Description

Etifoxine, sold under brand names like Stresam, is a non-benzodiazepine anxiolytic and anticonvulsant medication. It is a benzoxazine derivative, meaning its chemical structure is distinct from that of benzodiazepines, even though it shares some similar anxiolytic effects. A key difference is that etifoxine is known for having a lower risk of sedation, dependence, and withdrawal symptoms compared to traditional benzodiazepines.

Indication

Etifoxine is primarily indicated for the short-term management of anxiety disorders, particularly those related to a stressful event or situation, also known as adjustment disorder with anxiety. It is used to alleviate a range of symptoms, including emotional and physical reactions to stress such as tension, lack of concentration, and some autonomic nervous system disorders (e.g., heart palpitations).

It’s also being studied for its potential in promoting peripheral nerve healing and treating chemotherapy-induced pain, but its primary established use is for anxiety.

Mechanism of Action

Etifoxine has a unique and dual mechanism of action, which is what distinguishes it from other anxiolytic drugs.

1. Direct Allosteric Modulation of GABAA​ Receptors: Similar to benzodiazepines, etifoxine acts as a positive allosteric modulator of the GABAA​ receptor. This means it binds to the receptor at a site different from where the neurotransmitter GABA binds, enhancing the inhibitory effects of GABA. This leads to an increase in chloride ion flow into the neuron, which hyperpolarizes the cell and makes it less likely to fire an action potential, thus producing a calming effect. However, unlike benzodiazepines, etifoxine binds to the β2​ or β3​ subunits of the GABAA​ receptor complex, not the classical benzodiazepine site. This difference in binding site is one reason why its effects are not completely reversed by the benzodiazepine antagonist flumazenil.
2. Indirect Action through Translocator Protein (TSPO): Etifoxine’s second mechanism involves binding to the 18 kDa mitochondrial translocator protein (TSPO), previously known as the peripheral benzodiazepine receptor. This binding stimulates the synthesis of neurosteroids, such as allopregnanolone, in both the central and peripheral nervous systems. These neurosteroids are themselves positive allosteric modulators of the GABAA​ receptor, further contributing to the drug’s anxiolytic and neuroprotective effects.