Acamprosate

Barbara J. Mason1, Charles J. Heyser2 1Committee on the Neurobiology of Addictive Disorders, Pearson Center for Alcoholism and Addiction Research, The Scripps Research Institute, TPC-5, La Jolla, CA, USA 2Department of Psychology, Franklin and Marshall College, Lancaster, PA, USA

Synonyms

Calcium acetylhomotaurinate; Campral Definition

Acamprosate, marketed under the brand name Campral, is an orally administered drug approved in the USA and throughout much of the world for treating ► alcohol abuse and dependence.

Pharmacological Properties History

Alcohol-use disorders, which include both alcohol abuse and dependence, make up one of the most prevalent categories of substance use disorders in the USA, affecting almost 18 million Americans. The Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition (DSM-IV; APA 1994) characterizes alcohol dependence as a maladap-tive pattern of drinking leading to clinically significant impairment, as manifested by a compulsion to drink, a lack of control over the amount of alcohol consumed and continued drinking, despite a realization of the problems associated with it. Physiological symptoms oftolerance and withdrawal may also be present. one of the most challenging aspects ofrecovering from alcohol dependence is maintaining abstinence after acute withdrawal and avoiding subsequent relapse to drinking (Koob and Le Moal 2006). The goal of maintaining abstinence can be undermined by acute stressors like anger, loneliness, or hunger or by more chronic conditions such as cognitive impairment, polysubstance abuse, and mood and sleep disturbances. Supplementing counseling approaches with medications targeted to treat the biological aspects of drinking behavior can help in the maintenance of abstinence.

Three medications are currently approved for the treatment of alcohol dependence - ► disulfiram, ► naltrexone (oral and injectable extended release), and acamprosate (Koob and Le Moal 2006). A number of other therapeutic agents are under investigation; these include serotonergic agents, anticonvulsants, GABA receptor agonists, cannabinoid receptor antagonists, and corticotrophin-releasing factor antagonists. Disulfiram has been available for decades; however, high rates (up to 80%) of nonadherence to this aversive medication have contributed to its decreased use by the treatment community. Naltrexone has been available since 1994; however, it has not been readily adopted by practitioners to treat alcohol dependence. The recent Food and Drug Administration (FDA) approvals of acamprosate (2004) and an injectable extended formulation of naltrexone (2006) offer new pharmacologic options for treating this disorder.

Acamprosate is a safe and well-tolerated pharmaco-therapy that has been studied in numerous clinical trials worldwide. It has been used successfully for over 15 years in 28 countries and has been prescribed for more than 1.5 million alcohol-dependent patients. Clinical trials have consistently shown that acamprosate is effective in maintaining abstinence in recently detoxified patients, especially when patients are motivated to be abstinent (Mason and Crean 2007). Current research also indicates that acam-prosate has a unique mechanism of action, which may have implications for its therapeutic use (De Witte et al. 2005). In contrast to disulfiram, which causes aversive behavior through negative physical effects, or naltrexone, which tempers the pleasurable effects of alcohol, acam-prosate acts to normalize dysregulation in neurochemical systems that have been implicated in the biological mechanisms of alcohol dependence.

Mechanism of Action

Acamprosate is an analog of amino acid neurotransmit-ters such as taurine and homocysteic acid and it has been demonstrated that acamprosate binds to a specific spermidine-sensitive site that modulates the NMDA receptor in a complex way. The NMDA receptor is one of the ► glutamate receptor subtypes. This work suggests that acamprosate acts as a "partial co-agonist'' at the

NMDA receptor, such that low concentrations enhance activation when receptor activity is low, and high concentrations inhibit activation when receptor activity is high. This may be particularly relevant to the success of acam-prosate as a pharmacotherapy given that chronic exposure to ethanol results in an upregulation of ► NMDA receptors and an upregulation in the density of ► voltage-dependent calcium channels (Littleton 2007). Thus, sudden alcohol abstinence causes the excessive numbers of NMDA receptors to be more active than normal, and to produce the symptoms associated with acute ► alcohol withdrawal, such as ► delirium tremens and seizures and with the more persisting symptoms associated with early abstinence, such as craving and disturbances in sleep and mood (Tsai and Coyle 1998). Withdrawal from alcohol induces a surge of excitatory neurotransmitters like glutamate, which in turn activates the NMDA receptors (Tsai and Coyle 1998). Conversely, acamprosate promotes the release of taurine in the brain (Dahchour and De Witte 2000). Taurine is a major inhibitory neuromodulator/ neurotransmitter and an increase in taurine availability would also contribute to a decrease in hyperexcitability. Thus, each of these changes produced by acamprosate may contribute to a decrease in the neuronal hyperexcit-ability commonly observed following acute alcohol withdrawal and that may underlie symptoms associated with relapse, like craving, negative affect and insomnia. Therefore, it has been hypothesized that acamprosate may promote abstinence by minimizing or normalizing some of the physiological changes produced by chronic heavy ethanol exposure.

Animal Models

Acamprosate has been shown to reduce ethanol consumption in rodents that have an extended history of ethanol exposure or are ethanol-dependent (Spanagel et al. 1996). It also has been shown to reduce the increased ethanol consumption associated with a period of enforced abstinence from ethanol (the alcohol deprivation effect) in rats (Heyser et al. 1998; Spanagel et al. 1996). In contrast, acamprosate appears to have less of an effect on alcohol consumption in alcohol naive and nondependent rats (Heyser et al. 1998). Acamprosate also has been reported to attenuate some of the behavioral and neurochemical events associated with ethanol withdrawal (Dahchour and De Witte 2000). For example, acamprosate reduces the hyperactivity and elevated glutamate levels observed during the first 12 h of ethanol withdrawal. However, not all aspects of withdrawal are reduced by acamprosate, such as withdrawal-induced hypothermia. In addition to the direct effects on ethanol consumption, acamprosate has been shown to inhibit cue-induced ► reinstatement of alcohol-seeking behavior in an operant conditioning model (Bachteler et al. 2005). Taken together, these results provide support for the use of acamprosate specifically as an anti-relapse medication following acute alcohol withdrawal.

Pharmacokinetics

The recommended dosage of acamprosate is two 333-mg tablets taken three times daily, with no dose adjustment required for body weight or gender (Campral package insert, 2005). Acamprosate is absorbed via the gastrointestinal tract, with pharmacokinetic linearity in terms of dose and time. Absolute bioavailability of acamprosate under fasting conditions is approximately 11%; after food intake, bioavailability decreases by approximately 20%, but this decrease lacks clinical significance (Wilde and Wagstaff 1997). Plasma protein binding is negligible. Importantly, acamprosate is not metabolized in the liver and approximately 90% of the drug is excreted unchanged in the urine (Wilde and Wagstaff 1997). Therefore, the pharmacokinetics of acamprosate are not altered in patients with mild to moderate hepatic impairment and no dose adjustment is required in such patients. Since there is a risk of accumulation of acamprosate with prolonged administration of therapeutic doses in renally impaired patients, the use of acamprosate is contraindicated in patients with severe renal impairment. The pharmacoki-netics of acamprosate have not been evaluated in pediatric or geriatric populations.

Because acamprosate is not metabolized by the liver, it is unlikely to cause drug-drug interactions via cytochrome P450 inhibition. Its pharmacokinetics are not altered by co-administration with ► diazepam, ► disulfiram, ► antide-pressants, or ► alcohol - substances that are often taken by patients with alcohol dependence. In pharmacokinetic studies with human subjects, co-administration with nal-trexone increased the rate and extent of acamprosate absorption. These results suggest that combination therapy may improve the ► bioavailability of acamprosate without compromising its tolerability (Mason and Crean 2007).

Efficacy

Acamprosate was initially studied in Europe, and more recently, in Brazil, Korea, Australia, and the USA. The acamprosate double-blind, placebo-controlled clinical trial database included over 6500 outpatients from 15 countries and is reported in 23 published studies (Mason and Crean 2007). Nineteen of these trials used relatively equivalent methodology in terms ofentry criteria, treatment, handling of drop-outs, outcome measures, and assessment of compliance. Patients received the psychosocial intervention typical of their treatment setting. Treatment duration ranged from 2 to 12 months with 13 trials 6 months or longer in duration. Patients were generally recently detoxified and typically had been abstinent for about 5 days at entry into the trials. In these studies, the principal ► efficacy measure was abstinence, which was assessed as the rate of patients completing the trial with no consumption of alcohol at all, the cumulative proportion of the study duration when the patients remained abstinent, and/or the time to first drink.

The results have been consistent in the majority of published studies, and generally show a significant beneficial effect of acamprosate on abstinence outcomes relative to placebo. A factor of 2 in the difference in the proportion of patients achieving stable abstinence was observed in approximately one-third of studies. A beneficial effect on the time to first drink was also frequently observed.

Overall, the published placebo-controlled studies demonstrate the efficacy of acamprosate for supporting abstinence over a broad range of patients in association with a variety of different psychosocial interventions. A number of these studies assessed the persistence of a treatment benefit after the study medication was stopped, and found acam-prosate efficacy was maintained for up to 12 months post-treatment relative to placebo. In addition, the result of a recent multi-center, ► double-blind, ► placebo-controlled clinical trial of acamprosate conducted in the United States showed that the benefits of acamprosate were optimized in patients who had a clearly identified goal of abstinence at the start of treatment (Mason and Crean 2007).

Safety and Tolerability

The safety profile of acamprosate appears favorable. The only adverse event consistently reported across trials more frequently in acamprosate-treated patients with respect to placebo-treated patients was mild and transient diarrhea. Across clinical trials, the rate of early terminations due to drug-related adverse events did not differ between acam-prosate and placebo-treated patients. Pharmacovigilance subsequent to the commercialization of acamprosate in 1989 has not identified any health risk associated with acamprosate use in over 1.5 million patients. Clinical investigations show no evidence of ► tolerance, ► dependence, or the emergence of a ► withdrawal syndrome or rebound drinking when treatment is ceased (Mason and Crean 2007). Comprehensive safety guidelines may be reviewed in the package insert for acamprosate (Forest Pharmaceuticals, Inc. 2005).

Conclusion

Acamprosate appears to be useful in the treatment of alcohol dependence above and beyond the effects of counseling alone. Acamprosate appears to work by normalizing the dysregulation of NMDA-mediated glutamatergic neurotransmission that occurs during chronic alcohol consumption and withdrawal, and thus attenuates one of the physiological mechanisms that may prompt relapse. Acam-prosate requires around a week to reach steady-state levels in the nervous system and its effects on drinking behavior typically persist after the treatment is completed.

Studies into the efficacy of acamprosate in alcohol-dependent patients are generally favorable. Clinical studies and post-marketing experience indicate that acamprosate is typically safe when used as approved by the FDA in alcohol-dependent patients, including those dually diagnosed with psychiatric disorders. The majority of randomized controlled trials of acamprosate given in conjunction with counseling show significantly improved alcoholism treatment outcome relative to counseling administered with placebo. This evidence base suggests that acampro-sate should be routinely considered by medical professionals for patients entering alcoholism treatment, taking into account the patient's treatment goals and preferences as well as the safety considerations outlined above.

Cross-References

► Alcohol Dependence

► Alcohol Withdrawal

► Disulfiram

► Glutamate Receptors

► Naltrexone

► Voltage-Gated Calcium Channels (VDCC) References

Bachteler D, Economidou D, Danysz W, Ciccocioppo R, Spanagel R (2005) The effects of acamprosate and neramexane on cue-induced reinstatement of ethanol-seeking behavior in rat. Neuropsychophar-macology 30:1104-1110 Dahchour A, De Witte P (2000) Ethanol and amino acids in the central nervous system: assessment of the pharmacological actions of acamprosate. Prog Neurobiol 60:343-362 De Witte P, Littleton J, Parot P, Koob G (2005) Neuroprotective and abstinence-promoting effects of acamprosate: elucidating the mechanism of action. CNS Drugs 19:517-537 Heyser CJ, Schulteis G, Durbin P, Koob GF (1998) Chronic acamprosate eliminates the alcohol deprivation effect while having limited effects on baseline responding for ethanol in rats. Neuropsychopharmacol-ogy 18:125-133

Koob GF, Le Moal M (2006) Neurobiology of Addiction. Academic Press, London

Littleton JM (2007) Acamprosate in alcohol dependence: implications of a unique mechanism of action. J Addict Med 1:115-125

Mason BJ, Crean R (2007) Acamprosate in the treatment of alcohol dependence: clinical and economic considerations. Expert Rev Neurother 7:1465-1477 Spanagel R, Holter SM, Allingham K, Landgraf R, Zieglgansberger W (1996) Acamprosate and alcohol: I. Effects on alcohol intake following alcohol deprivation in the rat. Eur J Pharmacol 305:39-44 Tsai G, Coyle JT (1998) The role of glutamatergic neurotransmission in the pathophysiology of alcoholism. Annu Rev Med 49:173-184 Wilde MI, Wagstaff AJ (1997) Acamprosate. A review of its pharmacology and clinical potential in the management of alcohol dependence after detoxification. Drugs 53:1038-1053

Alcohol No More

Alcohol No More

Do you love a drink from time to time? A lot of us do, often when socializing with acquaintances and loved ones. Drinking may be beneficial or harmful, depending upon your age and health status, and, naturally, how much you drink.

Get My Free Ebook


Post a comment