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Naltrexone Cuts Hospitalization, Deaths in Alcohol Use Disorder

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Naltrexone reduces the risk for hospitalization for alcohol use disorder (AUD), regardless of whether it is used alone or in conjunction with disulfiram or acamprosate, new research suggests.

Investigators analyzed 10-year data on more than 125,000 Swedish residents with AUD and found that naltrexone, used as monotherapy or combined with acamprosate or disulfiram, was associated with significantly lower risk for AUD hospitalization or all-cause hospitalization in comparison with patients who did not use AUD medication. The patients ranged in age from 16 to 64 years.

By contrast, benzodiazepines and acamprosate monotherapy were associated with increased risk for AUD hospitalization.

“The take-home message for practicing clinicians would be that especially naltrexone use is associated with favorable treatment outcomes and should be utilized as part of the treatment protocol for AUD,” study investigator Milja Heikkinen, MD, specialist in forensic psychiatry and addiction medicine, University of Eastern Finland, Kuopio, Finland, told Medscape Medical News.

On the other hand, “benzodiazepines should be avoided and should not be administered other than for alcohol withdrawal symptoms,” she said.

The study was published online January 4 in Addiction.

Real-World Data

Previous research has shown that disulfiram, acamprosate, naltrexone, and nalmefene are efficacious in treating AUD, but most studies have been randomized controlled trials or meta-analyses, the authors write.

“Very little is known about overall health outcomes (such as risks of hospitalization and mortality) associated with specific treatments in real-world circumstances,” they write.

“The study was motivated by the fact that, although AUD is a significant public health concern, very little is known, especially about the comparative effectiveness of medications indicated in AUD,” said Heikkinen.

To investigate, the researchers drew on data from several large nationwide Swedish registers that encompassed 125,556 patients who had been diagnosed with AUD (62.5% men; mean [SD] age, 38.1 [15.9] years). They followed the cohort over a median of 4.6 years (interquartile range, 2.1 – 7.2 years).

During the follow-up period, roughly one quarter of patients (25.6) underwent treatment with one or more drugs (see Table 1).

Table 1. Drug Treatment for Patients With AUD

Drug Percentage of patients
Disulfiram 15.4
Acamprosate 9.1
Naltrexone 8.7
Nalmefene 0.60%
≥2 of the above drugs concomitantly 5.1

The main outcome measure was AUD-related hospitalization. Secondary outcomes were hospitalization due to any cause and to alcohol-related somatic causes; all-cause mortality; and work disability.

Two types of analyses were conducted. The within-individual analyses, designed to eliminate selection bias, compared the use of a medication to periods during which the same individual was not using the medication.

Between-individual analyses (adjusted for sex, age, educational level, number of previous AUD-related hospitalizations, time since first AUD diagnosis, comorbidities, and use of other medications) utilized a “traditional” multivariate-adjusted Cox hazards regression model.

AUD Pharmacotherapy “Underutilized”

Close to one quarter of patients (23.9%) experienced the main outcome event (AUD-related hospitalization) during the follow-up period.

The within-individual analysis showed that naltrexone — whether used as monotherapy or adjunctively with disulfiram or acamprosate — “was associated with a significantly lower risk of AUD-related hospitalization, compared to those time periods in which the same individual did not use any AUD medication,” the authors report.

By contrast, they state, acamprosate monotherapy and benzodiazepines were associated with a significantly higher risk for AUD-related hospitalization.

Table 2. Risks Associated With Drug Use

Drug Hazard ratio (95% CI)
Naltrexone + acamprosate .74 (.61 – .89)
Naltrexone + disulfiram .76 (.60 –.96)
Naltrexone monotherapy .89 (.81 – .97)
Acamprosate monotherapy 1.10 (1.04 – 1.17)
Benzodiazepines 1.18 (1.14 – 1.22)

Similar results were obtained in the between-individual analysis. Longer duration of naltrexone use was associated with lower risk for AUD-related hospitalization.

The pattern was also found when the outcome was hospitalization due to any cause. However, unlike the findings of the within-individual model, the second model found that acamprosate monotherapy was not associated with a higher risk for any-cause hospitalization.

Polytherapy, including combinations of the four AUD medications, as well as disulfiram monotherapy were similarly associated with lower risk for hospitalization due to alcohol-related somatic causes.

Of the overall cohort, 6.2% died during the follow-up period. No association was found between disulfiram, acamprosate, nalmefene, and naltrexone use and all-cause mortality. By contrast, benzodiazepine use was associated with a significantly higher mortality rate (hazard ratio [HR], 1.11; 95% CI, 1.04 –1.19).

“AUD drugs are underutilized, despite AUD being a significant public health concern,” Heikkinen noted. On the other hand, benzodiazepine use is “very common.”

“Ravages” of Benzodiazepines

Commenting on the study for Medscape Medical News, John Krystal, MD, professor and chair of psychiatry and director of the Center for the Translational Neuroscience of Alcoholism, Yale University, New Haven, Connecticut, said, “The main message from the study for practicing clinicians is that treatment works.”

Krystal, who was not involved with the study, noted that “many practicing clinicians are discouraged by the course of their patients with AUD, and this study highlights that naltrexone, perhaps in combination with other medications, may be effective in preventing hospitalization and, presumably, other hospitalization-related complications of AUD.”

Also commenting on the study for Medscape Medical News, Raymond Anton, MD, professor, Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, South Carolina, suggested that the “clinical knowledge of the harm of benzodiazepines in those with AUD is reinforced by these findings.”

In fact, the harm of benzodiazepines might be the study’s “most important message…[a message that was] recently highlighted by the Netflix series The Queen’s Gambit, which shows the ravages of using both together, or how one leads to potential addiction with the other,” said Anton, who was not involved with the study.

The other “big take-home message is that naltrexone should be used more frequently,” said Anton. He noted that there are “recent data suggesting some clinical and genetic indicators that predict responsiveness to these medications, improving efficacy.”

The study was funded by the Finnish Ministry of Social Affairs and Health. Heikkinen reports no relevant financial relationships. The other authors’ disclosures are listed on the original article. Krystal consults for companies currently developing other treatments for AUDs and receives medications to test from AstraZeneca and Novartis for NIAAA-funded research programs. Anton has consulted for Lundbeck, Alkermes, and Lipha in the past. He is also chair of the Alcohol Clinical Trials Initiative (ACTIVE), which is a pubic- private partnership partially sponsored by several companies and has received grant funding from the NIH/NIAAA to study pharmacotherapies, including naltrexone, nalmefene, and acamprosate.

Addiction. Published online January 4, 2021. Full text

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