What is iontophoresis

Iontophoresis is a procedure in which an electrical current is passed through skin soaked in tap water or normal saline (0.9%), allowing ionized (charged) particles to cross the normal skin barrier. Iontophoresis is a method of non-invasive transdermal drug delivery based on the transfer of charged molecules using a low-intensity electric current ¹. Iontophoresis has been used to reduce sweating and enhances the delivery of drugs and macromolecules into and through the skin. Iontophoresis is safe, effective and inexpensive.

Battery-powered direct current (DC) and mains-powered alternating current (AC) iontophoresis devices are available. Individual machines vary, and the instructions provided by the manufacturer should be followed carefully.

Two mechanisms are involved in iontophoretic transport. Electromigration (also referred to as electrorepulsion) is the movement of ions across a membrane (i.e. the skin) under the direct influence of an electric field. Negatively charged drugs are therefore repelled into the skin under the cathode, whereas the transfer of positively charged drugs occurs under the anode (Figure 1). The second mechanism is called electro-osmosis, which can be schematized as the volume flow induced by the current flow. As the isoelectric point (pI) of human skin is around 4–4.5, which is below its pH in physiological conditions, the skin will be charged negatively. Application of an electric field across the skin will therefore favour the movement of cations. Therefore, volume flow will be directed in the anode-to-cathode direction, facilitating the transport of positively charged drugs (Figure 1). Electro-osmosis also allows the diffusion of neutral molecules with anodal iontophoresis. The respective part of the transfer explained by electromigration or electro-osmosis depends mostly on the physicochemical properties of the molecules and the polarity of the applied current.

For palmar hyperhidrosis, each hand is placed in a tray of water that contains the electrodes. It is recommended that petroleum jelly is applied to the skin at the water-line, and to any small cuts or wounds to prevent discomfort and localized inflammation. The device is switched on so that current passes through the water between the electrodes. The initial current should be very low, and then adjusted according to tolerance.

Initially treatment is undertaken for 20–30 minutes every 1–3 days until the desired effect is achieved, and then reduced to once per week to maintain the result. It is up to the patient to find what treatment regime works best for them long term to maintain results.

Figure 1. Iontophoresis

Footnote: Schematic representation of iontophoretic transport. Positively charged drugs (+ve) migrate under the anode, whereas negatively charges drugs (-ve) migrate under the cathode. The black arrows represent anodal and cathodal electromigration. The red arrow represents electro-osmosis.

Iontophoresis as drug delivery module

The potential of iontophoresis has been exploited for the transdermal delivery of many drugs with poor penetration properties e.g., high molecular weight electrolytes such as proteins, peptides and oligonucleotides which are normally difficult to administer except through parenteral route. It also offers a great potential for the delivery of charged peptides used as drugs. Although iontophoresis has been able to achieve significant increase in the transdermal absorption of many drugs, it has not been able to show significant permeation of larger peptides like insulin ².

An iontophoretic drug delivery system has these basic components:

• An energy source of electronic current, which usually consists of a battery and controlled electronics;
• An active reservoir, which contains the ionic therapeutic agent; and
• An indifferent or return reservoir system, which contains an electrolyte and serves to complete the electric circuit.
• Also a control system, to monitor the overall process.

When the active and indifferent reservoir systems are placed on the skin, the current source causes electronic current to flow to the active reservoir where the electronic current is transformed into ionic current. The ionic current flows through the active reservoir, through the skin, beneath the skin towards the indifferent reservoir, and back through the skin into the indifferent reservoir. At the indifferent reservoir, it is transformed back into electronic current, completing the circuit at the opposite pole of the current source ³.

Factors affecting iontophoresis transport system

Human skin is not all the same. There are numerous differences among patient groups as well as between various regions of the body, age and ethnicity. Various factors have been shown to affect the results of iontophoresis. The following factors have to be considered ⁴ because they may improve the delivery from the device and drug release kinetics. One of these factors, regional blood flow (dermal blood supply), determines the systemic and underlying tissue solute absorption. Blood supply, however, does not appear to affect the drug penetration fluxes through the epidermis during iontophoretic delivery. Cross and Roberts showed that solute in the upper layer of the skin following iontophoresis was comparable in anaesthetized rats and sacrificed rats. It can thus be presumed that the blood did not affect the penetration through the epidermis since the latter has no blood supply ⁵. Condition of skin also affects the penetrating properties of permeant. Roberts et al., studied the in-vivo passive diffusion of methyl salicylate using skin from different areas of the human body and observed the following rank order: abdomen > forearm > instep > heel > planter, for all subjects.

Drug concentration is another factor influencing iontophoretic transfer ¹. However, while in some cases there is an almost linear relationship between concentration and flux, the flux often reaches a plateau as the concentration increases, which means that above a given concentration there is a saturation in the iontophoretic transport ⁶. The quantity of charge, the skin area and the drug concentration are experimental variables that can be adjusted to modify the electrophoretic transfer.

Other parameters, such as the physicochemical properties of the molecule, cannot easily be influenced by the operator. The size, the partition ratio and, of course, the charge of the molecule are of primary importance ⁷. In general, small and hydrophilic molecules are transported at a faster rate than larger, lipophilic molecules ⁷. Nonetheless, this rule is not exclusive, because larger molecules, such as peptides, can be administered iontophoretically ⁸. In the same way, iontophoresis of rather lipophilic drugs is possible (e.g. treprostinil log octanol/water partition coefficient is 4) ⁹.

The pH of the solution is of primary importance, because it will determine the ionization of the compound ¹. Indeed, according to the Henderson–Hasselbalch equation for weak acids, the ionic fraction increases with increasing pH of the solution. On the contrary, undissociated weak base increases with increasing pH. Therefore, one can calculate the percentage of ionization if the pKa of the compound (or its pI when there are several weakly acidic or basic groups) and the pH of the solution are known. Practically, the pH must be carefully set and controlled to ensure that the drug is ionized, while preserving skin integrity.

Figure 1. Factors affecting iontophoresis transport system

[Source ¹⁰ ]

Iontophoresis treatment

The main use of iontophoresis is to treat focal areas of excessive sweating (hyperhidrosis), particularly on the palms or soles. Tap water iontophoresis is less effective in the axilla (armpit).

Limited robust data is available; however some studies suggested that up to 80-85% of patients with palmar hyperhidrosis notice subjective improvement in their symptoms within 2–4 weeks. One study showed that 33% of sole sites, and 37.5% of axillae sites had improved after 14 days, which increased to 78%, and 75% respectively over 20 days. Delivering antiperspirants or botulinum toxin A via iontophoresis has not been shown to be superior to tap water alone.

Iontophoresis has also been successfully used to deliver drugs to the skin in order to:

• Reduce sweating further using botulinum toxin A.
• Anesthetize an area of skin with lidocaine.
• Treat fungal infection of nail plate (onychomycosis).
• Eradicate infection due to resistant micro-organisms using silver ions
• Treat bursitis or tendonitis with anti-inflammatory drugs.

Iontophoresis for hyperhidrosis

The mechanism of action of iontophoresis in reducing sweating is not completely understood. Sweat forms in response to an electrical gradient produced by sympathetic nerve activity on the cells of the sweat gland. There are several theories as to how a change in electrical gradient reduces sweat production.

• Ions produced by iontophoresis may physically block the sweat ducts in the stratum corneum.
• The external electrical current may disrupt normal sympathetic nerve transmission.
• The pH drops in the sweat gland due to an accumulation of hydrogen ions.

Iontophoresis for hyperhidrosis is usually carried out with ordinary tap water, however, an electrolyte solution or drugs (eg an anticholinergic agent such as glycopyrronium bromide) can be added if the water alone is not effective.

Iontophoresis physical therapy

Iontophoresis of acetylcholine and sodium nitroprusside, when combined with laser Doppler, have been used as markers of microvascular endothelium-dependent and -independent vasodilatation, respectively ¹¹. Several decades before being used as reactivity tests, iontophoresis had known therapeutic applications, particularly in physical therapy and dermatology ¹². Indeed, tap water has been used in the treatment of palmar-plantar and axillary hyperhidrosis ¹³. In the same way, the current itself may enhance wound healing ¹⁴, as exploited in electrotherapy. In this section, however, we will only focus on iontophoretically delivered drugs approved by regulatory agencies or undergoing clinical development. Iontophoresis may be used as a route of administration for systemic drugs or as local therapy. Indeed, cutaneous iontophoretic delivery is faster than the usual topical routes and allows the administration of high concentrations in the target tissue while limiting systemic toxicity.

Iontophoresis medication

Systemic drugs

Fentanyl

Iontophoretic delivery of fentanyl, an opioid analgesic, through a patient-controlled transdermal system (Ionsys®; Janssen, Beerse, Belgium) was approved in 2006 in Europe for the management of acute moderate to severe postoperative pain. Unlike lidocaine, fentanyl is not used topically but as a systemic drug, and iontophoresis allows on-demand administration ¹⁵. In a large prospective, randomized, unblinded, controlled trial comparing iontophoresis of fentanyl with conventional patient-controlled analgesia with morphine, the investigators did not show any difference in efficacy ¹⁶, which was confirmed by analysis of pooled data from three trials ¹⁷. However, although not statistically different, withdrawals because of inadequate analgesia were fewer in the intravenous patient-controlled analgesia morphine group than in the fentanyl iontophoresis group (10.3 and 15.2%, respectively) ¹⁶.

However, technical issues concerning the device led to a suspension of marketing authorization by the European Medicines Agency in January 2009.

Treatment of migraine

Among the drugs in the pipeline which could lead to new marketing applications soon, agonists of the 5-HT1 family receptors used as anti-migraine agents (i.e. triptans) have raised interest. Indeed, subcutaneous (s.c.) administration of sumatriptan leads to a rapid but transient effect, whereas oral or nasal administration suffers from poor bioavailability. The pharmacokinetics of iontophoretically delivered sumatriptan (4 mA for 1 h followed by 2 mA for 3 h) in healthy subjects showed comparable concentration over time areas under the curve to the s.c. route ¹⁸, but the maximal concentration was about 30% of that by the s.c. route, whereas time to maximum plasma concentration was 5.6- to 8.3-fold that of the s.c. route ¹⁹. Given that it avoids patient exposure to a rapid increase and high plasma concentrations of sumatriptan in comparison to s.c. administration, iontophoresis may reduce typical triptan-related adverse events (i.e. chest tightness, chest heaviness, paresthesias and sedation/fatigue/malaise) ²⁰. A new drug application for an iontophoretic device containing sumatriptan (Zecuity®) has been approved by the US Food and Drug Administration (FDA) in January 2013 ¹.

Other iontophoretically delivered 5-HT1 agonists, such as zolmitriptan or almotriptan, have been studied recently; to date, only preclinical data are available and suggest that these molecules are appropriate candidates for iontophoresis ²¹.

Other potential applications

Iontophoresis has been suggested as a route of administration for nicotine in smoking cessation ²².

Recent investigations in animals highlighted the potential of iontophoresis of ranitidine ²³ or phenobarbital ²⁴ in paediatric patients.

Finally, administration of proteins has raised interest in the past few years. Iontophoresis of insulin has been extensively studied since the mid-1980s, but a low penetration rate precluded its consideration for therapeutic use ²⁵. Recent improvements in penetration enhancement techniques and in formulation (i.e. nanovesicles) are encouraging ²⁶. Iontophoretic delivery of other proteins, such as calcitonin, luteinizing hormone-releasing hormone or vasopressin, has been also investigated in the late 1990s ²⁵, but no clinical applications have emerged yet from these experiments.

Local treatment

Lidocaine/epinephrine

Lidocaine combined with epinephrine was approved by the FDA as a local anaesthetic in 2004 (Lidosite®). Combination with epinephrine aims at decreasing skin blood flow, thus reducing skin clearance of the drug and consequently increasing the dermal concentration ²⁷ and prolonging the anaesthetic action of lidocaine in a dose-dependent manner ²⁸. The current density of Lidosite® is 0.35 mA cm−2, and it is applied for 10 min with a patch electrode pH of 4.5, at which both lidocaine and epinephrine are positively charged ²⁹.

In a randomized, open-label, crossover study conducted in children undergoing repeated procedures requiring peripheral intraveous access, pain relief after 10 min of lidocaine/epinephrine iontophoresis (Iontocaine®) was similar to that found after 60 min of local anaesthesia with lidocaine/prilocaine cream ³⁰. Two of 22 children discontinued iontophoresis before the complete dose was delivered because of intolerable tingling, itching and discomfort from the procedure ³⁰. In a randomized, double-blind study comparing iontophoresis of lidocaine/epinephrine with that of placebo, erythema at the site of iontophoresis was observed in about 50% of adults and in 60% of children, whatever the group. In most cases, it was mild, but still detectable after 24 h in about 6.5% of the adults ³¹. Additional adverse events included mild edema, itching and urticaria ³¹.

The pharmacokinetics of lidocaine iontophoresis have been assessed in animals and in humans. In a study using microdialysis in animal models, iontophoresis of lidocaine at 0.15 mA/cm² resulted in a 40-fold increase in dermal lidocaine concentrations in comparison to passive drug delivery ³². In children, lidocaine plasma concentrations were below the lower limit of detection (<5 ng/ml; or below 10 ng/ml for one observation after three applications) ³³.

Current clinical investigations

Iontophoretic delivery of terbinafine has been proposed in the treatment of onychomycosis ³⁴. Preliminary data in humans compared terbinafine patches with (100 μA/cm², the active electrode polarity being positive) or without current during 4 weeks (6–8 h overnight, every day, 5 days a week). Clinical improvement was observed in the iontophoresis group compared with control subjects from the second follow-up visit ³⁵. At the end of follow-up, mycological improvement (i.e. decrease in fungal elements) was also observed in patients from the iontophoresis group compared with control subjects ³⁵. The investigators hypothesized that deeper penetration of the drug into the nail bed under the influence of the electric field was responsible for these encouraging results ³⁵. Despite the prolonged treatment with elevated intensity, iontophoresis of terbinafine was well tolerated. Besides a tingling sensation, local irritation was reported by only two of 20 patients at the first application of the patch, and none of them stopped the therapy ³⁵. Nonetheless, iontophoresis was performed over a small area (1 cm²) on the toenail, which is less sensitive than plain skin.

Iontophoresis of antiviral agents was proposed in the treatment of herpes labialis as early as the mid-1980s. Indeed, the efficacy of topical cream is limited by low penetration of the drug into the basal epidermis. A single 10 min iontophoretic application of 5% acyclovir cream was superior to placebo in the time to healing ³⁶. Further research using a modified, self-administered, iontophoretic device (SoloVir®) was conducted in 2007, but the results have not been published (clinicaltrials.gov identifier: NCT00469300), and the development of SoloVir® was stopped ³⁷.

Among other local therapies being investigated, a study comparing the efficacy and safety of iontophoretically administered azelaic acid twice weekly to topical cream twice daily in women with melasma is ongoing (clinicaltrials.gov identifier: NCT00848458).

Finally, iontophoresis of corticosteroids has been extensively studied, especially since the marketing of new devices (e.g. EyeGate® delivery system) which enable drug delivery to both the anterior and posterior segments of the human eye. Recent controlled studies suggest that dexamethasone administered through ophthalmic iontophoresis may be an effective treatment of dry eye ³⁸, but this is beyond the scope of this review. On the skin, however, a pilot study reports the potential benefit of dexamethasone iontophoresis for temporomandibular joint involvement in juvenile idiopathic arthritis ³⁹. In contrast, dexamethasone iontophoresis was not effective in the treatment of mild to moderate carpal tunnel syndrome ⁴⁰.

Besides tap water iontophoresis, which has been used for years in hyperhidrosis, Clostridium botulinum toxin type A (BTX-A) was successfully administered iontophoretically (100 IU diluted in 3 ml of saline; 1.1–2.2 mA/cm² for 5 min) to two patients with severe palmar hyperhidrosis ⁴¹. A small (n = 8), double-blind, randomized, placebo-controlled study performed by the same group showed reduced palmar sweating in the BTX-A group at 14 days post-treatment ⁴². A preliminary randomized study comparing iontophoretically administered vs. intradermal injections of botulinum toxin treatment in patients with palmar hyperhidrosis recently showed that injections are more effective but more painful for the administration of BTX-A ⁴³. A larger trial is currently ongoing (clinicaltrials.gov identifier: NCT01262339) and will provide further data.

Iontophoresis contraindications

Iontophoresis should not be used by:

• Patients who are epileptic or have a history of seizures
• Patients with heart conditions or a pacemaker
• Patients with metal implants
• Pregnant woman

Patients should delay treatment if they have recent wounds, skin grafts, or scars in the area requiring treatment, as iontophoresis may be painful and the treatment less effective.

Iontophoresis side effects

Iontophoresis is generally a safe procedure. It is important to avoid direct contact with the electrodes during treatment, as it may cause a mild electric shock.

A feeling of pins and needles or burning sensation is experienced by most people. Adverse effects may include:

• Redness of treated skin
• Small blisters(vesicles) or pompholyx
• Dry and cracked skin or dermatitis

Although these side effects from iontophoresis are expected to resolve within a few days, emollients/moisturisers should be applied several times daily to reduce symptoms. Topical corticosteroids can be applied.

If used, anticholinergic drugs such as glycopyrronium may be absorbed into the body and produce systemic side effects such as dizziness, dry eyes and dry mouth.

Cutaneous adverse events

Iontophoresis induces a sensation of tingling or itching, depending on the density of the applied current. Besides these uncomfortable but harmless effects, skin irritation is the most common local adverse effect of cutaneous iontophoresis. It occurs at both the anode and the cathode. Erythema is the most frequently described adverse effect, with a variable frequency according to the iontophoresis protocols ³¹. It was shown to occur consistently after 3 h iontophoresis at 250 μA/cm², was rated as very slight (grade 1) and lasted up to 3 h after removal of iontophoresis ⁴⁴. Using the same protocol, edema was observed in half of the patients, and both erythema and oedema were enhanced by non-occlusive pretreatment with a surfactant ⁴⁴. Skin irritation spontaneously and rapidly resolves, does not lead to permanent skin damage and does not disturbs the barrier function of the skin ⁴⁴.

Although rare, burns have been observed, mainly due to operator error and the incorrect choice of electrodes/formulation composition. Indeed, the electrochemistry at bare metal or graphite electrodes involves electrolysis of water, which induces changes in the pH of the skin by generating H+ and OH− at the positive and negative electrodes, respectively ⁴⁵. Variations in pH beyond the buffer capacities of the skin may lead to burns. High current density or prolonged application, as well as positioning of the electrodes over skin defects (which decrease skin resistance) increase the risk of burns. Burns are generally more serious under the cathode, due to involvement of OH− and rise in pH ¹². Indeed, an alkaline phase erodes the epidermis and reduces skin resistance, making skin erosion worse ⁴⁵. Therefore, an appropriate choice of buffer concentration in the formulation is needed to reduce the risk of burns. A better solution is to use Ag–AgCl rather than bare metal or carbon active electrodes, because they function at a lower potential and do not operate by water electrolysis.

Other cutaneous adverse effects have occasionally been described, such as galvanic urticaria ⁴⁶. However, this was observed at high current intensities up to 24 mA, in the treatment of hyperhidrosis ⁴⁷.

Several simple recommendations can decrease the risk of skin injury, such as avoiding pressure on the electrodes (not taping, binding or compressing either electrode) and ensuring that the electrode is uniformly wetted [68]. Indeed, most of the commercially available electrodes are made of small sponges in contact with the skin. After dampening the sponge with the drug solution, it conducts the current. Therefore, heterogeneity in sponge dampening locally increases current density and may lead to skin injury. In the same way, the adhesive seal should adhere uniformly to the skin to avoid leaks ⁴⁸. Moreover, cleansing the skin with alcohol and avoiding skin defects and contact between metal components and the skin are also recommended ⁴⁸. Finally, current intensity should be <0.5 mA/cm² ⁴⁹.

Material defects

Material defects are the main cause of skin injuries, such as burns, usually resulting from a contact between metal components and the skin. For example, a partial-thickness burn has been reported in a paediatric patient, attributed to contact between the skin and a defect in the coating of the wires connecting the controller to the electrode patch ³¹.

Another consequence of material defects can be overdose, which is potentially harmful when drugs are delivered for a systemic action and have a narrow therapeutic index. The most striking example in the past few years was the iontophoretic delivery of fentanyl (Ionsys®); after receiving marketing authorization for the whole European Union in 2006, corrosion of a component within the system was found in one batch. Although no case of fentanyl overdose was reported, this defect could have resulted in fentanyl release without activation by the patient. This could have exposed patients to fentanyl overdose (the maximal theoretical dose was 3.2 mg), with a risk of severe respiratory depression ⁵⁰. Ionsys® has not been marketed in Europe since October 2008, and the marketing authorization holder did not apply for renewal of authorization ⁵¹. Ionsys® has recently been acquired by another pharmaceutical company (Incline Therapeutics Inc., Redwood City CA, USA) currently developing new features into the system in order to obtain regulatory approval in the next few years.

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