjusted to body weight in the early trials, but more recent studies have used a fixed dose of about 2 grams a day given in divided doses. Behavioral interventions were usually center specific. The primary outcome measures included retention in treatment and measures of abstinence (i.e., rate of abstinence preceding study visits), continuous abstinence (i.e., completing the study without having a drink), or a measure of cumulative abstinence duration. Cumulative abstinence duration was defined in some studies as the total number of days abstinent during the study and, in other studies, as the percentage of days abstinent during the study. Few studies reported on the amount of alcohol consumed during nonabstinent days. In a 12-week trial of 569 patients, 61% of patients treated with acamprosate were abstinent compared to only 32% of those treated with placebo.38 In a study of 272 severely dependent alcoholics who had been abstinent 14 - 28 days prior to acamprosate treatment, 43% of the acamprosate treated patients were continuously abstinent compared to 21% of those who received placebo over the course of 48 weeks.39 While overall abstinence rates were lower in a sample of severely dependent alcoholics with only 5 days of abstinence pretreatment, differences in abstinence rates were found favoring acamprosate over placebo during the 360-day treatment period.40 The advantage of acamprosate over placebo continued once acamprosate was discontinued after 6 and 12 months of active treatment. The majority of acamprosate studies report an advantage of acamprosate over placebo for measures of craving, abstinence, relapse, and/or percent drinking days (Table 2). In the United States, a 21-site, 6 month, double-blind, placebo-controlled trial has recently been conducted to determine safety and efficacy of acamprosate.49 Alcohol dependent patients (n = 601) were randomized, after 2 days of abstinence, to receive either placebo or a 2 gm (or 3 gm) daily dose of acamprosate. In addition to other parameters, daily reports of drinking quality were obtained. The results of this study are not published as of this time. Summary. In conclusion, the evidence suggests that acamprosate can have a positive effect on measures of abstinence from alcohol following inpatient detoxification. While it is hypothesized that this is due to the effects that acamprosate has on conditioned withdrawal and withdrawal-related craving, this theory has not been directly examined. Furthermore, ratings on analogue scales of craving have not distinguished acamprosate and placebo treated patients in the clinical trials to date. The potential effect of acamprosate on alcohol reinforcement and drinking following a lapse in abstinence is not understood at this time, because the majority of studies collected information on abstinence only. It is expected that the results of the US trial will provide additional information. Serotonin Specific Reuptake Inhibitors (SSRIs) Clinical observations of associations between alcoholism and psychiatric disorders (such as mood, anxiety, impulse control, and antisocial personality disorders) have prompted the use of medications that affect the serotonin system. There is a presumed relationship between these psychiatric disorders and a dysfunction in the serotonin system, which has led to speculation that alcohol dependence may also be related to some serotonin dysfunction. Pre-clinical research in animals and social drinkers suggests that alcohol drinking compensates for some deficiency in serotonergic activity. Studies conducted in animals selectively bred for high or low alcohol drinking behavior, indicate that the tissue content of serotonin is lower in certain brain regions of alcohol-preferring animals (P) as compared to non-preferring (NP) animals. This also the case with high alcohol drinking (HAD) rats compared to low alcohol drinking (LAD) rats.50 Another study recently reported that ethanol naive P rats have higher basal levels 5-hydroxyindoleacetic acid (5-HT) release compared with NP rats while chronic alcohol treated P rats had decreased extracellular levels of 5-HT in comparison to NP rats. Additional preclinical studies indicate that medications that enhance serotonergic activity concomittently reduce alcohol drinking in P and HAD rats as well as in unselected rat lines.50,51 For example, studies using serotonin uptake inhibitors such as fluoxetine reported robust decreases in alcohol drinking in the P rats.52,53 The clinical effects of medications that enhance serotonergic activity are controversial. Some studies demonstrate reductions in alcohol preference. In social drinkers the serotonin specific reuptake inhibitors (SSRIs), fluoxetine and citalopram, were found to reduce the amount of drinking in heavy social drinkers. More recent studies have indicated that alcohol dependent individuals with comorbid depression may benefit from fluoxetine therapy.54,55 Efficacy. Studies using SSRIs (summarized in Table 3) for the treatment of alcohol dependence have led to conflicting results. Thus, none of the SSRIs are currently approved for the treatment of alcoholism. In an Italian study with 81 subjects randomized to placebo, fluvoxamine or citalopram, both of the SRRI groups showed a higher incidence of continuous abstinence compared to the placebo group.58 Similarly, in a Finnish study of 62 randomized subjects, citalopram was more effective then placebo in alcohol drinking outcomes.59 In contrast, in the United States, a 12-week trial using fluoxetine in a general sample of alcohol dependent subjects, found no overall differences between the medication and placebo groups.54 In another study, doses of up to 60 mg per day of fluoxetine in a group of 101 participants, who also received weekly sessions of relapse prevention therapy, failed to reduce any measure of alcohol drinking. While there may be important sub-groups of alcoholics who self-medicate with alcohol, Kranzler and colleagues subsequently reanalyzed their fluoxetine results using a k-cluster technique to identify Type A and Type B alcoholics in order to evaluate for differences in the fluoxetine effects. The Type B alcoholic is thought to reflect some underlying serotonergic dysfunction since they tend to be more impulsive, have more emotional distress, and increased alcohol dependence severity. Contrary to predictions, when given fluoxetine, the Type B alcoholics drank more compared to placebo subjects.61 There were no medication differences in the Type A alcoholics. A variety of other medications affect the serotonin system but work through different mechanisms than the reuptake inhibitors. Once again, however, the results are inconsistent. For example, in a large multicenter placebo controlled trial, 493 participants were randomized to receive placebo or 1 of 3 doses of ritanserin, a 5-HT2 receptor antagonist with a treatment duration of 6 months. The results of the study showed no differences between the placebo group and any of the 3 medication groups.65 Summary. While several studies suggest that serotonergic mechanisms are involved in excessive drinking for some alcoholics, there have been no consistent results in clinical trials of serotonergic medications for alcoholism treatment. The heterogeneous nature of alcoholism may explain these inconsistencies and serotonergic medications may be helpful for only a subset of alcoholics. The finding that some subtypes of alcoholics may do worse while taking serotonergic medications is of considerable clinical interest and deserves further investigation. -Introduction-Detoxification -Reduce Relapse -Co-morbid Psychiatric Rx -Rx and Psychotherapy -Combining Rx -Conclusions -References Medications for Patients with Co-Morbid Psychiatric Conditions Lithium Many patients with mood disorders, particularly bipolar disorder, report alcohol use as a way to control mood instability. These reports led to some early small-scale trials of lithium for the treatment of alcoholism.67 Some studies suggested there were improved treatment outcomes among patients who received therapeutic levels of lithium.68 However, in a large multicenter, placebo-controlled trial of 457 male alcoholics involving both depressed and non-depressed individuals, no significant improvements in alcohol drinking outcomes were observed, either overall or in the depressed subgroup.69 Similarly, in a recent placebo-controlled double blind study there were no significant reductions in alcohol drinking for a general population of alcoholics.62 In general, the use of lithium to treat alcoholism does not receive empirical support. The most important role for lithium may be that its use in controlling bipolar symptoms may allow the patient with co-existing bipolar disorder and alcoholism a better opportunity to respond to treatment for alcoholism. Double-blind placebo-controlled trials are summarized in Table 4. Tricyclic Antidepressants (TCAs) The tricyclic antidepressants (i.e., impramine, des-ipramine, amytryptyline) represent a rather large class of medications that have been used to successfully treat mood and anxiety disorders for several decades. This class of medications, like the SSRIs, blocks the reuptake of serotonin but are far less specific in their actions. To varying degrees, they also block the reuptake of norepinephine, dopamine, and antagonize muscarinic and histaminic receptors. The effect of TCAs on antagonizing muscarinic receptors and histaminic receptors give TCAs substantial anticholinergic and sedative effects. These anticholinergic effects include dry mouth, constipation, and tachycardia. The antihistamine effects include drowsiness and sedation. Tricyclic antidepressants are metabolized in the liver by the cytochrome P-450 2D6 system and, thus, can interact with medications that are also metabolized by the P-450 system. It should also be considered that alcohol can induce liver enzyme activity and reduce plasma TCA levels. Efficacy. Studies using TCAs for the treatment of co-morbid depression and alcohol dependence have generally shown that the TCA effectively reduces symptoms of depression but has little effect on alcohol drinking. In a double-blind placebo-controlled trial of 71 alcohol dependent subjects, the effectiveness of desipramine for treating alcohol dependence was evaluated.73 Study participants with concurrent symptoms of depression (n = 28) were compared to those without depression (n = 41). While desipramine was effective in reducing depression scores in those with co-existing depression, there was no impact on reducing alcohol drinking. Another placebo-controlled double-blind study of alcohol dependent individuals and primary depression was conducted to evaluate the effectiveness of imipramine.74 Combined with relapse prevention therapy, imipramine was effective in improving depression. In this study, a subgroup of patients who demonstrated a good clinical response also demonstrated greater reductions in alcohol drinking compared to placebo. Thus, a subgroup of alcohol dependent patients with co-existing depression may decrease their alcohol drinking by treatment with TCA's, but more research is needed to establish this benefit. Double-blind placebo-controlled trials are summarized in Table 4. Serotonin
Specific Reuptake Inhibitors BRENDA Approach Behavioral interventions have been implemented to enhance motivation to remain in treatment and comply with taking medication. One intervention protocol, the BRENDA approach, developed at the University of Pennsylvania,76 incorporates various behavioral strategies. The main components of the BRENDA approach are giving people feedback, developing an empathic therapeutic relation, working collaboratively with the patient to develop treatment goals, and continuing to assess treatment adherence. Historical compliance rates at the Treatment Research Center of the University of Pennsylvania suggest that the BRENDA condition enhances treatment and medication compliance (Figure 1).77 A randomized controlled study is currently underway to directly compare the BRENDA approach to cognitive behavioral therapy and simple physician medication management. Combination TherapyThe acute reinforcing effects and the effects of chronic alcohol intake involve a number of neurotransmitter systems. Thus, a therapeutic approach targeting more than 1 system may be more effective than monotherapy. In addition, medications may be combined to target distinct aspects of the process of relapse (craving, abstinence, and/or relapse following an initial lapse in abstinence) in order to help a larger number of individuals with alcohol dependence. Finally, combination therapy of efficacious agents may permit the use of lower doses of 1 or both medications, thereby potentially improving tolerability and compliance with The effect of combining naltrexone and other agents thought to alter alcohol intake, including fluoxetine,78,79 a thyrotropin-releasing hormone analog TA-0910 fluoxetine, and naltrexone,80 the calcium channel blocker isradipine,81 the 5HT3 antagonist ondansetron82 and the 5-HT1A antagonist WA-100635 have been evaluated in rodent models.83 The majority of these studies have found at least an additive effect of combining naltrexone with these agents. Whether or not similar effects will be obtained in human subjects is under investigation for the combination of naltrexone and ondansetron64 and the SSRI, sertraline. Preliminary reports suggest some optimism for continuing to investigate these approaches to combination therapy.64,84 Secondary analyses of a double-blind placebo controlled study have been used to evaluate the potential for disulfiram to augment the efficacy of acamprosate.85 The trial of 118 Swedish subjects who were randomized to either acamprosate or placebo allowed disulfiram use on a voluntary basis. The secondary analysis compared subjects who took disulfiram in combination with either acamprosate (n = 24) or placebo (n = 22) and those who received only acamprosate or only placebo. The results indicated that combined therapy of acamprosate and disulfiram was associated with the highest continuous days abstinent compared to the other 3 groups. Since taking disulfiram was voluntary and requires supervision, differences between groups cannot be ruled out and indicate that these results should be considered with regard. Additional studies with randomization to these therapies would be beneficial. Preliminary safety data from normal volunteers and alcohol dependent subjects indicate a potential for the combined use of naltrexone and acamprosate.86 Targeting different neurobiological systems (i.e., the effect of naltrexone on reducing relapse and the impact of acamprosate on abstinence), the combination of these 2 drugs is considered so promising that a large, multicenter trial has been initiated to evaluate the efficacy of this combination.87 ConclusionsDuring the past 20 years, dramatic changes have occurred in the understanding of the pharmacology of alcohol. Advances, such as understanding alcohol's non-specific effects on membranes and specific effects on neurotransmitter systems and second messengers have led to newer, more effective treatments for alcoholism. The development of new medications has improved treatment outcomes and led to improved understanding of the vulnerability to alcohol dependence. Of the new medications, naltrexone and acamprosate offer the most immediate promise. For specific populations, serotonergic medications, tricyclic antidepressants, and mood stabilizers offer hope for treatment. The use of these medications alone or in combinations remains fertile avenues for research. Finally, special challenges are involved with the clinical use of medications for alcoholism treatment. Psychosocial treatments designed to improve motivation to remain in treatment and adhere to the medication regimen are important adjuncts to pharmacological treatment. The use of the compliance enhancing techniques can be safely and effectively integrated into primary care models and thus bring addiction treatment to a wide range of health care providers and thereby provide more people with successful therapy for alcoholism. References1. 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