A repurposed anti-inflammatory drug may help treat alcohol use disorder and related pain

The results, published in JCI Insight on April 22, 2025, suggest that the drug apremilast -- a phosphodiesterase-4 (PDE4) inhibitor, or a compound that blocks an enzyme involved in inflammation -- could be repurposed as a dual-acting therapy for AUD, particularly in individuals who have pain during and after alcohol use.

AUD affects an estimated 400 million people aged 15 years or older, according to the World Health Organization. Chronic pain is one of the strongest predictors of alcohol relapse, yet it's often overlooked in AUD treatment strategies. People with AUD frequently experience mechanical allodynia as well, a condition in which even light touch is perceived as painful. This sensitivity can persist during abstinence and contribute to ongoing alcohol use and relapse.

"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," says senior author Marisa Roberto, a professor of neuroscience at Scripps Research.

Currently FDA-approved for treating psoriasis (a chronic autoimmune skin condition) and psoriatic arthritis (a related joint disease), apremilast has previously been shown to reduce alcohol drinking in both mice and humans. The new study builds on that work by examining whether apremilast could also ease pain linked to alcohol exposure.

To investigate, the research team tested apremilast in a type of rat genetically predisposed to higher alcohol consumption and in a standard genetic strain of rats. Both rat strains were given access to alcohol and treated with either apremilast or a placebo.

Apremilast significantly reduced alcohol intake across strains and biological sexes. It also decreased pain sensitivity in most groups, both immediately after drinking and during abstinence -- ranging from 24 hours to four weeks after alcohol had been removed.

"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. For example, the pain-relieving effects of apremilast weren't observed in some of the male rats, underscoring the importance of considering biological sex in future studies.

In another set of experiments, apremilast increased GABAergic transmission -- a type of inhibitory signaling that helps regulate pain and stress -- in the central amygdala, a cerebral region involved in both addiction and pain. 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. While other PDE4 inhibitors have been studied for pain unrelated to alcohol consumption, apremilast may offer a path toward more personalized therapies for those with both AUD and pain. But clinical research is still needed to determine the drug's efficacy for such conditions in humans.

Going forward, the researchers also plan to explore whether apremilast can 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."

This work was supported by funding from the National Institute on Alcohol Abuse and Alcoholism (grants AA027700, AA013498, P60 AA006420, AA017447, AA021491, AA029841, K99 AA030609, T32 AA007456, K99 AA031718, AA013519 and AA010760); the U.S. Department of Veteran Affairs (grant I01 BX004699); and the Schimmel Family Chair.