ACAMPROSATE — 333 mg delayed‑release tablets

Acamprosate is a medication used to maintain abstinence from alcohol in individuals with alcohol dependence who have already stopped drinking. It was first approved in Europe in 1989 and received FDA approval in 2004. It is currently available only as a generic 333 mg delayed‑release tablet, as the original brand Campral has been discontinued. Acamprosate is one of the few medications proven to significantly reduce the risk of relapse to any drinking, with a relative risk of 0.86 based on a Cochrane Review of 24 randomized controlled trials.

Mechanism of action: The exact mechanism remains under investigation, but acamprosate is thought to restore the balance between excitatory (glutamate) and inhibitory (GABA) neurotransmission that is disrupted by chronic alcohol use and withdrawal. Chronic alcohol consumption leads to a hyperglutamatergic state during withdrawal, which may drive alcohol-seeking behavior and relapse. Acamprosate modulates N‑methyl‑D‑aspartate (NMDA) receptor transmission and may have indirect effects on GABA_A receptors. It decreases brain glutamate levels and increases β‑endorphins in both animals and humans. Interestingly, research suggests that the calcium moiety of acamprosate may be the active component, as N‑acetylhomotaurinate alone (without calcium) is ineffective in preclinical models of relapse. Patients with higher plasma calcium levels due to acamprosate treatment show better outcomes such as longer time to relapse and greater cumulative abstinence.

Pharmacokinetics: Acamprosate has low oral bioavailability (~11%) due to slow absorption. The enteric‑coated formulation results in a time to peak concentration of approximately 6.3 hours. It has a long half‑life of about 32 hours, requiring 4 days for complete elimination after cessation. Acamprosate is not protein bound, is not metabolized by the liver, and is excreted unchanged in the urine. Therefore, renal impairment significantly increases plasma concentrations, requiring dose adjustment or contraindication depending on severity. Food decreases absorption, but the drug can be taken without regard to meals.

Clinical context: Acamprosate is used to maintain abstinence, not to treat alcohol withdrawal symptoms. It should be initiated after detoxification when the patient is already abstinent. It is most effective as part of a comprehensive management program that includes psychosocial support. Unlike naltrexone, acamprosate does not reduce heavy drinking days or craving intensity as strongly, but it may be slightly more effective at helping patients remain completely abstinent. It has no abuse potential and does not interact with alcohol, benzodiazepines, or disulfiram.

• Severe renal impairment (creatinine clearance ≤30 mL/min).
• Known hypersensitivity to acamprosate calcium or any component of the formulation.

• Naltrexone: May increase acamprosate plasma levels by approximately 25% (clinical significance unclear). No dose adjustment required, but monitor for increased side effects if used together.
• Alcohol, benzodiazepines, disulfiram: No pharmacokinetic interactions. Acamprosate can be safely combined with these agents.
• Food: Decreases acamprosate absorption by about 20%. Tablets can be taken without regard to meals; consistency in dosing timing is recommended.

• Pregnancy: FDA Category C. No adequate human studies; animal studies show no teratogenicity. Use only if benefit outweighs risk.
• Breastfeeding: Excretion in human milk unknown; caution advised. Consider benefits versus potential infant exposure.
• Pediatric use: Safety and efficacy not established for alcohol dependence (not indicated in minors). Investigational use in fragile X syndrome (orphan drug designation granted 2013) but not FDA‑approved.
• Geriatric use: No specific problems demonstrated, but elderly more likely to have age‑related renal impairment; assess creatinine clearance and adjust dose accordingly.
• Renal impairment: Mild (CrCl >50 mL/min): usual dose 666 mg three times daily. Moderate (CrCl 30‑50 mL/min): reduce to 333 mg three times daily. Severe (CrCl ≤30 mL/min): contraindicated.
• Hepatic impairment: No dose adjustment needed (Child‑Pugh A, B, or C). Acamprosate is not hepatically metabolized and has not been associated with liver toxicity.

• Efficacy differences: Meta‑analysis suggests acamprosate may be slightly more effective at helping patients maintain complete abstinence from alcohol, while naltrexone may be more effective at reducing heavy drinking days and craving intensity.
• Head‑to‑head study (157 men): No difference in average time to first drink. Naltrexone recipients had significantly longer time to relapse (63 vs 42 days, p=0.02). More naltrexone recipients remained relapse‑free at one year (41% vs 17%, p=0.0009). Naltrexone also associated with more sober days, fewer drinks per occasion, and lower craving severity.
• Combination therapy: Some studies have explored combining acamprosate and naltrexone, but evidence for additive benefit is mixed.
• Dosing frequency: Acamprosate requires three times daily dosing; naltrexone is once daily (oral) or once monthly (injectable).
• Side effect profiles: Acamprosate primarily causes gastrointestinal effects (diarrhea); naltrexone has boxed warnings for hepatotoxicity, opioid withdrawal precipitation, and opioid overdose vulnerability.

• Symptoms: Diarrhea, nausea, vomiting, hypercalcemia (rare). No fatal overdoses reported in clinical trials.
• Management: Supportive care, monitoring of vital signs and electrolytes. Activated charcoal may be considered if recent ingestion. Hemodialysis removes acamprosate.