Pharmacology in Alcohol Use Disorder: Naltrexone, Acamprosate, and Disulfiram

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

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