VALUTAZIONE DELL’IMPATTO DELL’ ELETTROSTIMOLAZIONE MEDIANTE FREQUENCY RHYTHMIC ELECTRICAL MODULATION SYSTEM (F.R.E.M.S.™) SUL DOLORE NELL’ULCERA CUTANEA CRONICA. STUDIO CLINICO DI FATTIBILITA’

According to WHO 20% of population worldwide is affected by chronic non cancer pain (CNCP). Prescribed pharmacological treatments not only can result partially ineffective but also often complicated by important side effects. It is therefore crucial to identify adjuvant antalgic therapies, such as transcutaneous electrical stimulation (ESt). In the past 20 years several clinical trials regarding ESt have been conducted leading to not-conclusive results, mainly because of limits of the study design. Aiming to investigate ESt effect as adjuvant therapy we choose chronic leg ulcer (CLU) related pain as a clinical setting of CNCP and F.R.E.M.S.™ as model of ESt. Study design: we draw a two-phase clinical trial: PHASE 1: clinical study of feasibility (object of the present thesis): observational prospective trial. Aims: a.To establish and to apply a multi-disciplinary protocol of standard care and to verify its effects, never published so far, primarily on perceived pain (NRS), and secondly on quality of life (SF 36) and CLU evolution (surface cm2, Falanga score, TIME-H score). b.To execute a run-in period during which to stratify the enrolled population according to age and aetiology in order to identify subsets onto which focus the efficacy trial. c.To test the validity of the chosen Mock Treatment (M.T., T.E.N.S. set at sub-threshold stimulation frequency) PHASE 2: clinical study of efficacy: randomized double blind placebo controlled trial with two arms (standard care plus F.R.E.M.S.™ versus standard care plus M. T.) Results. Feasibility study showed that: -The sample population affected by CLU (810 patients screened in 12 months, 114 patients enrolled) endures severe pain (mean NRS at T0 7.1±1.8) and receives inadequate pharmacological treatment; -To apply a multi-disciplinary protocol of standard care drawn according to current CNCP guidelines allows a fast and complete control of pain (mean NRS at seven days 1.07±1.58) with a statistically significant reduction compared to the baseline that lasts up to the last follow up at 120 days. -Albeit 68.4% of enrolled patients was more than 75 years old, to use a long lasting therapy with a major opioid did not cause relevant side effects; -IV stage Peripheral Occlusive Artery Disease (PAOD) patients experience a pain overall more severe than the general sample and refractory to standard care, resulting therefore a optimal target for alternative adjuvant treatments; -in spite of being previously tested with healthy volunteers, T.E.N.S. set at a sub-threshold frequency is not applicable as M.T. in the control arm, because patients have been capable of identifying it, in violation of the blinding. Conclusions: from the previous results we derive the following recommendations for the future efficacy trial: -new tests are necessary in order to identify an alternative M.T. really undistinguishable from the ESt object of the study, because to maintain the double blinding is mandatory to obtain conclusive results. In our opinion such tests need to be done not only with healthy volunteers but also in the clinical setting where the treatment will then be applied. -Efficacy trial should be focused on IV stage PAOD patients (which turned out to be not-responders to the standard care protocol applied) because aetiological heterogeneity of enrolled sample would generate confounding factors in respect to the effects of the ESt object of the study. -In order to have adequate statistical power, efficacy trial should be able to enroll at least 50 patients for each treatment arm: because of selection based upon aetiological criteria restricts even more inclusion and exclusion criteria initially established, adequate numerosity can be obtained only through a multi-center trial.