A patient with alcohol‑use disorder on naltrexone is experiencing significant weight loss; should I switch to acamprosate?

Weight Loss on Naltrexone: Switch to Acamprosate

Do not switch to acamprosate based solely on weight loss, as naltrexone is expected to cause weight loss and this is not a contraindication to its use in alcohol use disorder. However, if the weight loss is clinically significant and concerning, acamprosate is the appropriate alternative medication as it has no hepatotoxicity risk and is the preferred agent in patients with alcohol-associated liver disease. 1, 2

Understanding Naltrexone's Weight Loss Effect

• Naltrexone causes intentional weight loss through its mechanism of action. When combined with bupropion (as naltrexone-bupropion), it is FDA-approved specifically for obesity treatment, achieving approximately 6% weight loss at 56 weeks. 3

• The weight loss occurs because naltrexone blocks opioid-mediated feedback loops that normally limit appetite suppression, activating pro-opiomelanocortin neurons in the hypothalamus that release anorectic neuropeptides. 3

• Weight loss is an expected pharmacologic effect, not an adverse reaction requiring medication discontinuation in most patients with alcohol use disorder. 3

When to Consider Switching to Acamprosate

Switch to acamprosate if:

• The patient has clinically significant unintentional weight loss (>5% body weight) that is causing medical complications or malnutrition 1

• The patient has alcohol-associated liver disease, where acamprosate is actually the preferred first-line agent due to complete lack of hepatotoxicity 1, 2

• The patient has contraindications to naltrexone including hepatic dysfunction (naltrexone is contraindicated in alcoholic liver disease due to hepatotoxicity risk) 3, 1

Acamprosate as the Alternative

Acamprosate is the safest medication for alcohol use disorder in patients with liver disease or concerning weight loss:

• No hepatotoxicity risk whatsoever - acamprosate has no hepatic metabolism and is exclusively renally excreted, making it particularly advantageous in patients with liver disease. 1, 2

• Weight gain is actually reported as a side effect in the FDA label, with peripheral edema and weight gain listed as frequent adverse events (≥1% incidence). 4

• The American Association for the Study of Liver Diseases recommends acamprosate as the preferred agent in patients with alcohol-associated liver disease. 1, 2

Acamprosate Dosing and Initiation

Standard dosing protocol:

• For patients ≥60 kg: 666 mg (two 333 mg tablets) three times daily = 1,998 mg/day total 3, 2

• For patients <60 kg: reduce dose by one-third to 1,332 mg/day 3

• Critical timing requirement: Initiate 3-7 days after last alcohol consumption, once withdrawal symptoms have completely resolved. 3, 1

• Treatment duration: typically 3-6 months, can extend to 12 months. 3

Important Caveats

Before switching, assess renal function:

• Acamprosate is exclusively renally excreted, so renal function must be assessed before initiating therapy. 2

• Contraindicated in severe renal impairment (CrCl <30 mL/min); dose reduction required for moderate impairment (CrCl 30-50 mL/min). 1

Efficacy considerations:

• Acamprosate is more effective at maintaining abstinence (effect size favors acamprosate over naltrexone for abstinence maintenance), while naltrexone is more effective at reducing heavy drinking and craving. 5, 6

• Acamprosate works best when patients are detoxified before starting medication. 5

• The combination of naltrexone plus acamprosate shows the lowest relapse rates, significantly better than either medication alone. 6

Clinical Decision Algorithm

1. Assess the severity and clinical significance of weight loss - Is it >5% body weight? Is it causing medical complications? 1

2. Evaluate liver function - Does the patient have alcohol-associated liver disease? If yes, acamprosate should have been first-line. 1, 2

3. Check renal function - Is CrCl >30 mL/min? If no, acamprosate is contraindicated. 1

4. Determine treatment goal - Is the goal complete abstinence or harm reduction? Acamprosate is superior for abstinence maintenance. 5

5. If switching is warranted: Ensure patient is abstinent and withdrawal has resolved before starting acamprosate at appropriate weight-based dosing. 3, 1