Stresam (Etifoxine, Strezam)

stresam

Stresam (a brand name for Etifoxine) is an anti-anxiety and anticonvulsant medication of the benzoxazine family. The anxiolytic effects of Stresam are comparable to benzodiazepines. However, etifoxine is a non-benzodiazepine anxiolytic. One of its biggest advantages over benzos is a lack of side effects typical for them. They include sedation, myorelaxation, memory and attention impairments, tolerance, withdrawal, and addiction.

The drug has neurotrophic, analgesic, anti-inflammatory properties and stimulates neurosteroidogenesis. It was shown that etifoxine promote the functional recovery in the traumatic injury of peripheral nerve and reduce neuropathic pain symptoms caused by vincristine.

Etifoxine first synthesized in 1966 by Hoechst AG, Germany. Studies performed in 1972 revealed its anxiolytic, anticonvulsant and spasmolytic action. In 1979 French company “Biocodex” bought etifoxine and started its production under “Stresam” brand name. Since then it is used in France to treat anxiety disorders. As of today, Stresam registered in 42 different countries.

 

Usage of Stresam

On-label usage includes the treatment of anxiety disorders, fears, irritability and decreased mood.

Its anxiolytic action is comparable to benzodiazepines and confirmed by various studies.

In a comparative study on 189 patients with adjustment disorder with anxiety, one group of patients took 150mg of Stresam daily for 28 days, while the other group took 2mg of Lorazepam (Ativan). The treatment efficiency was similar for both drugs regarding mean HAM-A score. However, more people from etifoxine group responded to the treatment by the day 28 (72% and 56%). The first group also experienced fewer side effects compared to lorazepam group and fewer cases of rebound anxiety. Similar results were obtained in the comparative study of Stresam with Alprazolam (Xanax).

In a double-blind placebo-controlled study on healthy adults performed to evaluate the adverse effects of Stresam and Lorazepam, Stresam did not caused amnesia and sedation as Lorazepam.

Another study was carried out to compare the efficiency of Stresam and Gidazepam in the treatment of the anxiety-depressive disorder. In case if you didn’t heard of Gidazepam, it is a benzodiazepine tranquilizer developed in the Soviet Union. The first group took 150mg of Etifoxine daily for 28 days, while the second group took 100mg of Gidazepam daily. The final results of the treatment were similar on the 28th day, but the first group experienced a faster onset of therapeutic action.

Stresam can potentiate the effects of benzodiazepines, alcohol, barbiturates, antipsychotics and opioid analgesics. Also, an important note that I think is fair to mention, that the comparative studies with Lorazepam and Xanax were supported by Biocodex.

 

Mechanism of action

Two primary mechanisms of action are responsible for the anxiolytic action of this drug. Stresam does enhance GABAergic neurotransmission by allosteric modulation of GABA-A receptor. It acts preferentially on GABA-A receptors containing the β2 and/or β3 subunit at a different binding site than benzodiazepines. This is in agreement with studies showed that Flumazenil (benzodiazepines site antagonist) does not interfere with the behavioral effects of etifoxine.

Another mechanism of anxiolytic action is a stimulation of neurosteroid synthesis.

Etifoxine does stimulate steroid synthesis by activating the translocator protein (TSPO). TSPO activation enhances cholesterol transportation into mitochondria. Cholesterol side-chain cleavage enzyme (P450scc) converts cholesterol to pregnenolone in mitochondria. Then, 3β-HSD converts pregnenolone to progesterone. Progesterone is a precursor for Allopregnanolone and Tetrahydrodeoxycorticosterone, an endogenous neurosteroids with anxiolytic and anticonvulsant action.

 

Neurotrophic effects

This drug also exhibits neurotrophic properties. In studies, Etifoxine increased neuronal-like outgrowth in PC12 cells, and GDNF expression with a 2-fold increase (p<0.01). It showed an impact on neurotrophins expression after peripheral nerve injury in rats. In 7 days after injury, etifoxine treatment had a significant neurotrophic effect (1.9 fold NGF increase over control, 2.1 fold increase of GDNF over control and 1.7 fold increase of VEGF).

In another study, rats with the freeze injury of the sciatic nerve received etifoxine or placebo. In the 7 and 15 days after injury, the regeneration of myelinated axons was most pronounced in etifoxine group. Their functional recovery time improved as well. In PC12 cells, etifoxine enhanced neurite extension in the presence of NGF, with a 2-fold increase of maximum neurite length compared to cells treated with NGF alone (p<0.001).

 

Stresam side effects

According to instruction, Stresam has quite a few side effects. They include:

  • Drowsiness in the first days of treatment.
  • Allergic reactions characterized by the skin rash.

According to the user feedbacks, skin rash is possible. This is also confirmed by French pharmacovigilance survey. Hypersensitivity reactions were the most frequent adverse effects (59% out of reported cases). This study also reported liver disorders cases. According to 2012 research, side effects on liver are rare but possible, although not mentioned in the leaflet.

Contraindications for use are:

  • Hypersensitivity.
  • Shock states.
  • Myasthenia.
  • Liver, kidney disorders.
  • Age below 18 years old.

 

Stresam dosage

The dosage suggested by the manufacturer is one 50mg capsule three times a day, or two capsules twice daily. The length of treatment is from couple days to 4-6 weeks, depending on the patient’s condition.

 

Conclusion

Stresam is an effective anxiolytic with an anti-anxiety effect comparable to benzodiazepines. It has an advantage over benzos because it does not cause withdrawal, oversedation, and cognitive impairments, and do not form an addiction. However, Stresam has some significant disadvantages – possible skin rash and liver injury.

 

 

 

References

  1. Hamon A, Morel A, Hue B, Verleye M, Gillardin JM. “The modulatory effects of the anxiolytic etifoxine on GABA(A) receptors are mediated by the beta subunit.”
  2. Girard C, Liu S, Cadepond F, Adams D, Lacroix C, Verleye M, Gillardin JM, Baulieu EE, Schumacher M, Schweizer-Groyer G. “Etifoxine improves peripheral nerve regeneration and functional recovery.”
  3. Maya Aouad, Alexandre Charlet, Jean-Luc Rodeau, Pierrick Poisbeau “Reduction and prevention of vincristine-induced neuropathic pain symptoms by the non-benzodiazepine anxiolytic etifoxine are mediated by 3α-reduced neurosteroids.”
  4. Dai T, Zhou X, Li Y, He B, Zhu Z, Zheng C, Zhu S, Zhu Q, Liu X. “Etifoxine promotes glia-derived neurite outgrowth in vitro and in vivo.”
  5. do Rego JL, Vaudry D, Vaudry H. “The non-benzodiazepine anxiolytic drug etifoxine causes a rapid, receptor-independent stimulation of neurosteroid biosynthesis.”
  6. Céline Mocha, Fanny Rocher, Pascale Lainéc, Jacqueline Lacotted, Michel Bioure, Aurore Gourauda, Nathalie Bernarda, Jacques Descotesa, Thierry Vial “Etifoxine-induced acute hepatitis: A case series”
  7. Torshin I.U, Gromova O.A, Semenov V.A, Limanova O.A, Gogoleva I.V “Neurotrophic effects of etifoxine.”
  8. J. Micallef, C. Soubrouillarda, F. Guet, M. E. Le Guern, C. Alquier, B. Bruguerolle, O. Blina “A double blind parallel group placebo controlled comparison of sedative and amnesic effects of etifoxine and lorazepam in healthy subjects.”
  9. Dan J. Stein “Etifoxine Versus Alprazolam for the Treatment
    of Adjustment Disorder with Anxiety: a Randomized
    Controlled Trial.”
  10. N. Nguyen, E. Fakra, V. Pradel, E. Jouve, C. Alquier, M-E. Le Guern, J. Micallef, O. Blin “Efficacy of etifoxine compared to lorazepam monotherapy in the treatment of patients with adjustment disorders with anxiety: a double-blind controlled study in general practice.”
  11. V.I Borodin, V.G Zubko “Wide application range of the new anxiolytic Stresam.”
  12. Torshin I.U, Gromova O.A, Semenov V.A, Grishina T.R “Systhematic analysis of the fundamental and clinical studies of etifoxine.”
  13. Yurieva L.N, Ogorenko V.V, Anisimov S.V “Comparative evaluation of the efficacy of Etifoxine(Stresam) and Gidazepam in patients with the anxiety-depressive disorder.”

 

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