Acamprosate for Alcohol Dependence: An Update for the Clinician

Alcohol abuse and dependence are among the most prevalent mental disorders in the United States. In 2002–2004, 7.6% (18.2 million) of the U.S. population met the current criteria for these disorders (1–3). Of these individuals, approximately 7.9 million are considered alcohol dependent (4, 5). Additionally, more than 50% of American adults have a family member who is alcohol dependent (6).

Alcohol dependence not only has tremendous health consequences for those with the disorder (e.g., liver disease, cancer, high blood pressure, heart disease, psychiatric disorders, and injury from alcohol-related accidents) (7, 8), but it also affects their families, friends, and coworkers. Nearly 4 in 10 violent victimizations and about 4 in 10 fatal motor vehicle accidents are alcohol related (9), and fetal alcohol syndrome is the most common cause of preventable mental retardation in the industrialized world. The economic costs of alcohol abuse and dependence exceeded $185 billion in 1998, with more than 70% of the estimated costs being attributed to lost work productivity, treatment of alcohol-related illness, and premature death (10).

Over the last decade, a better understanding of pathophysiology and neurochemistry has revealed that alcohol dependence is a disease of the brain as well as of behavior. Central to a diagnosis of dependence is the concept of loss of control over alcohol use. Research shows that specific neurotransmitter systems associated with alcohol seeking and drinking influence an alcoholic’s preoccupation and compulsive desire to drink. Two motives for alcohol consumption include the positive rewarding effects associated with binge drinking (i.e., pleasurable, euphoric effects) and the negative effects associated with protracted abstinence (i.e., drinking to relieve stress and negative emotions associated with alcohol withdrawal) (11). Neurotransmitters related to these effects are potential targets for development of medications for alcohol dependence.

Neurotransmitters with notable sensitivity to the effects of alcohol include γ-aminobutyric acid, the main inhibitory neurotransmitter, and the excitatory neurotransmitter, glutamate, which acts mainly through N-methyl-d-aspartate (NMDA) receptors (12, 13). Acute alcohol consumption disrupts the normal equilibrium between excitatory and inhibitory mechanisms by exaggerating inhibitory neurotransmission. With chronic alcohol exposure, the brain compensates by up-regulating excitatory mechanisms while concurrently decreasing the inhibitory neurotrans-mission to restore equilibrium. With the abrupt removal of alcohol, the excitatory mechanisms remain unopposed, resulting in a hyperexcitability state that is characteristic of alcohol withdrawal (14). Presently, there are no clinically useful antagonists that can successfully reverse all of the pharmacological effects of alcohol. Although the exact mechanism of action of acamprosate is not known, preclinical data suggest that it modulates glutamate function both pre- and postsynaptically and may increase taurine availability in the brain (15). Importantly, acamprosate is thought to reduce the neuronal hyperexcitability and physiological dysregulation that lingers after acute alcohol withdrawal (16). Other neurotransmitters affected by alcohol include dopamine, serotonin, and opioid systems (17, 18), which are also under investigation for drug development.

The clinical efficacy and safety of acamprosate were initially evaluated in Europe in the 1990s and, more recently, in Brazil, Korea, and the United States. Overall, more than 5,000 male and female alcohol-dependent outpatients in 19 randomized, placebo-controlled clinical trials in 14 different countries have been evaluated (20–38). Most studies used relatively similar methodology for inclusion and exclusion criteria and assessment of outcome. Treatment duration ranged from 2 to 12 months; approximately 97% of subjects had recently undergone detoxification, and nearly 94% had been abstinent for at least 5 days at study entry. Additionally, more than half of the studies evaluated the effectiveness of acamprosate in a follow-up period without medication (24, 25, 27–32, 34–38). Two dose-ranging studies evaluated acamprosate at 1332 and 1998 mg/day (26, 36), whereas 10 trials (20, 22, 23, 27–30, 34, 35, 37) studied acamprosate with a dose adjusted by body weight (1332 mg/day for subjects weighing < 60 kg and 1998 mg/day for those weighing > 60 kg). Later studies used a fixed dose of 1998 mg/day (24, 25, 31–33), shown earlier to be more effective than the 1332 mg/day dose (26), except for the U.S. study, in which a higher dose of 3 g/day was compared with the standard dose of 2 g/day (38).

The primary efficacy measure for the majority of trials was rate of complete abstinence, which assessed the rate of patients completing the trial with no alcohol consumption. Other efficacy measures were percent days abstinent (PDA) over the study duration, also referred to as cumulative abstinence duration, and/or time to first relapse. Patients typically received whatever psychosocial intervention was routinely provided for alcohol dependence at their study site, except the U.S. study provided manual-guided counseling for all patients (www.alcoholfree.info).

Approval of acamprosate by the FDA was based primarily on efficacy data from three pivotal European studies of 13 (26), 48 (34), and 52 weeks’ (36) duration. All three studies demonstrated that, in combination with psychosocial support, acamprosate was superior to placebo in maintaining complete abstinence, increasing PDA, and prolonging time to first relapse in alcohol-dependent patients. The 13-week (26) and 48-week studies (34) showed that in conjunction with psychosocial treatment, acamprosate prolonged the time to first drink by 3 times compared with placebo and psychosocial treatment. Overall, these pivotal trials are representative of the European studies of which 13 of 18 have statistically shown that twice as many patients receiving acamprosate were completely abstinent from alcohol at the end of the treatment period than those receiving placebo. A number of the European studies (Table 1) assessed the treatment benefit of acamprosate after the study medication was stopped and found that acamprosate efficacy was maintained. In a 48-week study (34), patients who had been taking acamprosate had a significantly greater rate of complete abstinence than patients who had been taking placebo (p < 0.001) for up to 12 months posttreatment.

Only 3 of 18 international trials failed to show between-group differences with respect to rates of complete abstinence (22, 23, 31). One 12-week study included a number of patients meeting the criteria for alcohol abuse rather than alcohol dependence (22). Acamprosate is indicated for the treatment of alcohol dependence and appears to be specific to the mechanisms of alcohol dependence and not abuse. A 2-month clinical trial in South Korea (N =142) and a 24-week trial in the United Kingdom (N = 581) also showed no between-group differences in alcohol consumption (23, 31). These were the only two international trials in which actively drinking patients were randomized, and the observed lack of efficacy may be a function of non-abstinence. Acamprosate is not indicated for the induction of abstinence but rather for the maintenance of abstinence in alcohol-dependent patients who have been withdrawn from alcohol.

In addition to the primary objective of maintaining complete abstinence, a 24-week study also showed that during active treatment, acamprosate-treated patients had significantly less frequent drinking episodes and consumed less alcohol during relapses than patients receiving a placebo (32). These findings were confirmed in two subsequent publications. A post hoc analysis of 15 placebo-controlled studies (N = 3309) showed that acamprosate reduced the quantity and frequency of alcohol consumption in patients who continued to receive acamprosate therapy during a relapse (39). Additionally, reanalysis of the three pivotal trials (26, 34, 36) demonstrated that after a relapse, continuous acamprosate treatment prolonged the abstinence period (time to first drink: acamprosate, 28 mean days, versus placebo, 12 mean days, p < 0.01) and resulted in nearly three times as many patients regaining and maintaining abstinence compared with placebo (40). The increased control over drinking when relapse occurs suggests that continued acamprosate treatment during a relapse may have clinical benefits because it reduces the severity of relapse.

A meta-analysis of 13 acamprosate clinical trials reported that acamprosate produced few side effects, with mainly diarrhea, and occasionally headaches, dizziness, and pruritus being reported (41). Diarrhea was mild to moderate and transient. Importantly, no statistically significant differences were observed between groups in terms of withdrawals because of drug-related adverse events. There are no known drug-related serious adverse events or negative drug interactions associated with acamprosate. Acamprosate is not metabolized in the liver and is excreted unchanged via the kidneys. Therefore, acamprosate can be given to patients with liver disease, but is contraindicated in patients with severe renal impairment (see package insert for full prescribing information).

In contrast with the majority of worldwide trials, one study conducted in the U.S. was not successful in demonstrating the superiority of acamprosate (2 g or 3 g daily) over placebo on primary outcome measures (38). The trial differed from worldwide studies in several ways (Table 2). In the U.S. population, 50% of the patients had not discontinued drinking at randomization. Unlike in the worldwide clinical trials, patients with a history of poly-substance abuse were included in the U.S. study. There were no upper limits for age or liver function test values. These factors are generally considered negative determinants on alcohol dependence treatment outcomes in clinical trials (42). Additionally, this was the only acamprosate trial to provide manual-guided counseling for all patients, which may have increased the placebo response rate.

The PDA did not differ across groups in the intent-to-treat population (54.3% for placebo, 56.1% for 2 g, and 60.7% for 3 g). However, post hoc analysis controlling for baseline variables (e.g., severity of polysubstance abuse, goal of total abstinence, and stage of readiness to change) and treatment exposure found that acamprosate was associated with a significantly higher percentage of abstinent days than placebo (52.3% for placebo, 58.2% for 2 g, and 62.7% for 3 g; p = 0.01). An even greater effect was observed in a subgroup of 241 patients having a baseline goal of abstinence (58.1% for placebo, 70.0% for 2 g, and 72.5% for 3 g; p = 0.02), suggesting that motivation to be abstinent is an important determinant of success in patients treated with acamprosate. There were no between-group differences in drug-related adverse events, thus supporting the excellent safety and tolerability profile of acamprosate, even in a heterogeneous, polysubstance-abusing population.

Because a significant number of patients in randomized, clinical trials fail to maintain abstinence, despite optimal treatment conditions, it is important to identify potential determinants of treatment response. A meta-analysis of potential outcome predictors based on individual patient data from 16 randomized double-blind, placebo-controlled, acamprosate trials conducted in Europe and the United States was carried out with the objective of identifying factors that could meaningfully influence abstinence outcome (43). The primary outcome variable was cumulative abstinence duration, defined as the total duration of abstinence on the study divided by the treatment duration. Significant predictors of positive outcome were abstinent at least 2 days at onset of treatment, initial medication compliance, living with a partner and/or children, moderate alcohol dependence severity, and treatment with acamprosate.

The rationale for combining acamprosate and naltrexone is primarily to target different neurobiological mechanisms at the same time to produce a synergistic effect that cannot be obtained with either pharmacotherapy agent alone. The clinical efficacy of combination treatment was first demonstrated in a single-site, placebo-controlled study (44). In addition to cognitive behavioral therapy (CBT), patients were randomly assigned to receive placebo, acamprosate (1998 mg/day), or naltrexone (50 mg/day), alone or in combination. Both acamprosate and naltrexone alone increased the time to first drink and the time to first relapse into heavy drinking (i.e., ≥5 drinks/day for men and ≥ 4 drinks/day for women) compared with placebo. The proportion of patients remaining completely abstinent after 12 weeks was almost twice as high in the group receiving combined medications compared with either group receiving mono-therapy. These findings were confirmed in an open cohort study, which reported that CBT plus combined medication produced the greatest improvement, although not significant, across all outcome measures (45).

A large collaborative 16-week study (46) [Combining Medications and Behavioral Interventions (COMBINE)] evaluated the efficacy of acamprosate (3 g/day) and naltrexone (100 mg/day) alone and in combination with two intensity levels of manualized psychosocial treatments designed specifically for this trial (47): medical management or more intensive psychosocial therapy, combined behavioral intervention (CBI). All treatment interventions resulted in marked improvement, including those groups receiving placebo pills. Overall, PDA tripled from baseline to the end of study, and overall consumption decreased by 80%. Naltrexone, but not acamprosate, was associated with a statistically significant reduction in relapse to heavy drinking, a common outcome measure used in naltrexone studies, but not in acamprosate clinical trials. In contrast, acamprosate clinical trials report rate of complete abstinence (48), a key outcome measure on which FDA approval was based (26, 34, 36).

The only interaction between medications and behavioral treatments involved significantly improved PDA with naltrexone in the absence of CBI. However, the direction of the interaction indicated that the naltrexone effect was weaker when CBI was added, an unexpected finding because earlier studies showed a positive interaction between CBT and naltrexone treatment (49, 50). Unlike previous reports, acamprosate did not show superior efficacy relative to other treatments, either alone or in combination with naltrexone or CBI in improving PDA. High placebo response rates (≥73.8% across all groups), possibly due to the time-intensive psychosocial assessments, may be responsible, in part, for this apparent lack of superior efficacy.