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02. Naltrexone for Alcohol Use Disorder: Dosing, Monitoring, and Liver Safety

Published on August 1, 2025 Certification expiration date: August 1, 2028

Kevin A. Sevarino, M.D.C.M., Ph.D.

Associate Clinical Professor of Psychiatry - Yale School of Medicine

Key Points

Naltrexone reduces heavy drinking more than promoting abstinence by blocking opioid receptors that potentiate alcohol's dopamine-releasing effects.
Monitor for dysphoria, depression or anxiety as potential side effects of naltrexone that clinicians may overlook.
Verify patients aren't using opioids before starting naltrexone, including those using stimulants potentially contaminated with fentanyl.

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Slides and Transcript

Slide 1 of 20

Now, we’re going to be talking about naltrexone for managing alcohol use disorder. This is the, at least in the United States, the biggest gun, the most widely used medication.

Naltrexone for Alcohol Use Disorder: Dosing, Monitoring, and Liver Safety Slide 1 of 20

Slide 2 of 20

Oral naltrexone was FDA approved in the US in 1994 on the basis of reducing heavy drinking, not abstinence. Its mechanism is by blocking endogenous opioid release in response to alcohol intake and thereby reduces the rewarding effects of alcohol. Effects are greatest when craving is prominent and that’s probably because in all substances of abuse it is the anticipatory phase of using a substance that actually results in a greater release of dopamine than when we’re actually using the substance. And that’s true for alcohol as well.

References:

Richardson, K., Baillie, A., Reid, S., Morley, K., Teesson, M., Sannibale, C., Weltman, M., & Haber, P. (2008). Do acamprosate or naltrexone have an effect on daily drinking by reducing craving for alcohol?. Addiction, 103(6), 953–959. https://doi.org/10.1111/j.1360-0443.2008.02215.x
Singh, D., & Saadabadi, A. (2023). Naltrexone. In StatPearls. StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK534811/
Oasa, S., Sezgin, E., Ma, Y., et al. (2024). Naltrexone blocks alcohol-induced effects on kappa-opioid receptors in the plasma membrane. Translational Psychiatry, 14, 477. https://doi.org/10.1038/s41398-024-03172-8

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Slide 3 of 20

Naltrexone can be initiated in a once-daily dose of 25 mg and after three days increased to 50 mg. There are a lot of people that start right at 50 mg, but I find this dosing regimen eases the stomach problems and reduces any perceived side effects. If naltrexone is ineffective, as early as seven days you can increase the dose to 100 mg. I actually rarely see this done. People tend to stick at 50 mg, and add other medications. But if the liver is doing fine and you’re getting partial effect with the naltrexone, you should consider going up on the dose.

References:

Richardson, K., Baillie, A., Reid, S., Morley, K., Teesson, M., Sannibale, C., Weltman, M., & Haber, P. (2008). Do acamprosate or naltrexone have an effect on daily drinking by reducing craving for alcohol?. Addiction, 103(6), 953–959. https://doi.org/10.1111/j.1360-0443.2008.02215.x
Singh, D., & Saadabadi, A. (2023). Naltrexone. In StatPearls. StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK534811/

Naltrexone for Alcohol Use Disorder: Dosing, Monitoring, and Liver Safety Slide 3 of 20

Slide 4 of 20

If there are reasons of compliance where a person doesn’t want to dose every day, you can dose it as 100 mg on Monday, 100 mg on Wednesday, and 150 mg on Friday. That’s basically the equivalent of 50 mg a day, but it’s just given in three doses instead of five.

References:

Richardson, K., Baillie, A., Reid, S., Morley, K., Teesson, M., Sannibale, C., Weltman, M., & Haber, P. (2008). Do acamprosate or naltrexone have an effect on daily drinking by reducing craving for alcohol?. Addiction, 103(6), 953–959. https://doi.org/10.1111/j.1360-0443.2008.02215.x
Singh, D., & Saadabadi, A. (2023). Naltrexone. In StatPearls. StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK534811/

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Slide 5 of 20

I show here the reason why this medication was approved for the basis of reducing heavy drinking but not abstinence. So this is a graph showing on the left the dopaminergic neuron in the VTA, the ventral tegmental area, in the midbrain going out in the ventral striatum to the nucleus accumbens. Dopamine release in the nucleus accumbens is the final pathway for the reward of multiple substances. Well, it turns out that in the hypothalamus you release beta-endorphins from the arcuate nucleus in response to alcohol use. So what do those beta-endorphins do? Well, they impact the nerve terminal, the VTA, dopaminergic neuron nerve terminal to potentiate release of dopamine. On the opposite side, they inhibit the inhibitory GABA-ergic interneuron in the VTA that impacts the cell body. So that’s a double negative. What does that mean? That it’s the second mechanism that actually potentiates dopamine release. So alcohol potentiates dopamine release. That is increased by endogenous opioid tone. And therefore, how would you block it? You block it with an opiate blocker and that’s naltrexone.

References:

Johnson, B. A. (2008). Update on neuropharmacological treatments for alcoholism: Scientific basis and clinical findings. Biochemical Pharmacology, 75(1), 34-56. https://doi.org/10.1016/j.bcp.2007.08.005

Naltrexone for Alcohol Use Disorder: Dosing, Monitoring, and Liver Safety Slide 5 of 20

Slide 6 of 20

The meta-analysis from McPheeters, O’Connor, Riley et al. from 2023 shows that for return to heavy drinking naltrexone versus placebo had a risk ratio of 0.86. So it cuts down the return to heavy drinking. But for return to any drinking that is abstinence, the risk ratio is 0.95. Basically, no effect on abstinence but a moderate effect on reducing heavy drinking. So again, I emphasize these are not magic bullets. These are meant to be used in combination with behavioral treatments.

References:

McPheeters, M., O'Connor, E. A., Riley, S., Kennedy, S. M., Voisin, C., Kuznacic, K., Coffey, C. P., Edlund, M. D., Bobashev, G., & Jonas, D. E. (2023). Pharmacotherapy for alcohol use disorder: A systematic review and meta-analysis. JAMA, 330(17), 1653–1665. https://doi.org/10.1001/jama.2023.19761

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Slide 7 of 20

Oral naltrexone. What are its adverse effects? Administering naltrexone as an opioid blocker will cause opioid withdrawal in those that are physically dependent on opioids. So make sure that your patient isn’t expecting to be using p.r.n. opioids or maintained on long-term opioid therapy. And interestingly, make sure that since the comorbidity of opioid use disorder and alcohol use disorder is definitely present that if somebody is using even methamphetamine and cocaine, which in the United States is virtually always contaminated with fentanyl, make sure that you don’t have the risk of inducing opioid withdrawal when you put somebody on this.

References:

Singh, D., & Saadabadi, A. (2023). Naltrexone. In StatPearls. StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK534811/
Bolton, M., Hodkinson, A., Boda, S., Mould, A., Panagioti, M., Rhodes, S., Riste, L., & van Marwijk, H. (2019). Serious adverse events reported in placebo randomised controlled trials of oral naltrexone: a systematic review and meta-analysis. BMC Medicine, 17, Article 10. https://doi.org/10.1186/s12916-018-1242-0

Naltrexone for Alcohol Use Disorder: Dosing, Monitoring, and Liver Safety Slide 7 of 20

Slide 8 of 20

Common side effects. Nausea, vomiting, abdominal cramping, elevated LFTs but it’s uncommon at standard dosing, headache. And something I’ve seen in colleagues who acted as controls in their own studies, you can get dysphoria. Some people actually get feelings of depression on them or anxiety.

References:

Singh, D., & Saadabadi, A. (2023). Naltrexone. In StatPearls. StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK534811/
Substance Abuse and Mental Health Services Administration. (2025). What is Naltrexone? Side effects, uses, dose & risk. https://tinyurl.com/2sx7eptm

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Slide 9 of 20

Avoid using naltrexone if you’re seeing LFTs are five times the upper limit of normal, and of course in severe liver impairment, Child-Pugh Class C. I do not say rule out the use of naltrexone when you have high LFTs, but if you’re going to do that make sure you’re monitoring very quickly what’s happening to the LFTs after you start it.

References:

Singh, D., & Saadabadi, A. (2023). Naltrexone. In StatPearls. StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK534811/
Substance Abuse and Mental Health Services Administration. (2025). What is Naltrexone? Side effects, uses, dose & risk. https://tinyurl.com/2sx7eptm

Naltrexone for Alcohol Use Disorder: Dosing, Monitoring, and Liver Safety Slide 9 of 20

Slide 10 of 20

In hepatic disease for oral and injectable naltrexone, cases of hepatitis and clinically significant liver dysfunction have been observed during clinical development but no cases of hepatic failure or death. Therefore, the FDA has advised patients be warned of the risk of hepatic injury and advised to seek medical attention if they experience any symptoms of acute hepatitis in which case naltrexone should be discontinued right away. The levels of oral naltrexone in compensated and decompensated cirrhosis are markedly elevated. Since we have a very high therapeutic window of safety for this agent, that’s not so bad but you may have increased side effects.

References:

Ayyala, D., Bottyan, T., Tien, C., Pimienta, M., Yoo, J., Stager, K., Gonzalez, J. L., Stolz, A., Dodge, J. L., Terrault, N. A., & Han, H. (2022). Naltrexone for alcohol use disorder: Hepatic safety in patients with and without liver disease. Hepatology Communications, 6(12), 3433–3442. https://doi.org/10.1002/hep4.2080

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Slide 11 of 20

So in those cases of cirrhosis, you may want to use a lower dose, say 25 mg. The injectable naltrexone pharmacokinetics aren’t altered in mild or moderate hepatic impairment but adequate studies in severe hepatic impairment, again Child-Pugh C, have not been conducted.

References:

Ayyala, D., Bottyan, T., Tien, C., Pimienta, M., Yoo, J., Stager, K., Gonzalez, J. L., Stolz, A., Dodge, J. L., Terrault, N. A., & Han, H. (2022). Naltrexone for alcohol use disorder: Hepatic safety in patients with and without liver disease. Hepatology Communications, 6(12), 3433–3442. https://doi.org/10.1002/hep4.2080

Naltrexone for Alcohol Use Disorder: Dosing, Monitoring, and Liver Safety Slide 11 of 20

Slide 12 of 20

How should we adjust naltrexone in the presence of hepatic disease? Well, concerns about hepatotoxicity and altered pharmacokinetics underlie much of the use of naltrexone. I think that’s unfortunate because in many cases you’re going to find when you start naltrexone in somebody with elevated LFTs or even somebody with cirrhosis who’s been waiting on a transplant list, you’ll find not only do the LFTs go down but if you can keep somebody from drinking, you might get them to that lifesaving liver transplant.

References:

Ayyala, D., Bottyan, T., Tien, C., Pimienta, M., Yoo, J., Stager, K., Gonzalez, J. L., Stolz, A., Dodge, J. L., Terrault, N. A., & Han, H. (2022). Naltrexone for alcohol use disorder: Hepatic safety in patients with and without liver disease. Hepatology Communications, 6(12), 3433–3442. https://doi.org/10.1002/hep4.2080

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Slide 13 of 20

Clinical experience in many reports support the safe use of naltrexone in those with liver disease despite transient elevations in transaminases which is about 1.5% of those on naltrexone and almost 1% of those on placebo.

References:

Ayyala, D., Bottyan, T., Tien, C., Pimienta, M., Yoo, J., Stager, K., Gonzalez, J. L., Stolz, A., Dodge, J. L., Terrault, N. A., & Han, H. (2022). Naltrexone for alcohol use disorder: Hepatic safety in patients with and without liver disease. Hepatology Communications, 6(12), 3433–3442. https://doi.org/10.1002/hep4.2080

Naltrexone for Alcohol Use Disorder: Dosing, Monitoring, and Liver Safety Slide 13 of 20

Slide 14 of 20

In a study of 160 patients by Ayyala et al., 63% of those had alcoholic liver disease, 30% had cirrhosis, and 14% had decompensated cirrhosis. All three groups showed improvement in AST and ALT values with naltrexone treatment. So we can conclude naltrexone is safe with those in underlying liver disease, including compensated cirrhosis, but I would be more careful in decompensated cirrhosis with very careful monitoring.

References:

Ayyala, D., Bottyan, T., Tien, C., Pimienta, M., Yoo, J., Stager, K., Gonzalez, J. L., Stolz, A., Dodge, J. L., Terrault, N. A., & Han, H. (2022). Naltrexone for alcohol use disorder: Hepatic safety in patients with and without liver disease. Hepatology Communications, 6(12), 3433–3442. https://doi.org/10.1002/hep4.2080

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Slide 15 of 20

Let’s talk about extended-release naltrexone, which is in the United States becoming more used because the formularies are becoming less restrictive. In 2006, the first injectable naltrexone was approved for treatment of alcohol use disorder. It’s a 380 mg injection which is given in the deep gluteal muscle every four weeks, and you tend to alternate sides. It blocks opioid receptors for one entire month and its effects on heavy drinking are greatest in those with at least four days of abstinence prior to treatment initiation. And in this group, treatment improved continuous abstinence rates as well as reduced heavy drinking.

References:

Murphy, C. E., 4th, Wang, R. C., Montoy, J. C., Whittaker, E., & Raven, M. (2022). Effect of extended-release naltrexone on alcohol consumption: a systematic review and meta-analysis. Addiction (Abingdon, England), 117(2), 271–281. https://doi.org/10.1111/add.15572

Naltrexone for Alcohol Use Disorder: Dosing, Monitoring, and Liver Safety Slide 15 of 20

Slide 16 of 20

So is this much of a limitation, the abstinence? Well, first of all, many of us would like to see people tolerate some oral naltrexone before they go on to the injectable. So either they’ve gotten the four days of abstinence from being in a detox or they’ve been on the oral naltrexone before they go on the injectable. So in practical terms, it really doesn’t limit our use of the agent.

References:

Murphy, C. E., 4th, Wang, R. C., Montoy, J. C., Whittaker, E., & Raven, M. (2022). Effect of extended-release naltrexone on alcohol consumption: a systematic review and meta-analysis. Addiction (Abingdon, England), 117(2), 271–281. https://doi.org/10.1111/add.15572

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Slide 17 of 20

Adverse effects. It is a fairly large volume for inject so you get injection site reactions. You can get nausea and vomiting but less than the oral. You can get precipitated opioid withdrawal in those that were dependent. Again, depression, elevated LFTs. If somebody goes into an emergency room, for example, having broken an arm and they’re on the injectable, they should be at a medically monitored setting because to override the blockade you’d probably need to use higher doses of the opioid.

References:

Murphy, C. E., 4th, Wang, R. C., Montoy, J. C., Whittaker, E., & Raven, M. (2022). Effect of extended-release naltrexone on alcohol consumption: a systematic review and meta-analysis. Addiction (Abingdon, England), 117(2), 271–281. https://doi.org/10.1111/add.15572
Krupitsky, E., Nunes, E. V., Ling, W., Gastfriend, D. R., Memisoglu, A., & Silverman, B. L. (2013). Injectable extended-release naltrexone (XR-NTX) for opioid dependence: Long-term safety and effectiveness. Addiction, 108(9), 1628-1637. https://doi.org/10.1111/add.12208

Naltrexone for Alcohol Use Disorder: Dosing, Monitoring, and Liver Safety Slide 17 of 20

Slide 18 of 20

The next slide shows a nice meta-analysis by Murphy et al. showing the effect sizes for reducing of heavy drinking days. Both drinking days and heavy drinking days are moderately significantly reduced by extended-release naltrexone.

References:

Murphy, C. E., 4th, Wang, R. C., Montoy, J. C., Whittaker, E., & Raven, M. (2022). Effect of extended-release naltrexone on alcohol consumption: a systematic review and meta-analysis. Addiction (Abingdon, England), 117(2), 271–281. https://doi.org/10.1111/add.15572

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Slide 19 of 20

So the key points in this section: Oral and injectable naltrexone are FDA-approved medications to treat alcohol use disorder, and in fact they’re the most widely used agent. Naltrexone blocks mu-opioid receptors and so reduces the rewarding effects of alcohol, thereby reducing heavy drinking more than abstinence.

Naltrexone for Alcohol Use Disorder: Dosing, Monitoring, and Liver Safety Slide 19 of 20

Slide 20 of 20

Naltrexone is well supported as an efficacious treatment for alcohol use disorder in combination with behavioral treatments, AA, etc. And naltrexone can be safely used in those with alcoholic liver disease. The worse the liver disease, the more careful the monitoring you want to do in followup.

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Next Section

03. Acamprosate in Alcohol Use Disorder: Mechanism of Action, Dosing, Efficacy and Safety

Learning Objectives:

After completing this activity, the learner will be able to:

Select appropriate medications for alcohol use disorder based on patient-specific factors including hepatic function, treatment goals, and comorbid medical conditions.
Monitor and manage potential adverse effects of medications for alcohol use disorder, including hepatotoxicity with naltrexone and disulfiram, and metabolic acidosis with topiramate.
Implement evidence-based combination therapy using medications for alcohol use disorder with behavioral interventions to optimize treatment outcomes in patients with varying degrees of liver disease.

Original Release Date: August 1, 2025

Expiration Date: August 1, 2028

Expert: Kevin A. Sevarino, M.D.

Medical Editor: Flavio Guzmán, M.D.

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None of the faculty, planners, and reviewers for this educational activity have relevant financial relationships to disclose during the last 24 months with ineligible companies whose primary business is producing, marketing, selling, re-selling, or distributing healthcare products used by or on patients.

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