Double Effect: Common Medication May Help Treat Alcohol Addiction and Chronic Pain

The study shows that apremilast, a PDE4 enzyme inhibitor already approved for other diseases, can reduce both excessive alcohol consumption and pain associated with alcohol use disorder (AUD). It works by increasing the activity of brain signals that control inflammation and stress, especially in regions such as the amygdala. The effects vary according to the genetic profile and sex of the individual, suggesting a promising path for more personalized treatments.

Alcohol use disorder (AUD) is a serious public health problem worldwide, both for its medical and economic impacts. Many people end up using alcohol as a way to relieve symptoms of stress, anxiety or pain.

This self-medication behavior helps explain why alcohol use disorder often appears alongside other problems such as depression, anxiety and chronic pain.

In addition, men and women are not affected in the same way by these disorders; they present different physiological and emotional responses, which makes treatment more complex and requires personalized approaches.

Scientists have recently begun investigating an enzyme called phosphodiesterase type 4 (PDE4) as a possible target for treating alcohol use disorder.

PDE4's function is to "break down" a molecule called cAMP, which acts as a messenger within cells, controlling processes such as inflammation and brain signaling. There are four types of this enzyme (PDE4A, B, C, and D), and it is found both in the immune system and in regions of the brain linked to pleasure and addiction.

Genetic studies have already associated changes in PDE4 with several neurological and behavioral disorders.

The drug apremilast, which is already approved to treat inflammatory diseases such as psoriasis and psoriatic arthritis, works by inhibiting PDE4. By blocking this enzyme, apremilast allows cAMP to remain active for longer in cells, which can reduce inflammatory processes and modulate the activity of brain regions involved in reward, stress, and pain.

In studies with humans and animals, this medication has already demonstrated the ability to reduce alcohol consumption, especially in situations of compulsion and stress.

This new study assessed how apremilast works not only to reduce alcohol consumption, but also to reduce pain sensitivity associated with chronic alcohol use, a condition called allodynia, in which normally harmless stimuli become painful.

The researchers tested the drug in two types of rats: Wistar rats, which serve as a standard model, and msP rats, a genetically selected strain for a high preference for alcohol, as well as greater anxiety and sensitivity to pain. They found that prolonged alcohol consumption did indeed increase pain sensitivity, especially in msP rats.

However, when these animals were treated with apremilast, both alcohol consumption and pain were reduced, and these effects persisted even after alcohol was stopped.

The researchers also investigated the effects of apremilast on a specific region of the brain called the central nucleus of the amygdala (CeA), which is important for regulating emotions such as fear and stress, and is also linked to alcohol consumption and pain.

This region is composed mainly of neurons that use GABA, an inhibitory neurotransmitter that "slows down" brain activity.

The study showed that apremilast increased GABAergic activity in these neurons in Wistar rats, but not in msP rats, suggesting that msP rats already have altered brain pathways due to excessive alcohol use.

Finally, they analyzed how alcohol affects PDE4-related genes in the brain. They observed that alcohol consumption increases the activity of the Pde4a and Pde4b genes in the amygdala, which reinforces the idea that this enzyme is directly involved in how the brain responds to alcohol and pain.

The drug apremilast significantly reduced alcohol consumption in both male and female rats and in two different strains: Wistar (a common laboratory strain) and msP (rats with a genetic preference for alcohol). The graphs on the left (A, B, E, F) show that as the dose of the drug increases (10 or 20 mg/kg), the rats drink less alcohol. The graphs on the right (C, D, G, H) show the animals’ “preference,” that is, how much they choose to drink alcohol instead of water. This preference also decreased in some groups, especially in female Wistar rats. Symbols with asterisks indicate that the results were statistically significant, that is, the changes did not occur by chance. In summary, apremilast appears to reduce both the amount and preference for alcohol in different types of rats and in both sexes. In summary, the study suggests that apremilast may be a promising approach to treating both excessive alcohol consumption and the pain associated with this disorder.

The drug works by regulating important cellular signals in the brain, especially in the amygdala region, and its effects appear to depend on an individual’s genetic and biological background, including possible differences between males and females. These findings pave the way for more effective and personalized therapies in the treatment of alcohol use disorder.

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Apremilast reduces co-occurring alcohol drinking and mechanical allodynia and regulates central amygdala GABAergic transmission

Valentina Vozella, Vittoria Borgonetti, Bryan Cruz, Celsey M. St. Onge, Ryan Bullard, Roman Vlkolinsky, Diego Gomez Ceballos, Angela R. Ozburn, Amanda J. Roberts, Roberto Ciccocioppo, Michal Bajo, and Marisa Roberto 

JCI Insight. 2025;10 (8) : e189732. 

https://doi.org/10.1172/jci.insight.189732.

Abstract

The FDA-approved phosphodiesterase type 4 (PDE4) inhibitor, apremilast, has been recently investigated as a pharmacotherapy for alcohol use disorder (AUD) with promising efficacy in rodent models and humans. However, apremilast’s effects on mechanical allodynia associated with AUD as well as distinct responses of this drug between males and females are understudied. The present study examined the behavioral and electrophysiological effects of apremilast in Marchigian Sardinian alcohol-preferring (msP) rats and their Wistar counterparts. We used a 2–bottle choice (2-BC) alcohol drinking procedure and tested mechanical sensitivity across our drinking regimen. Spontaneous inhibitory GABA-mediated postsynaptic currents from the central nucleus of the amygdala (CeA) following apremilast application were tested in a subset of rats using ex vivo electrophysiology. Transcript levels for Pde4a or -4b subtypes were assessed for their modulation by alcohol. Apremilast reduced alcohol drinking in both strains of rats. Apremilast reduced mechanical allodynia immediately after drinking, persisting into early and late abstinence. Apremilast increased GABAergic transmission in CeA slices of alcohol-exposed Wistars but not msP rats, suggesting neuroadaptations in msPs by excessive drinking and mechanical allodynia. Pde4 subtype transcript levels were increased in CeA by alcohol. These results suggest that apremilast alleviates co-occurring excessive drinking and pain sensitivity, and they further confirm PDE4’s role in pain-associated AUD.