0
Get Alert
Please Wait... Processing your request... Please Wait.
You must sign in to sign-up for alerts.

Please confirm that your email address is correct, so you can successfully receive this alert.

1
REVIEW   |    
Acamprosate for Alcohol Dependence: An Update for the Clinician
Barbara J. Mason, Ph.D.
FOCUS 2006;4:505-511.
View Author and Article Information

Copyright 2006 American Psychiatric Association

Abstract

Alcohol dependence is a chronic, relapsing disorder affecting more than 8 million Americans who are at increased risk for negative interpersonal and health consequences from pathological drinking. Successful treatment would potentially decrease these risks and lessen the tremendous personal and societal burdens attributed to this disorder. Psychosocial interventions without pharmacotherapy have long been the traditional treatment approach, but relapse is common. Advances in the identification of neurotransmitter systems involved in the addiction cycle have led to the development of new medications that, used in combination with counseling, further improve treatment outcome over that with counseling alone. Acamprosate is one of the medications that have shown success in promoting abstinence in alcohol-dependent individuals. For some patients, integrating acamprosate therapy into clinical practice as a complement to psychosocial interventions would enhance therapeutic options to assist in recovery. This article provides a clinically focused review of alcohol dependence as well as evidence of the safety and efficacy of acamprosate for treating this disorder.

Abstract Teaser
Figures in this Article

+

Prevalence and consequences

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 (13). 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).

+

Pathophysiology of alcohol dependence

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.

Managing the treatment of alcohol dependence is challenging because of the chronic, relapsing nature of the disease. Psychosocial support or behavioral interventions can be effective approaches in decreasing relapses to drinking; however, recent research has focused on the addition of pharmaco-therapies to counseling to improve the treatment outcomes for alcohol dependence.

Acamprosate [approved by the Food and Drug Administration (FDA) in 2004], is one of two drugs currently at the forefront of the available pharmacological options for treating this chronic disorder; the other is naltrexone (oral, approved in 1994, and injectable, approved in 2006). Acamprosate differs from naltrexone in its mechanism of action and its ability to target a specific drinking behavior. Naltrexone, an opioid antagonist, interferes with neurotransmitter systems that produce the rewarding effects of alcohol. Alcohol must be consumed for naltrexone to be effective. This is consistent with much of the clinical data suggesting that naltrexone is effective in reducing heavy drinking. On the other hand, acamprosate works to support abstinence in the absence of alcohol, primarily by normalizing the imbalances in NMDA-mediated glutamatergic neurotransmission that can linger long after acute alcohol withdrawal, a physiological dysregulation that may prompt relapse (16, 19).

+

Clinical trial design

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 (2038). 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, 2732, 3438). Two dose-ranging studies evaluated acamprosate at 1332 and 1998 mg/day (26, 36), whereas 10 trials (20, 22, 23, 2730, 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, 3133), 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).

+

Efficacy in worldwide trials

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 1T1) 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).

+

Efficacy in U.S. trials

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 2T2). 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.

+

Efficacy of combination therapy: acamprosate and naltrexone

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.

Almost 19 million Americans require treatment for alcohol abuse or dependence. However, despite evidence from multiple clinical trials supporting the use of medications in enhancing abstinence and preventing relapse, fewer than 1% of alcoholics in the United States are estimated to receive a prescribed medication for alcohol dependence (51). A recent survey from the Community Anti-Drug Coalitions of America (CADCA) (52) reported that 74% of the general public acknowledged that alcoholism impacts their daily lives. Yet, the vast majority (80%) indicated a stigma toward alcoholics, which extends to people in recovery. Additionally, 63% of Americans believe that alcoholism is caused, at least in part, by moral weakness. Denial or refusal to admit severity and fear of social embarrassment or discrimination are major barriers to treatment for most people with an addiction to alcohol. One of the reasons that pharmacological therapies have not been widely used is lack of knowledge of available drug treatment options by both the patient and the physician. In fact, 64% of the general public are unaware that medications exist to treat alcohol dependence (52).

For practitioners who are aware of pharmacological therapeutic options, drug safety and efficacy are key considerations when prescribing medications. Clinical research is often difficult to translate to the real-world treatment setting, especially when clinicians are confused by conflicting findings in clinical trials. As evidence of the effectiveness of the combined use of medication and counseling over counseling alone continues to demonstrate improved treatment outcome, medications may become a common part of alcohol dependence treatment.

Research has consistently shown that acamprosate is safe and effective for treating alcohol dependence. Acamprosate has been used successfully in 28 countries and has been prescribed for more than 1.5 million patients. Although not all patients may respond to acamprosate, data show that continued use of acamprosate can aid in patients maintaining complete abstinence and also in regaining abstinence after a relapse. There are also definitive data supporting the sustained benefits of acamprosate during posttreatment periods as long as 1 year after the last dose of medication. The use of acamprosate in maintaining abstinence plays a vital role in rehabilitation by reducing a patient’s vulnerability to relapse through its normalizing effects in a key system in the brain that becomes dysregulated in alcohol dependence. This evidence-based review suggests that clinicians and patients should perceive acamprosate to be a safe and beneficial component of an alcohol dependence treatment program aimed to support an alcohol-free lifestyle.

 
Anchor for JumpAnchor for JumpAnchor for Jump
Table 1.

Published, Randomized, Double-Blind, Placebo-Controlled Non-U.S. Trials of Acamprosate

 
Anchor for JumpAnchor for JumpAnchor for Jump
Table 2.

Key Differences between the U.S. Trial and European Pivotal Trial Data Submitted for FDA Approval

CME Disclosure
Barbara J. Mason, Ph.D.; Professor and Director, Laboratory of Clinical Psychopharmacology; Co-Director, Pearson Center for Alcoholism and Addiction Research, The Scripps Institute; Consultant/Speakers Bureau: Forest Laboratories, Inc. Consultant: Lipha Pharmaceuticals, Inc.

Office of Applied Studies: Results from the 2002 National Survey on Drug Use and Health: National findings (DHHS Publication SMA 03-3836, NSDUH Series H-22). Rockville, MD, Substance Abuse and Mental Health Services Administration,  2003
 
Office of Applied Studies: Results from the 2003 National Survey on Drug Use and Health: National findings (DHHS Publication SMA 04-3964, NSDUH Series H-25). Rockville, MD, Substance Abuse and Mental Health Services Administration,  2004
 
Office of Applied Studies: Results from the 2004 National Survey on Drug Use and Health: National findings (DHHS Publication SMA 05-4062, NSDUH Series H-28). Rockville, MD, Substance Abuse and Mental Health Services Administration,  2005
 
American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th ed, Text Revision. Washington, DC, American Psychiatric Association,  2000
 
Grant BF, Dawson DA, Stinson FS, Chou SP, Dufour MC, Pickering RP: The 12-month prevalence and trends in DSM-IV alcohol abuse and dependence: United States, 1991—1992 and 2001—2002. Drug Alcohol Depend  2004; 74:223—234
[PubMed]
[CrossRef]
 
Dawson DA, Grant BF: Family history of alcoholism and gender: their combined effects on DSM-IV alcohol dependence and major depression. J Stud Alcohol  1998; 59:97—106
[PubMed]
 
Rehm J, Gmel G, Sempos CT, Trevisan M: Alcohol-related morbidity and mortality. Alcohol Res Health  2003; 27:39—51
[PubMed]
 
National Institute on Alcohol Abuse and Alcoholism: 10th Special Report to the U.S. Congress on Alcohol and Health (NIH Publication 00-1583). Rockville, MD, U.S. Department of Health and Human Services, National Institutes of Health,  2000
 
Greenfield LA: Alcohol and Crime: An Analysis of National Data on the Prevalence of Alcohol in Crime. Washington, DC, U.S. Department of Justice,  1998
 
Harwood H: Updating Estimates of the Economic Costs of Alcohol Abuse in the United States: Estimates, Update Methods, and Data. Report prepared by The Lewin Group for the National Institute on Alcohol Abuse and Alcoholism. Rockville, MD, U.S. Department of Health and Human Services,  2000
 
Kranzler HR, Koob G, Gastfriend DR, Swift RM, Willenbring ML: Advances in the pharmacotherapy of alcoholism: challenging misconceptions. Alcohol Clin Exp Res  2006; 30:272—281
[PubMed]
[CrossRef]
 
Mihic SJ, Harris RA: Pharmacological Effects of Ethanol on the Nervous System. Edited by Deitrich RA, Erwin VG. Boca Raton, FL, CRC Press,  1996, pp 51—72
 
Nevo I, Hamon M: Neurotransmitter and neuromodulatory mechanisms involved in alcohol abuse and alcoholism. Neurochem Int  1995; 26:305—336
[PubMed]
[CrossRef]
 
Swift RM: Drug therapy for alcohol dependence. N Engl J Med  1999; 340:1482—1490
[PubMed]
[CrossRef]
 
De Witte P, Liitleton J, Parot P, Koob G: Neuroprotective and abstinence-promoting effects of acamprosate: elucidating the mechanism of action. CNS Drugs  2005; 19:517—537
[PubMed]
[CrossRef]
 
Littleton J: Acamprosate in alcohol dependence: how does it work? Addiction  1995; 90:1179—1188
[PubMed]
[CrossRef]
 
Faingold CL, N’Gouemo P, Riaz A: Ethanol and neurotransmitter interactions—from molecular to integrative effects. Prog Neurobiol  1998; 55: 509—535
[PubMed]
[CrossRef]
 
Koob GF, Roberts AJ, Schulteis G, Parsons LH, Heyser CJ, Hyytia P, Merlo-Pich E, Weiss F: Neurocircuitry targets in ethanol reward and dependence. Alcohol Clin Exp Res  1998; 22:3—9
[PubMed]
[CrossRef]
 
Littleton J, Zieglgansberger W: Pharmacological mechanisms of naltrex-one and acamprosate in the prevention of relapse in alcohol dependence. Am J Addict  2003; 12(suppl 1):S3—S11
[PubMed]
[CrossRef]
 
Lhuintre JP, Daoust M, Moore ND, Chretien P, Saligaut C, Tran G, Bosimare F, Hillemand B: Ability of calcium bis acetyl homotaurine, a GABA agonist, to prevent relapse in weaned alcoholics. Lancet  1985; 1:1014—1016
[PubMed]
 
Lhuintre JP, Moore N, Tran G, Steru L, Langrenon S, Daoust M, Parot P, Ladure P, Libert C, Boismare F, Hillemand B: Acamprosate appears to decrease alcohol intake in weaned alcoholics. Alcohol Alcohol  1990; 25:613— 622
[PubMed]
 
Rousseaux JP, Hers D, Ferauge M: Does acamprosate diminish the appetite for alcohol in weaned alcoholics? J. Pharm Belg  1996; 51:65— 68
 
Namkoong K, Lee BO, Lee PG, Choi MJ, Lee E, Lee JS, Yoo SW, Kim JH, Shin JH, Sung SK, Kang WG, Kee SW, Yoon BH, Lee JT, Lee DG, Lee JH: Acamprosate in Korean alcohol-dependent patients: a multi-centre, randomized, double-blind, placebo-controlled study. Alcohol Alcohol  2003; 38:135—141
[PubMed]
 
Baltieri DA, de Andrade AG: Efficacy of acamprosate in the treatment of alcohol-dependent outpatients. Rev Bras Psiquiatr  2003; 25:156—159
[PubMed]
 
Pelc I, Le Bon O, Verbanck P, Lehert PH, Opsomer L: Calcium acetylho-motaurinate for maintaining abstinence in weaned alcoholic patients: a placebo-controlled double-blind multicenter study. In Novel Pharmacological Interventions for Alcoholism. Edited by Naranjo CA, Sellers EM. New York, Springer-Verlag,  1992, pp 348—352
 
Pelc I, Verbanck P, Le Bon O, Gavrilovic M, Lion K, Lehert P: Efficacy and safety of acamprosate in the treatment of detoxified alcohol-dependent patients: a 90-day placebo-controlled dose-finding study. Br J Psychiatry  1997; 171:73—77
[PubMed]
[CrossRef]
 
Ladewig D, Knecht T, Leher P, Fendl A: [Acamprosate—a stabilizing factor in long-term withdrawal of alcoholic patients]. Ther Umsch  1993; 50:182—188 (German)
[PubMed]
 
Barrias JA, Chabac S, Ferreira L, Fonte A, Potgieter AS, Teixeira de Sousa E: Acamprosate: multicenter Portuguese efficacy and tolerance evaluation study. Psiquiatria Clin  1997; 18:149—160
 
Geerlings PJ, Ansoms C, van den Brink W: Acamprosate and prevention of relapse alcoholics. Eur Addict Res  1997; 3:129—137
[CrossRef]
 
Poldrugo F: Acamprosate treatment in a long-term community-based alcohol rehabilitation programme. Addiction  1997; 92:1537—1546
[PubMed]
[CrossRef]
 
Chick J, Howlett H, Morgan MY, Ritson B: United Kingdom Multicentre Acamprosate Study (UKMAS): a 6-month prospective study of acampro-sate versus placebo in preventing relapse after withdrawal from alcohol. Alcohol Alcohol  2000; 35:176—187
[PubMed]
 
Tempesta E, Janiri L, Bignamini A, Chabac S, Potgieter A: Acamprosate and relapse prevention in the treatment of alcohol dependence: a placebo-controlled study. Alcohol Alcohol  2000; 35:202—209
[PubMed]
 
Gual A, Lehert P: Acamprosate during and after acute alcohol withdrawal: a double-blind placebo-controlled study in Spain. Alcohol Alcohol  2001; 36:413— 418
[PubMed]
 
Sass H, Soyka M, Mann K, Zieglgansberger W: Relapse prevention by acamprosate: results from a placebo-controlled study on alcohol dependence. Arch Gen Psychiatry  1996; 53:673— 680
[PubMed]
 
Whitworth AB, Fischer F, Lesch OM, Nimmerrichter A, Oberbauer H, Platz T, Potgieter A, Walter H, Fleischhacker WW: Comparison of acamprosate and placebo in long-term treatment of alcohol dependence. Lancet  1996; 347:1438—1442
[PubMed]
[CrossRef]
 
Paille FM, Guelfi JD, Perkins AC, Royer RJ, Steru L, Parot P: Double-blind randomized multicentre trial of acamprosate in maintaining abstinence from alcohol. Alcohol Alcohol  1995; 30:239—247
[PubMed]
 
Besson J, Aeby F, Kasas A, Lehert P, Potgieter A: Combined efficacy of acamprosate and disulfiram in the treatment of alcoholism: a controlled study. Alcohol Clin Exp Res  1998; 22:573—579
[PubMed]
[CrossRef]
 
Mason BJ, Goodman AM, Chabac S, Lehert P: Effect of oral acamprosate on abstinence in patients with alcohol dependence in a double-blind, placebo-controlled trial: the role of patient motivation. J Psychiatr Res  2006; 40:383—393
[PubMed]
[CrossRef]
 
Chick J, Lehert P, Landron F, Plinius Major Society: Does acamprosate improve reduction of drinking as well as aiding abstinence? J Psychopharmacol  2003; 17:397— 402
[PubMed]
[CrossRef]
 
Schneider E, Saikali K, Zhang D, Gage A: Acamprosate promotes abstinence in alcohol-dependent patients who relapse during treatment. Alcohol Clin Exp Res  2005; 29:160A
 
Bouza C, Angeles M, Munoz A, Amate JM: Efficacy and safety of naltrexone and acamprosate in the treatment of alcohol dependence: a systematic review. Addiction  2004; 99:811— 828
[PubMed]
[CrossRef]
 
Mason BJ, Ownby RL: Acamprosate for the treatment of alcohol dependence: a review of double-blind, placebo-controlled trials. CNS Spectr  2000; 5:58— 69
 
Mason BJ, Goodman AM, Lehert P: Individual patient data meta-analysis of predictors of outcome including USA and European studies. Alcohol Clin Exp Res  2005; 29:174A
 
Kiefer F, Jahn H, Tarnaske T, Helwig H, Briken P, Holzbach R, Kampf P, Stracke R, Baehr M, Naber D, Wiedemann K: Comparing and combining naltrexone and acamprosate in relapse prevention of alcoholism: a double-blind, placebo-controlled study. Arch Gen Psychiatry  2003; 60: 92—99
[PubMed]
[CrossRef]
 
Feeney GF, Connor JP, Young RM, Tucker J, McPherson A: Combined acamprosate and naltrexone, with cognitive behavioural therapy is superior to either medication alone for alcohol abstinence: a single centres’ experience with pharmacotherapy. Alcohol Alcohol  2006; 41:321—327
[PubMed]
 
Anton RF, O’Malley SS, Ciraulo DA, Cisler RA, Couper D, Donovan DM, Gastfriend DR, Hosking JD, Johnson BA, LoCastro JS, Longabaugh R, Mason BJ, Mattson ME, Miller WR, Pettinati HM, Randall CL, Swift R, Weiss RD, Williams LD, Zweben A: Combined pharmacotherapies and behavioral interventions for alcohol dependence: the COMBINE study: a randomized controlled trial. JAMA  2006; 295:2003—2017
[PubMed]
[CrossRef]
 
Pettinati HM, Weiss RD, Miller WR, Donovan D, Ernst DB, Rounsaville BJ: Medical Management Treatment Manual: A Clinical Research Guide for Medically Trained Clinicians Providing Pharmacotherapy as Part of the Treatment for Alcohol Dependence. NIAAA COMBINE Monograph Series, Vol. 2 (DHHS Publication 04—5289). Bethesda, MD, Department of Health and Human Services,  2004
 
Mason BJ: Rationale for combining acamprosate and naltrexone for treating alcohol dependence. J Stud Alcohol Suppl  2005; 148—156
 
Balldin J, Berglund M, Borg S, Mansson M, Bendtsen P, Franck J, Gustafsson L, Halldin J, Nilsson LH, Stolt G, Willander A: A 6-month controlled naltrexone study: combined effect with cognitive behavioral therapy in outpatient treatment of alcohol dependence. Alcohol Clin Exp Res  2003; 27:1142—1149
[PubMed]
[CrossRef]
 
Anton RF, Moak DH, Waid LR, Latham PK, Malcolm RJ, Dias JK: Naltrexone and cognitive behavioral therapy for the treatment of outpatient alcoholics: results of a placebo-controlled trial. Am J Psychiatry  1999; 156:1758—1764
[PubMed]
 
To SE: Alcoholism and pathways to recovery: new survey results on views and treatment options. Med Gen Med  2006; 8:2
 
These data are from the findings of three online surveys, conducted by Peter D. Hart Research Associates, Inc., Aug 10—26, 2005, among 1,000 members of the general public (aged 20+), 300 general practitioners and internists (aged 25+), and 503 people in recovery (aged 25—50)
 
Anchor for JumpAnchor for JumpAnchor for Jump
Table 1.

Published, Randomized, Double-Blind, Placebo-Controlled Non-U.S. Trials of Acamprosate

Anchor for JumpAnchor for JumpAnchor for Jump
Table 2.

Key Differences between the U.S. Trial and European Pivotal Trial Data Submitted for FDA Approval

+

References

Office of Applied Studies: Results from the 2002 National Survey on Drug Use and Health: National findings (DHHS Publication SMA 03-3836, NSDUH Series H-22). Rockville, MD, Substance Abuse and Mental Health Services Administration,  2003
 
Office of Applied Studies: Results from the 2003 National Survey on Drug Use and Health: National findings (DHHS Publication SMA 04-3964, NSDUH Series H-25). Rockville, MD, Substance Abuse and Mental Health Services Administration,  2004
 
Office of Applied Studies: Results from the 2004 National Survey on Drug Use and Health: National findings (DHHS Publication SMA 05-4062, NSDUH Series H-28). Rockville, MD, Substance Abuse and Mental Health Services Administration,  2005
 
American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th ed, Text Revision. Washington, DC, American Psychiatric Association,  2000
 
Grant BF, Dawson DA, Stinson FS, Chou SP, Dufour MC, Pickering RP: The 12-month prevalence and trends in DSM-IV alcohol abuse and dependence: United States, 1991—1992 and 2001—2002. Drug Alcohol Depend  2004; 74:223—234
[PubMed]
[CrossRef]
 
Dawson DA, Grant BF: Family history of alcoholism and gender: their combined effects on DSM-IV alcohol dependence and major depression. J Stud Alcohol  1998; 59:97—106
[PubMed]
 
Rehm J, Gmel G, Sempos CT, Trevisan M: Alcohol-related morbidity and mortality. Alcohol Res Health  2003; 27:39—51
[PubMed]
 
National Institute on Alcohol Abuse and Alcoholism: 10th Special Report to the U.S. Congress on Alcohol and Health (NIH Publication 00-1583). Rockville, MD, U.S. Department of Health and Human Services, National Institutes of Health,  2000
 
Greenfield LA: Alcohol and Crime: An Analysis of National Data on the Prevalence of Alcohol in Crime. Washington, DC, U.S. Department of Justice,  1998
 
Harwood H: Updating Estimates of the Economic Costs of Alcohol Abuse in the United States: Estimates, Update Methods, and Data. Report prepared by The Lewin Group for the National Institute on Alcohol Abuse and Alcoholism. Rockville, MD, U.S. Department of Health and Human Services,  2000
 
Kranzler HR, Koob G, Gastfriend DR, Swift RM, Willenbring ML: Advances in the pharmacotherapy of alcoholism: challenging misconceptions. Alcohol Clin Exp Res  2006; 30:272—281
[PubMed]
[CrossRef]
 
Mihic SJ, Harris RA: Pharmacological Effects of Ethanol on the Nervous System. Edited by Deitrich RA, Erwin VG. Boca Raton, FL, CRC Press,  1996, pp 51—72
 
Nevo I, Hamon M: Neurotransmitter and neuromodulatory mechanisms involved in alcohol abuse and alcoholism. Neurochem Int  1995; 26:305—336
[PubMed]
[CrossRef]
 
Swift RM: Drug therapy for alcohol dependence. N Engl J Med  1999; 340:1482—1490
[PubMed]
[CrossRef]
 
De Witte P, Liitleton J, Parot P, Koob G: Neuroprotective and abstinence-promoting effects of acamprosate: elucidating the mechanism of action. CNS Drugs  2005; 19:517—537
[PubMed]
[CrossRef]
 
Littleton J: Acamprosate in alcohol dependence: how does it work? Addiction  1995; 90:1179—1188
[PubMed]
[CrossRef]
 
Faingold CL, N’Gouemo P, Riaz A: Ethanol and neurotransmitter interactions—from molecular to integrative effects. Prog Neurobiol  1998; 55: 509—535
[PubMed]
[CrossRef]
 
Koob GF, Roberts AJ, Schulteis G, Parsons LH, Heyser CJ, Hyytia P, Merlo-Pich E, Weiss F: Neurocircuitry targets in ethanol reward and dependence. Alcohol Clin Exp Res  1998; 22:3—9
[PubMed]
[CrossRef]
 
Littleton J, Zieglgansberger W: Pharmacological mechanisms of naltrex-one and acamprosate in the prevention of relapse in alcohol dependence. Am J Addict  2003; 12(suppl 1):S3—S11
[PubMed]
[CrossRef]
 
Lhuintre JP, Daoust M, Moore ND, Chretien P, Saligaut C, Tran G, Bosimare F, Hillemand B: Ability of calcium bis acetyl homotaurine, a GABA agonist, to prevent relapse in weaned alcoholics. Lancet  1985; 1:1014—1016
[PubMed]
 
Lhuintre JP, Moore N, Tran G, Steru L, Langrenon S, Daoust M, Parot P, Ladure P, Libert C, Boismare F, Hillemand B: Acamprosate appears to decrease alcohol intake in weaned alcoholics. Alcohol Alcohol  1990; 25:613— 622
[PubMed]
 
Rousseaux JP, Hers D, Ferauge M: Does acamprosate diminish the appetite for alcohol in weaned alcoholics? J. Pharm Belg  1996; 51:65— 68
 
Namkoong K, Lee BO, Lee PG, Choi MJ, Lee E, Lee JS, Yoo SW, Kim JH, Shin JH, Sung SK, Kang WG, Kee SW, Yoon BH, Lee JT, Lee DG, Lee JH: Acamprosate in Korean alcohol-dependent patients: a multi-centre, randomized, double-blind, placebo-controlled study. Alcohol Alcohol  2003; 38:135—141
[PubMed]
 
Baltieri DA, de Andrade AG: Efficacy of acamprosate in the treatment of alcohol-dependent outpatients. Rev Bras Psiquiatr  2003; 25:156—159
[PubMed]
 
Pelc I, Le Bon O, Verbanck P, Lehert PH, Opsomer L: Calcium acetylho-motaurinate for maintaining abstinence in weaned alcoholic patients: a placebo-controlled double-blind multicenter study. In Novel Pharmacological Interventions for Alcoholism. Edited by Naranjo CA, Sellers EM. New York, Springer-Verlag,  1992, pp 348—352
 
Pelc I, Verbanck P, Le Bon O, Gavrilovic M, Lion K, Lehert P: Efficacy and safety of acamprosate in the treatment of detoxified alcohol-dependent patients: a 90-day placebo-controlled dose-finding study. Br J Psychiatry  1997; 171:73—77
[PubMed]
[CrossRef]
 
Ladewig D, Knecht T, Leher P, Fendl A: [Acamprosate—a stabilizing factor in long-term withdrawal of alcoholic patients]. Ther Umsch  1993; 50:182—188 (German)
[PubMed]
 
Barrias JA, Chabac S, Ferreira L, Fonte A, Potgieter AS, Teixeira de Sousa E: Acamprosate: multicenter Portuguese efficacy and tolerance evaluation study. Psiquiatria Clin  1997; 18:149—160
 
Geerlings PJ, Ansoms C, van den Brink W: Acamprosate and prevention of relapse alcoholics. Eur Addict Res  1997; 3:129—137
[CrossRef]
 
Poldrugo F: Acamprosate treatment in a long-term community-based alcohol rehabilitation programme. Addiction  1997; 92:1537—1546
[PubMed]
[CrossRef]
 
Chick J, Howlett H, Morgan MY, Ritson B: United Kingdom Multicentre Acamprosate Study (UKMAS): a 6-month prospective study of acampro-sate versus placebo in preventing relapse after withdrawal from alcohol. Alcohol Alcohol  2000; 35:176—187
[PubMed]
 
Tempesta E, Janiri L, Bignamini A, Chabac S, Potgieter A: Acamprosate and relapse prevention in the treatment of alcohol dependence: a placebo-controlled study. Alcohol Alcohol  2000; 35:202—209
[PubMed]
 
Gual A, Lehert P: Acamprosate during and after acute alcohol withdrawal: a double-blind placebo-controlled study in Spain. Alcohol Alcohol  2001; 36:413— 418
[PubMed]
 
Sass H, Soyka M, Mann K, Zieglgansberger W: Relapse prevention by acamprosate: results from a placebo-controlled study on alcohol dependence. Arch Gen Psychiatry  1996; 53:673— 680
[PubMed]
 
Whitworth AB, Fischer F, Lesch OM, Nimmerrichter A, Oberbauer H, Platz T, Potgieter A, Walter H, Fleischhacker WW: Comparison of acamprosate and placebo in long-term treatment of alcohol dependence. Lancet  1996; 347:1438—1442
[PubMed]
[CrossRef]
 
Paille FM, Guelfi JD, Perkins AC, Royer RJ, Steru L, Parot P: Double-blind randomized multicentre trial of acamprosate in maintaining abstinence from alcohol. Alcohol Alcohol  1995; 30:239—247
[PubMed]
 
Besson J, Aeby F, Kasas A, Lehert P, Potgieter A: Combined efficacy of acamprosate and disulfiram in the treatment of alcoholism: a controlled study. Alcohol Clin Exp Res  1998; 22:573—579
[PubMed]
[CrossRef]
 
Mason BJ, Goodman AM, Chabac S, Lehert P: Effect of oral acamprosate on abstinence in patients with alcohol dependence in a double-blind, placebo-controlled trial: the role of patient motivation. J Psychiatr Res  2006; 40:383—393
[PubMed]
[CrossRef]
 
Chick J, Lehert P, Landron F, Plinius Major Society: Does acamprosate improve reduction of drinking as well as aiding abstinence? J Psychopharmacol  2003; 17:397— 402
[PubMed]
[CrossRef]
 
Schneider E, Saikali K, Zhang D, Gage A: Acamprosate promotes abstinence in alcohol-dependent patients who relapse during treatment. Alcohol Clin Exp Res  2005; 29:160A
 
Bouza C, Angeles M, Munoz A, Amate JM: Efficacy and safety of naltrexone and acamprosate in the treatment of alcohol dependence: a systematic review. Addiction  2004; 99:811— 828
[PubMed]
[CrossRef]
 
Mason BJ, Ownby RL: Acamprosate for the treatment of alcohol dependence: a review of double-blind, placebo-controlled trials. CNS Spectr  2000; 5:58— 69
 
Mason BJ, Goodman AM, Lehert P: Individual patient data meta-analysis of predictors of outcome including USA and European studies. Alcohol Clin Exp Res  2005; 29:174A
 
Kiefer F, Jahn H, Tarnaske T, Helwig H, Briken P, Holzbach R, Kampf P, Stracke R, Baehr M, Naber D, Wiedemann K: Comparing and combining naltrexone and acamprosate in relapse prevention of alcoholism: a double-blind, placebo-controlled study. Arch Gen Psychiatry  2003; 60: 92—99
[PubMed]
[CrossRef]
 
Feeney GF, Connor JP, Young RM, Tucker J, McPherson A: Combined acamprosate and naltrexone, with cognitive behavioural therapy is superior to either medication alone for alcohol abstinence: a single centres’ experience with pharmacotherapy. Alcohol Alcohol  2006; 41:321—327
[PubMed]
 
Anton RF, O’Malley SS, Ciraulo DA, Cisler RA, Couper D, Donovan DM, Gastfriend DR, Hosking JD, Johnson BA, LoCastro JS, Longabaugh R, Mason BJ, Mattson ME, Miller WR, Pettinati HM, Randall CL, Swift R, Weiss RD, Williams LD, Zweben A: Combined pharmacotherapies and behavioral interventions for alcohol dependence: the COMBINE study: a randomized controlled trial. JAMA  2006; 295:2003—2017
[PubMed]
[CrossRef]
 
Pettinati HM, Weiss RD, Miller WR, Donovan D, Ernst DB, Rounsaville BJ: Medical Management Treatment Manual: A Clinical Research Guide for Medically Trained Clinicians Providing Pharmacotherapy as Part of the Treatment for Alcohol Dependence. NIAAA COMBINE Monograph Series, Vol. 2 (DHHS Publication 04—5289). Bethesda, MD, Department of Health and Human Services,  2004
 
Mason BJ: Rationale for combining acamprosate and naltrexone for treating alcohol dependence. J Stud Alcohol Suppl  2005; 148—156
 
Balldin J, Berglund M, Borg S, Mansson M, Bendtsen P, Franck J, Gustafsson L, Halldin J, Nilsson LH, Stolt G, Willander A: A 6-month controlled naltrexone study: combined effect with cognitive behavioral therapy in outpatient treatment of alcohol dependence. Alcohol Clin Exp Res  2003; 27:1142—1149
[PubMed]
[CrossRef]
 
Anton RF, Moak DH, Waid LR, Latham PK, Malcolm RJ, Dias JK: Naltrexone and cognitive behavioral therapy for the treatment of outpatient alcoholics: results of a placebo-controlled trial. Am J Psychiatry  1999; 156:1758—1764
[PubMed]
 
To SE: Alcoholism and pathways to recovery: new survey results on views and treatment options. Med Gen Med  2006; 8:2
 
These data are from the findings of three online surveys, conducted by Peter D. Hart Research Associates, Inc., Aug 10—26, 2005, among 1,000 members of the general public (aged 20+), 300 general practitioners and internists (aged 25+), and 503 people in recovery (aged 25—50)
 
+
+

CME Activity

Add a subscription to complete this activity and earn CME credit.
Sample questions:
1.
Which statement provides the most accurate information regarding comorbid persistent pain and psychiatric disorders?
2.
Which of the following best describes chronic pain?
3.
Regarding the pharmacological treatment of chronic pain which of the following statements is most accurate?
Submit a Comments
Please read the other comments before you post yours. Contributors must reveal any conflict of interest.
Comments are moderated and will appear on the site at the discertion of APA editorial staff.

* = Required Field
(if multiple authors, separate names by comma)
Example: John Doe



Related Content
Articles
Books
The American Psychiatric Publishing Textbook of Substance Abuse Treatment, 4th Edition > Chapter 7.  >
The American Psychiatric Publishing Textbook of Substance Abuse Treatment, 4th Edition > Chapter 9.  >
The American Psychiatric Publishing Textbook of Substance Abuse Treatment, 4th Edition > Chapter 9.  >
The American Psychiatric Publishing Textbook of Psychopharmacology, 4th Edition > Chapter 58.  >
The American Psychiatric Publishing Textbook of Psychopharmacology, 4th Edition > Chapter 58.  >
Topic Collections
Psychiatric News
APA Guidelines
PubMed Articles
Acamprosate produces its anti-relapse effects via calcium. Neuropsychopharmacology 2014;39(4):783-91.
[New treatment options for alcohol dependence]. MMW Fortschr Med 2013;155(8):63-5.