What is the recommended duration of naltrexone treatment for alcohol use disorder?

Background
Alcohol use disorder (AUD) is a major public health issue, affecting over 28 million people aged 12 years and older in the United States alone and contributing to approximately 178,000 deaths annually.¹ A wide range of serious health complications are linked to AUD, including liver disease, heart disease, mental health disorders, cancer, and increased risk of accidents and violence. Effective treatment often requires a combination of behavioral and pharmacologic interventions, with naltrexone being one of a few key drug therapies playing an important role in reducing cravings and preventing relapse.^2-5 This article reviews current evidence to inform decision-making on the optimal duration of naltrexone therapy for AUD.

Naltrexone
Naltrexone works by blocking opioid receptors in the brain, reducing the rewarding and pleasurable effects of alcohol, which can help decrease cravings and the likelihood of relapse.^2,3 Naltrexone is available as both an oral tablet and a long-acting injectable formulation.⁶ The oral tablet is typically taken once daily, while the extended-release injectable form is administered once monthly, offering a convenient option for individuals who may struggle with daily adherence. Despite the availability of naltrexone and other pharmacological agents that aid in the treatment of AUD, the literature reports relapse rates 1 year after AUD treatment of 40 to 60%.⁷ Furthermore, about two-thirds of those treated for AUD relapse within the first 6 months

Guidelines
Several guidelines are available to inform treatment decisions surrounding pharmacological therapy for patients with AUD (see Table 1).^2-5 However, none have definitively established an optimal duration of therapy for naltrexone.

In 2015, the Substance Abuse and Mental Health Services Administration (SAMHSA) suggested that the treatment of patients with AUD should continue for at least 6 months to 1 year.² This was a general recommendation and not specific to any particular treatment modality. Nonetheless, SAMSHA emphasized that the length of treatment should be tailored to individual patient needs.^2,3 In a 2013 guide from SAMSHA focused on alcohol pharmacotherapies, authors cite literature that demonstrates the safety of oral naltrexone for up to 1 year.² Additionally, for patients in stable recovery, authors state that oral or injectable naltrexone may be beneficial for short periods during times of increased risk for relapse.

More recent guidance for AUD pharmacotherapy was published in 2018 by the American Psychiatric Association (APA).⁴ At that time, the APA recommended that decisions regarding the duration of treatment with naltrexone should be individualized depending on patient preference, disorder severity, history or relapse, consequences of relapse, clinical response, and tolerability. Another guideline by the World Federation of Societies of Biological Psychiatry published in 2017 notes that the optimal duration of treatment with naltrexone is an important topic that remains to be adequately addressed in the literature.⁵

Lastly, in a now archived 2014 guidance from the National Institute on Drug Abuse, authors emphasized that good outcomes in patients with substance use disorders are contingent on adequate treatment length, and for residential or outpatient treatment, participation for less than 90 days is of limited effectiveness, and significantly longer treatment is recommended for maintaining positive outcomes.⁸

Primary Literature
As noted above, there is no scientific consensus on the optimal length of treatment with naltrexone for AUD that consistently leads to improved recovery outcomes.^2-5 Primary literature investigating the impact of pharmacologic treatment duration on outcomes in patients with AUD is also somewhat limited, with most studies reporting outcomes for treatment durations between 3 and 6 months.^9-12 Notably, a 2024 systematic review evaluating clinical trial methodologies for AUD pharmacotherapy found that the average duration of treatment in clinical trials was 3 months (interquartile range [IQR], 3 to 4 months).⁹

In a 2022 systematic review of 7 studies (N=1500) assessing injectable naltrexone for AUD over 2 to 6 months, a treatment duration greater than 3 months was associated with significantly reduced heavy drinking days by nearly 2 days per month (weighted mean difference [WMD], -1.86; 95% CI, -3.20 to -0.53).¹⁰ In contrast, pooled data from trials shorter than 3 months did not achieve statistical significance for this outcome (WMD, -0.49; 95% CI, -1.80 to 0.83). Similarly, a 2023 retrospective cohort study involving patients with alcohol-associated cirrhosis and high-risk AUD (N=9131) found that longer durations of acamprosate or naltrexone exposure were associated with improved survival.¹¹ The hazard ratio was 0.85 for durations of ≤3 months compared to no pharmacotherapy (95% CI, 0.69 to 1.05) and 0.73 for durations of 3 to 12 months compared to no pharmacotherapy (95% CI, 0.56 to 0.96). The author of this study also specifically recommended continuing pharmacotherapy for 12 months due to increased risk of relapse in the months and up to a year following treatment discontinuation.

Although not specific to pharmacotherapy, a 2021 systematic review evaluating long-term treatment models for substance use disorders found that patients undergoing treatment for 18 to 48 months had a 23.9% greater likelihood of achieving abstinence or consuming substances in moderation compared to those who were treated for shorter durations.¹² While this review focused on overall treatment models and not on pharmacotherapy specifically, it underscores the overall benefit of extended treatment durations in this population.

It is important to note that with long durations of naltrexone use, individuals lose tolerance to opioids, which can result in overdose and death if large, but previously tolerated, doses of opioids are taken after naltrexone is discontinued.^2,3 Another safety concern associated with naltrexone is hepatotoxicity.^6,13 However, it is unclear whether liver injury is directly caused by naltrexone or by the high background rate of preexisting liver conditions common among individuals for whom naltrexone is prescribed.¹³ Nonetheless, regular monitoring of liver function is recommended, and naltrexone should be used cautiously in patients with hepatic impairment.⁶ Discontinuation may be necessary if naltrexone-induced liver dysfunction occurs. Overall, considerations of tolerability and safety are crucial when determining the optimal duration of naltrexone treatment.^2-5 Common side effects, including nausea, headache, dizziness, and fatigue, may affect patient adherence to therapy.³ Therefore, healthcare professionals must carefully balance the benefits of ongoing pharmacotherapy with potential adverse effects, tailoring treatment plans to meet each patient’s individual needs.^2-5

Conclusion
In conclusion, the optimal duration of therapy for naltrexone in the treatment of AUD remains uncertain, necessitating an individualized approach based on the expected benefits and potential harms of treatment.^2-5 The literature has shown improved outcomes with naltrexone treatment durations greater than 3 months, and a 2015 SAMHSA guideline recommends an overall treatment duration of AUD of at least 6 to 12 months.^2,8 Since a significant proportion of patients relapse in the first year after starting therapy, it may be prudent to maintain pharmacotherapy for at least 12 months.^3,7,11 Regular monitoring of liver function in patients receiving naltrexone is recommended.⁶

References

1. National Institute on Alcohol Abuse and Alcoholism. Alcohol Facts and Statistics. Accessed November 8, 2024. https://www.niaaa.nih.gov/alcohols-effects-health/alcohol-topics/alcohol-facts-and-statistics
2. Substance Abuse and Mental Health Services Administration. Medication for the Treatment of Alcohol Use Disorder: A Brief Guide. Published October 2015. Accessed November 8, 2024. https://store.samhsa.gov/product/medication-treatment-alcohol-use-disorder-brief-guide/sma15-4907
3. Substance Abuse and Mental Health Services Administration. TIP 49: Incorporating Alcohol Pharmacotherapies Into Medical Practice. Published May 2013. Accessed November 8, 2024. https://store.samhsa.gov/product/tip-49-incorporating-alcohol-pharmacotherapies-medical-practice/sma13-4380
4. Reus VI, Fochtmann LJ, Bukstein O, et al. The American Psychiatric Association Practice Guideline for the Pharmacological Treatment of Patients With Alcohol Use Disorder. Am J Psychiatry. 2018;175(1):86-90. doi:10.1176/appi.ajp.2017.1750101
5. Soyka M, Kranzler HR, Hesselbrock V, et al. Guidelines for biological treatment of substance use and related disorders, part 1: Alcoholism, first revision. World J Biol Psychiatry. 2017;18(2):86-119. doi:10.1080/15622975.2016.1246752
6. Merative Micromedex. Merative US; 2024. Accessed November 8, 2024. https://www.micromedexsolutions.com
7. American Addiction Centers. Alcohol Relapse Statistics & Rates. American Addiction Centers. Published July 28, 2023. Accessed November 8, 2024. https://americanaddictioncenters.org/alcohol/relapse-statistics
8. National Institute on Drug Abuse. Principles of Drug Addiction Treatment: A Research-Based Guide (Third Edition). Accessed November 8, 2024. https://archives.nida.nih.gov/publications/principles-drug-addiction-treatment-research-based-guide-third-edition
9. Donato S, Meredith LR, Nieto SJ, Bujarski S, Ray LA. Medication development for AUD: A systematic review of clinical trial methodology. Alcohol. 2024;120:194-203. doi:10.1016/j.alcohol.2024.06.007
10. Murphy CE, Wang RC, Montoy JC, Whittaker E, Raven M. Effect of extended-release naltrexone on alcohol consumption: a systematic review and meta-analysis. Addiction. 2022;117(2):271-281. doi:10.1111/add.15572
11. Rabiee A, Mahmud N, Falker C, Garcia-Tsao G, Taddei T, Kaplan DE. Medications for alcohol use disorder improve survival in patients with hazardous drinking and alcohol-associated cirrhosis. Hepatol Commun. 2023;7(4):e0093. doi:10.1097/HC9.0000000000000093
12. Beaulieu M, Tremblay J, Baudry C, Pearson J, Bertrand K. A systematic review and meta-analysis of the efficacy of the long-term treatment and support of substance use disorders. Soc Sci Med. 2021;285:114289. doi:10.1016/j.socscimed.2021.114289
13. National Institute on Alcohol Abuse and Alcoholism. Medications Development Program. National Institutes of Health; 2018. Accessed November 8, 2024. https://www.ncbi.nlm.nih.gov/books/NBK548583/

Prepared by:
Katherine Sarna PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

December 2024

The information presented is current as November 8, 2024. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.