Pharmacology in Alcohol Use Disorder: Naltrexone, Acamprosate, and Disulfiram
Joji Suzuki, M.D.
Division of Addiction Psychiatry, Brigham and Women’s Hospital; Assistant Professor of Psychiatry, Harvard Medical School

Medications for Alcohol Use Disorder
• Access to addiction treatment remains limited
• Clinicians do not often utilize medications
• Compared with medications for opioid use disorders, medications for alcohol use disorder are not as impactful
Saitz, R. (2014). Medications for alcohol use disorders. JAMA, 312(13), 1349.

Medications Are Effective
• Help patients maintain sobriety
• Reduce heavy drinking
Saitz, R. (2014). Medications for alcohol use disorders. JAMA, 312(13), 1349.

Naltrexone for Alcohol Use Disorder
Mechanism of Action
• Decreases GABA inhibition
• Reduces dopamine release
Pharmacokinetics
• Short half-life
• Active metabolite has a longer half-life
Dose
• Therapeutic dose: 50 mg/day

• Pettinati, H. M., Dundon, W. D., & Casares López, M. J. (2013). Naltrexone and opioid antagonists for alcohol dependence. Interventions for Addiction, 375-384.
• Srisurapanont, M., & Jarusuraisin, N. (2005). Naltrexone for the treatment of alcoholism: A meta-analysis of randomized controlled trials. The International Journal of Neuropsychopharmacology, 8(2), 267-280. Naltrexone Side Effects
  Somnolence GI distress Liver enzyme elevations
• Pettinati, H. M., Dundon, W. D., & Casares López, M. J. (2013). Naltrexone and opioid antagonists for alcohol dependence. Interventions for Addiction, 375-384.
• Srisurapanont, M., & Jarusuraisin, N. (2005). Naltrexone for the treatment of alcoholism: A meta-analysis of randomized controlled trials. The International Journal of Neuropsychopharmacology, 8(2), 267-280.
• Pettinati, H. M., Dundon, W. D., & Casares López, M. J. (2013). Naltrexone and opioid antagonists for alcohol dependence. Interventions for Addiction, 375-384.
• Srisurapanont, M., & Jarusuraisin, N. (2005). Naltrexone for the treatment of alcoholism: A meta-analysis of randomized controlled trials. The International Journal of Neuropsychopharmacology, 8(2), 267-280.
  Liver Damage From Drinking Outweighs the Risk of Liver Toxicity From Treatment Naltrexone and Liver Function Monitoring
  Monitoring Frequency
  Comment
  Every 6 months
  Liver enzyme elevation up to 3 times the standard limit is normal as long as liver enzymes are trending down
• Pettinati, H. M., Dundon, W. D., & Casares López, M. J. (2013). Naltrexone and opioid antagonists for alcohol dependence. Interventions for Addiction, 375-384.
• Srisurapanont, M., & Jarusuraisin, N. (2005). Naltrexone for the treatment of alcoholism: A meta-analysis of randomized controlled trials. The International Journal of Neuropsychopharmacology, 8(2), 267-280. Naltrexone Precautions and Contraindications
  Precaution
  Contraindication
  Hepatitis C Current opioid use
• Pettinati, H. M., Dundon, W. D., & Casares López, M. J. (2013). Naltrexone and opioid antagonists for alcohol dependence. Interventions for Addiction, 375-384.
• Srisurapanont, M., & Jarusuraisin, N. (2005). Naltrexone for the treatment of alcoholism: A meta-analysis of randomized controlled trials. The International Journal of Neuropsychopharmacology, 8(2), 267-280. Clinical Effects of Naltrexone on Alcohol Use Disorder
  Reduces:
  • Subjective effects • Dopamine release • Euphoric effects
  • Heavy drinking
  Helps to maintain abstinence
• Pettinati, H. M., Dundon, W. D., & Casares López, M. J. (2013). Naltrexone and opioid antagonists for alcohol dependence. Interventions for Addiction, 375-384.
• Srisurapanont, M., & Jarusuraisin, N. (2005). Naltrexone for the treatment of alcoholism: A meta-analysis of randomized controlled trials. The International Journal of Neuropsychopharmacology, 8(2), 267-280. Clinical Effects of Naltrexone on Alcohol Use Disorder
  • Appropriate for patients who want to cut down or maintain their abstinence
  • The overall benefit seems to be better if the patient can maintain abstinence for at least 4 days
• Pettinati, H. M., Dundon, W. D., & Casares López, M. J. (2013). Naltrexone and opioid antagonists for alcohol dependence. Interventions for Addiction, 375-384.
• Srisurapanont, M., & Jarusuraisin, N. (2005). Naltrexone for the treatment of alcoholism: A meta-analysis of randomized controlled trials. The International Journal of Neuropsychopharmacology, 8(2), 267-280. Goals and Benefits of Treatment for Alcohol Use Disorder
  Goal
  Benefits
  • To cut back drinking is a reasonable initial goal, but it may not be appropriate in the longer term
  • Any reduction in drinking has health benefits
  • Mayleadtoabstinence
• Pettinati, H. M., Dundon, W. D., & Casares López, M. J. (2013). Naltrexone and opioid antagonists for alcohol dependence. Interventions for Addiction, 375-384.
• Srisurapanont, M., & Jarusuraisin, N. (2005). Naltrexone for the treatment of alcoholism: A meta-analysis of randomized controlled trials. The International Journal of Neuropsychopharmacology, 8(2), 267-280. IM Naltrexone for Alcohol Use Disorder
  Once-a-month gluteal injection
  May be more effective than the oral version
  • Gastfriend, D. R. (2011). Intramuscular extended-release naltrexone: Current evidence. Annals of the New York Academy of Sciences, 1216(1), 144-166.
• Pettinati, H. M., Dundon, W. D., & Casares López, M. J. (2013). Naltrexone and opioid antagonists for alcohol dependence. Interventions for Addiction, 375-384.
  More convenient
  Supports abstinence PRN Naltrexone for Alcohol Use Disorder
  • Gastfriend, D. R. (2011). Intramuscular extended-release naltrexone: Current evidence. Annals of the New York Academy of Sciences, 1216(1), 144-166.
• Pettinati, H. M., Dundon, W. D., & Casares López, M. J. (2013). Naltrexone and opioid antagonists for alcohol dependence. Interventions for Addiction, 375-384.
  For high-risk situations
  Minimal research on this approach Acamprosate for Alcohol Use Disorder
  Mechanism of Action
  • Glutamatergic antagonist
  • GABA agonist
  Pharmacokinetics
  • No drug–drug interactions
  • Effects begin in a couple of days
  Dose
  • 666 mg TID
  Rösner, S., Hackl-Herrwerth, A., Leucht, S., Lehert, P., Vecchi, S., & Soyka, M. (2010). Acamprosate for alcohol dependence. Sao Paulo Medical Journal, 128(6), 379-379. Acamprosate for Alcohol Use Disorder
  • Well-tolerated
  • Common side effects: GI distress and diarrhea
  • Absolute contraindication: Kidney failure (CrCl < 30mL/min)
  Rösner, S., Hackl-Herrwerth, A., Leucht, S., Lehert, P., Vecchi, S., & Soyka, M. (2010). Acamprosate for alcohol dependence. Sao Paulo Medical Journal, 128(6), 379-379. Acamprosate for Alcohol Use Disorder
  • Clinical effects: Promoting and maintaining abstinence
  • Project COMBINE: Failed to show superiority over placebo
  • Overall evidence supports its use
• Rösner, S., Hackl-Herrwerth, A., Leucht, S., Lehert, P., Vecchi, S., & Soyka, M. (2010). Acamprosate for alcohol dependence. Sao Paulo Medical Journal, 128(6), 379-379.
• Donovan, D. M., Anton, R. F., Miller, W. R., Longabaugh, R., Hosking, J. D., & Youngblood, M. (2008). Combined Pharmacotherapies and behavioral interventions for alcohol dependence (The combine study): Examination of Posttreatment drinking outcomes. Journal of Studies on Alcohol and Drugs, 69(1), 5-13. Acamprosate for Alcohol Use Disorder
  • A period of abstinence is recommended prior to initiation
  • Do not discount it, even if it has a small effect
• Rösner, S., Hackl-Herrwerth, A., Leucht, S., Lehert, P., Vecchi, S., & Soyka, M. (2010). Acamprosate for alcohol dependence. Sao Paulo Medical Journal, 128(6), 379-379.
• Rösner, S., Leucht, S., Lehert, P., & Soyka, M. (2007). Acamprosate supports abstinence, Naltrexone prevents excessive drinking: Evidence from a meta-analysis with unreported outcomes. Journal of Psychopharmacology, 22(1), 11-23. Disulfiram for Alcohol Use Disorder
  Mechanism of Action
  Inhibits acetaldehyde dehydrogenase
  Effect
  Accumulation of acetaldehyde
  Dose
  Target dose: 250 mg /day
• Krampe, H., & Ehrenreich, H. (2010). Supervised disulfiram as adjunct to psychotherapy in alcoholism treatment. Current Pharmaceutical Design, 16(19), 2076-2090.
• De Sousa, A. (2019). Disulfiram in the management of alcohol dependence. Disulfiram, 21-30. Disulfiram Side Effects
  Cognitive problems: • Delirium
  • Psychosis
  Liver failure
  • Krampe, H., & Ehrenreich, H. (2010). Supervised disulfiram as adjunct to psychotherapy in alcoholism treatment. Current Pharmaceutical Design, 16(19), 2076-2090.
• De Sousa, A. (2019). Disulfiram in the management of alcohol dependence. Disulfiram, 21-30. Disulfiram Is Contraindicated in Individuals With a Psychotic Disorder
• Krampe, H., & Ehrenreich, H. (2010). Supervised disulfiram as adjunct to psychotherapy in alcoholism treatment. Current Pharmaceutical Design, 16(19), 2076-2090.
• De Sousa, A. (2019). Disulfiram in the management of alcohol dependence. Disulfiram, 21-30. Disulfiram for Alcohol Use Disorder
  • Best for more motivated patients
  • Combine it with behavioral couples therapy to create accountability
  Krampe, H., & Ehrenreich, H. (2010). Supervised disulfiram as adjunct to psychotherapy in alcoholism treatment. Current Pharmaceutical Design, 16(19), 2076-2090. Patient Factors to Consider
  • Patient preference
  • Prior response
  • Contraindications
  • Comorbid conditions
  Saitz, R. (2014). Medications for alcohol use disorders. JAMA, 312(13), 1349. Key Points
  • Naltrexone reduces heavy drinking days, promotes abstinence, and reduces cravings.
  • Use naltrexone with caution in patients with liver dysfunction. Key Points
  • Acamprosate promotes abstinence and reduces cravings.
  • Use acamprosate with caution in patients with kidney dysfunction.
  • Disulfiram is a viable option, but it is important to select highly motivated individuals. Next Presentation
  Pharmacology in Alcohol Use Disorder: Gabapentin, Topiramate, and Baclofen