## 2 Therapeutic Methodologies
### Electotherapy
The combined use of iontophoresis and electroporation has been shown to be more effective in passing peptides, proteins, genes and oligonucleotides [25], expanding the scope of transdermal transmission to larger molecules by the improvement of the transport, the fast passage of large doses, better modulation control or transmission programming [26]. As the electrical current travels through the body, the cations present at the anode move towards the cathode, while the anions present at the cathode move in the opposite direction. By placing electrolytic solutions on the electrode of the same ionic nature, with the desired drug, its transdermic introduction is achieved. Negatively charged drug molecules are repelled by the cathode while positively charged ones are repelled by the anode. Electro-osmosis or electromigration represents the amount of flow that passes into the bloodstream, depending on the physicochemical properties of the molecules and the polarity of the applied current. Transdermal drug delivery by iontophoresis has been widely accepted in PMR for localized therapies, being frequently used in the localized application of analgesics and anti-inflammatory drugs and in the treatment of hyperhidrosis. This non-invasive method has been widely used for local anesthesia in pediatric patients, allowing for rapid and effective anesthesia before medical procedures such as intravenous injections or blood collection [25, 27]. Studies carried out to assess the initial electrical resistance and overtime of commercial gels in physiotherapy and liquids used in electotherapy for the electrode-skin interface, concluded that gels, drinking water and saline solutions are the most suitable for therapeutic electrical stimulation because they maintain low resistance during skin stimulation, in contrast to the use of distilled or deionized water with high resistance to the passage of electric current [28]. Some factors condition the iontophoretic effect. The pH of the solution is very important because it determines the ionization of the compound. The pH of the solution will have to be well determined and controlled to ensure that the drug is ionized and that it preserves the integrity of the skin [23]; this is due to the variation in the degree of ionization and the selective permeability of the skin [25]. The size of the molecule and ionic strength [25] are also decisive when passing through the stratum corneum. In general, small, and hydrophilic molecules are transferred more quickly than the largest and lipophilic ones, with some exceptions such as the case of peptides [23]. The integrity of the skin surface, namely the thickness of the stratum corneum, the presence or absence of hair, wounds, skin diseases (e.g., atopic dermatitis or psoriasis), the hydration status of the skin surface, also interfere. Parameters that can be adjusted by the operator and modify the iontophoretic transfer are the method of applying the current (continuous or pulsed) [25] and the amount of current, the area of the skin section in contact with the electrode and the concentration of the substance or drug because there is a quasi-linear relationship between concentration and flow. Saturation of iontophoretic transport may occur when the flow reaches the maximum concentration limit [23]. The known side effects resulting from the use of iontophoresis are, in most cases, adverse reactions with a very small dimension, being well tolerated by patients. The reactions that occur most frequently are associated with hypersensitivity to electrical stimulation, with pruritus, erythema, and irritation of the skin surface where iontophoresis was applied or sensitivity to the medication administered. This type of adverse reactions increases the risk of occurrence if the exposure time and/or the current value is increased. If the current density through the skin pores is greater than the current per unit area applied and depending on the density of the pores in that area, the possibility of skin injuries induced by the current may increase [23].