Researchers at Scripps Research have discovered that apremilast, an FDA-approved anti-inflammatory medication, shows promising potential as a dual-acting therapy for alcohol use disorder (AUD) and associated pain sensitivity. The preclinical study, published in JCI Insight on April 22, 2025, reveals that the drug could address two interconnected challenges that often complicate AUD treatment.
Apremilast, a phosphodiesterase-4 (PDE4) inhibitor currently approved for treating psoriasis and psoriatic arthritis, works by blocking an enzyme involved in inflammation. The new research demonstrates its ability to reduce both alcohol consumption and pain sensitivity in rat models, suggesting potential for repurposing in AUD treatment.
"Our findings highlight the therapeutic value of apremilast to reduce co-occurring drinking and mechanical allodynia in long-term abstinence—a critical component of harmful drinking and AUD psychopathology," explains senior author Marisa Roberto, professor of neuroscience at Scripps Research.
Addressing a Global Health Challenge
Alcohol use disorder affects approximately 400 million people aged 15 years or older worldwide, according to the World Health Organization. Chronic pain represents one of the strongest predictors of alcohol relapse, yet treatment strategies often overlook this connection.
People with AUD frequently experience mechanical allodynia, a condition where even light touch is perceived as painful. This heightened sensitivity can persist during abstinence periods, potentially contributing to continued alcohol use and relapse.
Study Design and Key Findings
The research team tested apremilast in two types of rats: one genetically predisposed to higher alcohol consumption and another standard genetic strain. Both groups were given access to alcohol and treated with either apremilast or a placebo.
Results showed that apremilast significantly reduced alcohol intake across all groups, regardless of genetic strain or biological sex. The drug also decreased pain sensitivity in most groups, with effects observed both immediately after drinking and during abstinence periods ranging from 24 hours to four weeks after alcohol removal.
"But at specific time points, the patterns of reduction differed between males and females, as well as between strains," notes first author Bryan Cruz, a postdoctoral fellow at Scripps Research. These variations highlight the importance of considering biological sex and genetic factors in future studies and potential clinical applications.
Neurobiological Mechanisms
Further experiments revealed that apremilast increased GABAergic transmission—a type of inhibitory signaling that helps regulate pain and stress—in the central amygdala, a brain region involved in both addiction and pain processing. This effect was only observed in the standard strain of rats, suggesting that apremilast's impact on brain signaling may depend on genetic background or vulnerability to AUD.
In both strains of male rats, alcohol exposure increased expression of PDE4 genes in the brain, further supporting a link between inflammation, pain, and compulsive alcohol use. This finding provides additional evidence for the mechanistic rationale behind apremilast's effectiveness.
Building on Previous Research
This study builds upon earlier work showing that apremilast reduced alcohol drinking in both mice and humans. The new findings extend this research by examining whether the drug could also address pain linked to alcohol exposure—a critical factor in AUD treatment and relapse prevention.
While other PDE4 inhibitors have been studied for pain unrelated to alcohol consumption, apremilast may offer a path toward more personalized therapies for those experiencing both AUD and pain. However, clinical research is still needed to determine the drug's efficacy for such conditions in humans.
Future Directions
The research team plans to explore whether apremilast can also mitigate anxiety and other negative emotional states that commonly emerge during alcohol withdrawal.
"For over a decade, it's been well-established that withdrawal-induced anxiety is a major driver of relapse," points out Roberto. "Therefore, addressing other key components of the addiction cycle is critical, as many individuals use alcohol to cope not only with physical pain but with emotional distress as well."
The potential to repurpose an already FDA-approved medication could significantly accelerate the development of new treatment options for AUD, particularly for patients experiencing comorbid pain conditions that complicate recovery efforts.
