Effetti anti-neuroinfiammatori di un preparato a base di Acido alfa-lipoico ed Acidi grassi polinsaturi omega 3 (DHA ed EPA) nella terapia della vcstibolodinia

Anti-neuroinflammatory effects of alpha-lipoic acid plus Omega 3 fatty acids (DHA and EPA) in vestibulodynia therapy Introduction The International Society for the Study of Vulvovaginal Disease defines vulvodynia as vulvar pain of at least 3 months’ duration without a clear identifiable cause that may have potential associated factors. This definition has been recently introduced in consensus with the International Society for the Study of Women’s Sexual Health and the International Pelvic Pain Society as a component of new terminology around vulvar pain. It outlines vulvodynia as a multifactorial condition, rather than a specific entity, in which the associated factors are themselves pathophysiological components of the disease, with differing relevance in each individual. Vestibulodynia describes the most common localization, at the vulvar vestibule. Two common elements characterize this disorder: (1) an increased number of activated mast cells located close to nerves with enhanced levels of proinflammatory cytokines on histologic examination and (2) histologic hyperinnervation in the stroma and epithelium of the affected mucosa (vulvar vestibule). Given the range of symptoms associated with vulvodynia and the possibly multifactorial etiology, the best approach to treatment is a multimodal one that can be tailored to each patient. Oral tricyclic antidepressants (TCAs) are commonly used in the treatment of vulvar pain, with amitriptyline often used as a first-line agent. Amitriptyline inhibits synaptic reuptake of serotonin and norepinephrine, thus inhibiting painful nociception at the affected mucosa at the level of the central nervous system. TCAs have been shown to be beneficial in the treatment of vestibulodynia, but the pain improvement seen with these agents is variable, ranging from 30% to 60% of patients treated, and side effects in some patients might influence compliance with treatment to a level that can cause withdrawal symptoms. Several studies indicate that alpha lipoic acid supplements provide antioxidant and anti inflammatory activity and that they improve pain and paraesthesia in patients with neuropathic pain syndromes such as carpal tunnel syndrome, diabetic neuropathy, and burning mouth syndrome. Moreover, recently, it has been demonstrated that intake of docosahexaenoic acid, a predominant omega-3 polyunsaturated fatty acid (PUFAs) , is associated with a markedly increased threshold for thermal pain and neuropathic pain with a subsequent anti-nociceptive effect. These findings indicate that n-3 PUFAs might exert anti-nociceptive effects via an endogenous opioidergic system or antiinflammatory system. Objective This study assessed the effectiveness of alpha lipoic acid (ALA) plus n-3 PUFAs in single therapy in patients with vestibulodynia (VBD). Methods Eligible patients comprised women diagnosed with VBD due to the coexistence of the following conditions: a history of vulvar pain of at least 3 months’ duration without a clear identifiable cause, a positive cotton-swab test (tenderness on palpation of the vestibular area with a cotton tip applicator). Additionally, eligible individuals did not demonstrate any other specific neuropathologies, atrophic vaginitis, dermatoses such as lichen sclerosus, or pathogens such as culture- or smear-proven Candida species. Institutional Review Board approval for the study was obtained, and all participating individuals gave written informed consent. Women with VBD received a preparation containing ALA 300 mg plus docosahexaenoic acid 125 mg and eicosapentaenoic acid 8,34 mg. The preparation containing ALA plus n-3 PUFAs was taken 3 times a day for 8 weeks. Symptoms of pain were assessed using a 10-cm visual analog scale and the short form of the McGill-Melzack Pain Questionnaire. The grading of dyspareunia was evaluated according to the classifications of Marinoff and Turner. The diagnosis of HTPFD (hypertonic pelvic floor dysfunction) needed to be established by physical examination. Results: Among 84 women who were enrolled the pain, as assessed using both the pain rating index of the visual analog scale and the short-form McGill Pain Questionnaire, decreased significantly after 8 weeks of treatment with ALA and n-3 PUFAs. When given in combination ALA and n-3 PUFAs, there are reductions in scores on the pain rating index of the VAS and the SF-MPQ (reductions of 39,2 % and 41,8 %, respectively). The use of this new treatment was also associated with improvements in dyspareunia. The decrease in the dyspareunia grade was significant in patients with score 3 prior to treatment demonstrated a significant reduction in dyspareunia ranging from 3 to 1 score in 29% of cases and score 2 in 19% with overall improvement in 48.4% of cases (p <0, 05). The change in the tone of the pelvic floor muscle obtained after 8 weeks of treatment with the preparation in the study was evaluated by semiquantitative digital study. If we consider the total of the sample being analyzed, 58.3% of patients did not show any changes in the tone of the perineal muscle, 33.3% had an improvement in muscle tone after treatment and 8.3% of the treated patients had a worsening tone in the pelvic floor muscle. The overall incidence of adverse events was low, and none led to treatment discontinuation. Discussion: Among available neuromodulators, strong evidence is accumulating regarding the clinical effectiveness of ALA for the treatment of chronic neuropathic pain. In fact, it has been recently recommended as a first-line choice in this indication. ALA has three main mechanisms of action: it acts as an antioxidant; as an anti-inflammatory (inhibition of interleukin-1, interluekin-6, and tumour necrosis factora biosynthesis; decreased nuclear factor-kB activation); and as a coenzyme of cellular energy metabolism (increased adenosine triphosphate biosynthesis). It crosses the blood-brain barrier and exerts a positive effect on neuroinflammation. The n-3 PUFAs have a wide range of physiologic roles in the cardiovascular and nervous systems. Their anti-inflammatory action involves various mechanisms; in particular, they are precursors of antiinflammatory eicosanoids. Eicosapentaenoic acid and DHA are also substrates for the production of resolvins and protectins, which seem to be biologically extremely potent in the resolution of chronic inflammation. The anti-inflammatory effect of n-3 PUFAs and ALA seems to be synergistic. The therapy with ALA/n-3 PUFAs in patients with VBD appears to improve outcomes and may lead to fewer adverse effects compared to oral tricyclic antidepressants.