Acamprosate vs. Naltrexone: A Comparison for Alcohol Use

Acamprosate and naltrexone are two distinct, FDA-approved medications for managing alcohol use disorder (AUD). Both are first-line treatments that operate through different biological pathways and are prescribed as part of a comprehensive plan that includes psychosocial support. This article explores how each medication functions, their applications, and considerations for their use.

Understanding Acamprosate for Alcohol Use Disorder

Acamprosate is prescribed to help individuals maintain abstinence from alcohol after they have completed detoxification. Its therapeutic action is not fully understood, but it is thought to work by restoring a chemical equilibrium in the brain disrupted by long-term, heavy alcohol consumption. Acamprosate appears to counteract some of these changes in key neurotransmitter systems.

The medication modulates the brain’s glutamate and gamma-aminobutyric acid (GABA) systems. Alcohol enhances the inhibitory effects of GABA and suppresses the excitatory effects of glutamate. When alcohol is withdrawn, the brain can enter a state of hyperexcitability, leading to withdrawal, anxiety, and cravings. Acamprosate is believed to reduce this hyperexcitability by acting on NMDA receptors and calcium channels, easing the post-withdrawal distress that can trigger a return to drinking.

Acamprosate is administered as oral tablets, with a common dosage of two 333 mg tablets taken three times per day. Because the medication is cleared by the kidneys, it is contraindicated in individuals with severe renal impairment. Kidney function must be assessed before starting treatment.

Common side effects are often mild and involve the gastrointestinal system, with diarrhea being the most common complaint. Other potential side effects include gas, upset stomach, and loss of appetite. Less common but more serious concerns include mood changes or suicidal thoughts, which require careful patient monitoring.

Understanding Naltrexone for Alcohol Use Disorder

Naltrexone functions differently from acamprosate by targeting the reward pathways associated with alcohol consumption. It is an opioid antagonist, meaning it blocks the activity of opioid receptors in the brain. Alcohol consumption leads to the release of endorphins, which activate these receptors and produce feelings of pleasure and reward.

By blocking these receptors, naltrexone diminishes the euphoric effects of alcohol. This mechanism reduces the reinforcing properties of drinking, which can decrease cravings and lower the probability of returning to heavy drinking. A person taking naltrexone will not become ill if they drink; the experience will simply be less rewarding.

Naltrexone is available as a once-daily oral tablet (typically 50 mg) and as a long-acting monthly intramuscular injection. The injectable form can be an advantage for individuals who have difficulty adhering to a daily medication schedule. Oral naltrexone is often initiated at a lower dose for the first few days to minimize side effects.

A patient must be completely free of all opioids before starting naltrexone, as the drug can trigger a sudden withdrawal syndrome. Because naltrexone is metabolized by the liver, liver function tests are recommended before and during treatment. It should be used with caution in individuals with liver disease. The most common side effects include nausea, headache, fatigue, and dizziness.

Comparing Acamprosate and Naltrexone

The choice between acamprosate and naltrexone depends on the individual’s specific treatment goals and clinical profile. Their primary distinctions relate to their therapeutic goals, patient suitability, and safety considerations.

Therapeutic Goal

Acamprosate is most effective for individuals who have already achieved abstinence and aim to maintain it. Its purpose is to prevent a return to drinking by reducing the discomfort that follows detoxification. In contrast, naltrexone is geared toward reducing cravings and the amount of alcohol consumed, making it a suitable option for those who wish to cut back on heavy drinking.

Patient Profile

Acamprosate is a strong candidate for individuals motivated to maintain complete abstinence after detoxification. Naltrexone may be preferred for those whose primary goal is to reduce their overall consumption. Furthermore, naltrexone’s interaction with opioids makes it unsuitable for patients who require opioid-based pain management.

Safety and Side Effects

The medications have different safety profiles based on how they are processed by the body.

• Acamprosate is cleared by the kidneys and is not recommended for patients with significant kidney disease.
• Naltrexone is metabolized by the liver, requiring caution in patients with hepatic impairment.
• While both can cause gastrointestinal upset, diarrhea is more common with acamprosate.
• Nausea is more frequent with naltrexone.

Combined Use of Acamprosate and Naltrexone

Given their distinct mechanisms, there is a clinical rationale for using acamprosate and naltrexone together. The strategy is to address alcohol use disorder from two different neurobiological angles simultaneously, by reducing the negative state of withdrawal with acamprosate and blocking the rewarding effects of alcohol with naltrexone.

Research into the effectiveness of this combined approach has produced mixed results. Some smaller studies suggested that using both medications together was more effective at preventing a return to heavy drinking than using either medication alone. This pointed toward a potential synergistic benefit.

However, a large clinical trial, the COMBINE study, did not find a significant advantage for the combination therapy over naltrexone monotherapy when paired with medical management. This result has led to inconsistencies in clinical recommendations, with some guidelines supporting its use while others remain cautious due to the lack of definitive evidence.

Combination therapy is considered safe and well-tolerated, though patients may experience a higher incidence of certain side effects, such as nausea. The decision to pursue combination therapy is made on a case-by-case basis, considering the patient’s history and treatment goals. This approach may be considered for individuals who have not had success with a single medication.