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Out of the Pipeline


Acamprosate: For discomfort of early alcohol abstinence

Vol. 4, No. 2 / February 2005

Acamprosate, a gamma-aminobutyric acid (GABA) analogue used worldwide to treat alcohol dependence, is available in this country (Table 1). The agent appears to reduce discomfort—including restlessness, anxiety, dysphoria, and insomnia—common within the first 6 months of alcohol abstinence. In clinical trials, it prolonged abstinence in alcohol-dependent patients who completed an initial detoxification and were receiving relapse prevention treatment.

HOW IT WORKS

Acamprosate’s chemical structure resembles both GABA and taurine, an endogenous amino acid derivative that enhances GABA-ergic activity.1 The drug’s synthetic structure facilitates its passage across the blood-brain barrier, and the brain mediates its major effect.

Table 1

Acamprosate: Fast facts

Brand name:

Campral

Class:

GABA analogue

FDA-approved indication:

Maintaining abstinence in alcohol-dependent patients

Approval date:

July 29, 2004

Manufacturer:

Forest Pharmaceuticals

Dosing form:

333-mg tablets

Recommended dosage:

Adults age <65: 666 mg tid. Not indicated for use in children, adolescents, or the elderly

The mechanisms by which acamprosate promotes abstinence in alcohol dependence are unknown. The drug may bind to N-methyl-D-aspartate (NMDA) glutamate receptors and work as a partial antagonist, but direct ligand activity does not appear to cause most of its central actions. Rather, acamprosate interacts with glutamate and GABA to normalize the hyperexcitability that accompanies early abstinence (Table 2).

Table 2

Acamprosate’s proposed mechanisms of action*

Neurotransmitter interactions

Pharmacologic effect

Clinical effect

Glutamatergic system (NMDA receptor)

Blocks increased glutamate release in nucleus accumbens during alcohol withdrawal; may bind to receptor site as partial antagonist

Decreased arousal, craving, and dysphoria associated with early abstinence

GABAergic system (GABAAreceptor)

Normalizes alcohol-induced decrease in basal GABA concentrations in nucleus accumbens

Same as above

Neuromodulator interactions

Taurine

Increases extracellular taurine concentrations in nucleus accumbens; taurine shifts the glutamate/GABA balance in favor of GABAergic activity

Mimics increase in taurine seen with acute alcohol intake, likely facilitating GABA normalization

* Based on animal models of alcohol dependence

Source: reference 3

PHARMACOKINETICS

Acamprosate’s bioavailability is relatively poor (11%), so it is prescribed to be taken three times daily. Although patients in clinical practice often have trouble following frequent daily dosing schedules, subjects in one study reportedly had little difficulty adhering to this regimen.2

Acamprosate’s half-life is approximately 13 hours, and it reaches peak plasma concentrations in 3.5 to 9.5 hours. Pharmaceutical studies indicate that food does not significantly affect absorption.

Although 666 mg tid has shown efficacy in clinical trials, the blood level at which acamprosate becomes therapeutic has not been determined.

The drug reaches steady-state blood levels within 1 week, meaning it will not be fully effective for 5 to 7 days but may still reach therapeutic blood levels during that time. Advise patients that adverse effects may not clear for 5 to 7 days after discontinuation.

Acamprosate does not bind with plasma proteins, so it will not interact with drugs that do. The drug, which is renally excreted in an unmetabolized state, has not been found to interact adversely with commonly prescribed antidepressants, anxiolytics, antipsychotics, alcohol, or disulfiram.3 How acamprosate interacts with renally excreted drugs such as lithium is unknown.

In two studies following 24 healthy volunteers4 and 23 alcohol-dependent patients,5 concomitant naltrexone, 50 to 100 mg/d, and acamprosate, 2 to 3 g/d, increased acamprosate plasma concentrations as much as 25%, but did not change plasma levels of naltrexone or its major metabolite. Naltrexone might delay gastric emptying, thereby increasing acamprosate absorption.

EFFICACY

Acamprosate with psychosocial treatment increased total abstinent days in:

  • 15 randomized, controlled trials (RCT) conducted in Europe6
  • a meta-analysis of 12 methodologically comparable RCTs conducted in Europe7
  • an open-label trial in France that studied acamprosate as an adjunct to treatment-as-usual in primary care settings.2

Acamprosate may improve patient retention in substance abuse treatment, which predicts favorable outcomes.7 Patients receiving acamprosate and treatment-as-usual reported fewer alcohol-related problems and improved quality of life compared with treatment-as-usual alone.2 Reduced subjective craving for alcohol is difficult to study and has not been sufficiently shown.

Combined pharmacotherapy. It is unclear whether acamprosate and naltrexone or disulfiram are more effective than acamprosate alone.3,6,7

In one multi-center, placebo-controlled trial, a subgroup of severely alcohol-dependent patients sought acamprosate/disulfiram therapy. The combination was shown to be safe and increased total abstinent days compared with acamprosate or disulfiram alone, but effectiveness could not be determined because of the self-selection bias of those who requested combined pharmacotherapy.

In one 12-week RCT,8 naltrexone/acamprosate therapy was more effective than acamprosate alone—but not more effective than naltrexone alone—in reducing time to first drink and relapse to heavy drinking.

The multi-center COMBINE (Combining Medications and Behavioral Interventions) study,9 funded by the National Institute on Alcohol Abuse and Alcoholism, is comparing the efficacy of naltrexone, acamprosate, and both agents when given with low-intensity psychosocial treatment or moderate-intensity, alcohol-specific psychosocial treatment. Preliminary safety, tolerability, and adherence results with the acamprosate/naltrexone combination have been promising. Efficacy findings are expected later this year.

SAFETY

Acamprosate is contraindicated in patients with severely compromised renal function (creatinine clearance <30 mL/min). Lower dosages (333 mg tid) are recommended for patients with reduced creatinine clearance (30 to 50 mL/min).

The drug is safe for patients with mild to moderate alcohol-related liver disease as defined by the Child-Pugh classification of hepatic impairment.10 For a patient with severe liver disease, consult his or her gastroenterologist to gauge risks and benefits, as acamprosate can cause adverse GI effects.

Acamprosate has not been tested in children or the elderly, although one study suggests efficacy in alcohol-dependent adolescents ages 16 to 19.7. The agent’s safety during pregnancy or lactation is unknown.

TOLERABILITY

Acamprosate has been well-tolerated in clinical trials. Discontinuation rates because of adverse effects have been similar in treatment and placebo groups.7

GI side effects are most common, with overall rates of 17% and 11% among acamprosate and placebo groups, respectively.7 Diarrhea may be transient and may also resolve with a reduced dosage.6

Slightly higher rates of suicidal ideation were reported among patients taking acamprosate vs those taking placebo (1.4 % vs. 0.5% in short-term [<6 months] studies and 2.4% vs. 0.8% in yearlong studies).10 Screen all patients taking acamprosate for suicidal ideation or behavior.

Other reported side effects include headache, abdominal pain, nausea and vomiting, dyspepsia, flatulence, pruritus, rash, drowsiness, and dizziness. Acamprosate has no abuse potential and low potential for toxicity in overdose. Higher acamprosate plasma levels during combined acamprosate/naltrexone treatment may increase risk of diarrhea.9

CLINICAL IMPLICATIONS

Drinking alcohol while taking acamprosate will not make a patient sick, which makes it an alternative for patients who fear the harsh effects of “slipping up” while taking disulfiram.

Also, acamprosate does not interact with prescription opioids. By contrast, naltrexone is contraindicated in patients taking opioids for pain.

Related resources

Drug brand names

  • Acamprosate • Campral
  • Disulfiram • Antabuse
  • Naltrexone • ReVia

Disclosure

Drs. Connery and Weiss receive research/grant support from Ortho-McNeil Pharmaceutical. Dr. Weiss is also a speaker for Forest Laboratories.

References

1. Dahchour A, De Witte P. Ethanol and amino acids in the central nervous system: assessment of the pharmacological actions of acamprosate. Prog Neurobiol 2000;60:343-62.

2. Kiritze-Topor P, Huas D, Rosenzweig C, et al. A pragmatic trial of acamprosate in the treatment of alcohol dependence in primary care. Alcohol Alcohol 2004;39:520-7.

3. Kiefer F, Wiedemann K. Combined therapy: what does acamprosate and naltrexone combination tell us? Alcohol Alcohol 2004;39:542-7.

4. Mason BJ, Goodman AM, Dixon RM, et al. A pharmacokinetic and pharmacodynamic drug interaction study of acamprosate and naltrexone. Neuropsychopharmacology 2002;27:596-606.

5. Johnson BA, O’Malley SS, Ciraulo DA, et al. Dose-ranging kinetics and behavioral pharmacology of naltrexone and acamprosate, both alone and combined, in alcohol-dependent subjects. J Clin Psychopharmacol 2003;23:281-93.

6. Overman GP, Teter CJ, Guthrie SK. Acamprosate for the adjunctive treatment of alcohol dependence. Ann Pharmacother 2003;37:1090-9.

7. Carmen B, Angeles M, Ana M, Maria AJ. Efficacy and safety of naltrexone and acamprosate in the treatment of alcohol dependence: a systematic review. Addiction 2004;99:811-28.

8. Kiefer F, Jahn H, Tarnaske T, et al. Comparing and combining naltrexone and acamprosate in relapse prevention of alcoholism: a double-blind, placebo-controlled study. Arch Gen Psychiatry 2003;60:92-9.

9. The COMBINE study research group. Testing combined pharmacotherapies and behavioral interventions in alcohol dependence: rationale and methods. Alcohol Clin Exp Res 2003;27:1107-22.

10. Campral prescribing information. Available at: http://www.campral.com. Accessed Jan. 7, 2005.

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