What is the role of acamprosate (Campral) and naltrexone (ReVia) in treating heavy alcohol abuse?

Acamprosate Plus Naltrexone for Heavy Alcohol Abuse

Direct Recommendation

Both acamprosate and naltrexone are FDA-approved and effective for maintaining abstinence in alcohol use disorder, but they should generally be used as monotherapy rather than in combination, with medication selection based primarily on liver function status. 1, 2

Medication Selection Algorithm

Step 1: Assess Liver Function

If the patient has alcohol-associated liver disease (ALD) or cirrhosis:

• Choose acamprosate exclusively 1, 2
• Acamprosate undergoes no hepatic metabolism and has no reported instances of hepatotoxicity 3
• Naltrexone is contraindicated due to hepatotoxicity concerns and hepatic metabolism 3, 1

If the patient has normal liver function:

• Choose naltrexone as first-line 1, 2
• Naltrexone has a number needed to treat (NNT) of approximately 20 compared to acamprosate's NNT of 12, suggesting naltrexone may be slightly more effective at preventing return to any drinking 3, 2
• Naltrexone is particularly effective for patients reporting strong cue-induced craving as their primary relapse trigger 1
• However, baseline liver function tests are required, with monitoring every 3-6 months 1

Alternative consideration for normal liver function:

• Acamprosate is more effective at maintaining continuous abstinence once achieved and reducing severity of relapse when it occurs 2

Critical Timing Requirements

Both medications must be initiated 3-7 days after the last alcohol consumption and only after withdrawal symptoms have completely resolved: 1, 4, 5

• Benzodiazepines remain the gold standard for managing acute alcohol withdrawal syndrome 1
• Starting acamprosate too early (before complete detoxification) reduces efficacy since its mechanism is maintaining rather than inducing abstinence 2, 4
• The efficacy of acamprosate has not been demonstrated in subjects who have not undergone detoxification and achieved abstinence prior to beginning treatment 5

Dosing Regimens

Acamprosate Dosing:

• 666 mg (two 333 mg tablets) three times daily for patients ≥60 kg 1, 2, 4
• Reduce dose by one-third for patients <60 kg 4
• 333 mg three times daily for moderate renal impairment (CrCl 30-50 mL/min) 1
• Contraindicated in severe renal impairment (CrCl ≤30 mL/min) 5
• Treatment duration: 3-6 months minimum, can extend to 12 months 2, 4

Naltrexone Dosing:

• 25 mg daily on days 1-3, then 50 mg daily for 3-6 months 1
• Monthly injection formulation available 1

Combination Therapy: Not Routinely Recommended

The evidence does not support routine combination of acamprosate plus naltrexone: 2

• The World Health Organization guidelines recommend choosing between these medications based on patient preferences, motivation, and availability rather than routinely combining them 2
• While one 2003 study showed the combination was more effective than placebo or acamprosate alone (but not significantly better than naltrexone alone) 6, this finding has not translated into guideline recommendations
• Pharmacokinetic studies show that co-administration increases acamprosate absorption by 25-33% without affecting naltrexone levels, with no safety contraindications 7
• However, animal studies provide conflicting evidence on additive effects 8, 9

Mechanism of Action

Acamprosate:

• Functions as an NMDA receptor antagonist, modulating glutamate transmission 3, 1, 5
• Reduces autonomic nervous system reactions to alcohol-related cues and withdrawal symptoms 1
• Restores the balance between neuronal excitation and inhibition altered by chronic alcohol exposure 5

Naltrexone:

• Competitive opioid receptor antagonist that blocks the reinforcing effects of alcohol consumption 1
• More effective at reducing cue-induced craving 2

Common Pitfalls to Avoid

• Never initiate either medication during active alcohol withdrawal - this is the most critical error 1, 2
• Never use naltrexone in patients with significant liver disease - this is an absolute contraindication 1, 2
• Never fail to combine medication with comprehensive psychosocial treatment - both the American Association for the Study of Liver Diseases and World Health Organization emphasize this requirement 2, 4, 5
• Never discontinue treatment prematurely - continue for at least 3-6 months for optimal results 4
• Never forget renal dose adjustments for acamprosate - elderly patients and those with renal impairment require monitoring as acamprosate is excreted unchanged in urine 5

Special Populations

Elderly patients:

• Acamprosate plasma concentrations are likely higher due to diminished renal function 5
• Monitor renal function and consider dose adjustment 5

Patients with moderate renal impairment:

• Reduce acamprosate dose to 333 mg three times daily 1
• Peak concentrations are approximately 2-fold higher than in healthy subjects 5