Iontophoresis: applications in transdermal medication delivery.

[Costello CT, Jeske AH. Iontophoresis: applications in transdermal medication delivery. Phys Ther. 1995; 75.-554-563J

Key Words: Controlled drug delivery, Drug delivery, Electroosmosis, Iontophoresis, Pharmacology, Transdermal drug delivery.

Iontopboresis is the introduction of various ions into the skin by means of electricity.[1] This definition, however, should be expanded because many nonionic materials such as polypeptides can be delivered into the body by iontophoresis. Physical therapists use iontophoresis with the objective of delivering a locally higher, therapeutic concentration of an ion or other medication, while minimizing the systemic concentration caused by circulatory removal of the material from the area. The use of iontophoresis has fluctuated over the years, partly due to concerns about chemical bums of the skin that can accompany iontophoresis treatment and the lack of research demonstrating the efficacy of the technique. Recently, there has been a resurgence in the use of iontophoresis, particularly for the delivery of anti-inflammatory medications. Interest has also grown in the use of iontophoresis for the percutaneous delivery into the body of systemically active drugs and maintenance of therapeutic levels. This approach has been termed "controlled release."

According to Chien et al,[2] there are several advantages of an effective, controlled percutaneous drug delivery system such as iontophoresis. These advantages are listed in the Table. Use of iontophoresis easily overcomes some of the major impediments to other passive transdermal drug delivery mechanisms, including requirements such as low molecular weight, low dose, and balanced oil-water partition coefficient (implying that the material is equally soluble in both water and organic solvents

The interests of the pharmaceutical and physical therapy professions in iontophoresis are often different. Many medical practitioners are interested primarily in the delivery of medication to achieve a systemic concentration sufficient for a desired effect (although medication uptake may occur preferentially in a specific target organ), whereas physical therapists are interested in directing larger quantities of a medication into a localized treatment region (under the electrode) and minimizing systemic levels of the medication.

The purposes of this article are to present what is known about the mechanisms of iontophoresis and to review the past and present clinical applications of this technique.

History of Iontophoresis

A comprehensive historical review of electrotherapy until 1965, including iontophoresis, is provided by Licht[4]; a more recent overview has been published by Chien and Banga.[3] According to Chien and Banga,[3] claims of medication transfer by electricity have been made as early as 1745. Not until 1879, however, did Munck truly demonstrate the ability to deliver ions, by delivering strychnine into a rabbit with an electric current.4 A few years later, in 1898, Morton published a book in which he described an experiment in which he drove finely powdered graphite into his skin.[3]

The first scientific experiments relating to the mechanism of iontophoresis were performed by LeDuc in 1908.[3] Using two rabbits placed in series, he introduced strychnine into one and cyanide into the other, each depending on the polarity. He was able to determine which ions were introduced by observing the signs preceding death.

Experimental and clinical trials have continued to establish a role for iontophoresis in clinical practice, in physical therapy and other health-related disciplines, most notably dermatology, otorhinolaryngology, ophthalmology, and dentistry.[5] Iontophoresis is also used in some research methods, particularly in neuroscience either to administer small quantities of neuroactive substances or to create small lesions within the central nervous system.[5]

Factors Influencing Iontophoresis

Ionization and Electrolysis 

The primary factors in iontophoresis relate to the movement of ions. In aqueous solution, an inorganic compound dissociates into positively charged cations and negatively charged anions. When a direct electric current is passed through this solution, the cations move toward the negative electrode (the cathode) and the anions move toward the positive anode where the ion either picks up or releases electrons. When a direct current is passed through the body, electrolysis of sodium chloride takes place. This electrolysis results in the formation of sodium hydroxide and a rise in the pH at the cathode and in the formation of hydrochloric acid and a lowering of the pH at the anode.[6] When the electrodes contain solutions of ions, negatively charged anions are repelled from the cathode into the body. Positively charged cations are repelled into the body from the anode. This effect is specific for ions of the same polarity as the electrode. Ions of the opposite polarity are not transferred into the body.[7] If iontophoretic medication delivery were dependent solely on this mechanism, nonionized drugs, including most organic compounds, would not be appropriate for delivery with this technique.

Electroosmosis

Another primary means by which ions and other substances traverse the skin during iontophoresis is via the passage of a solvent, carrying with it other dissolved substances, through the skin under the influence of direct current. This process been termed iontobydrokinesis.[8] This effect and its dependence on the pH were first demonstrated by Rein.[9] The relevance of this effect to medical iontophoresis was later discussed by Harpuder[10,11] and was more recently studied by Praissman et al[12] and Gangarosa et al.[8]

The skin is isoelectric (carries no charge) at a pH of between 3 and 4.[13,14] At a physiologic pH (around 7), the skin carries a, negative charge, which enhances the migration of cations at the anode.[8,9,12] This greater migration seems to drag the solvent through the skin, carrying with it any dissolved substances.[8,9,12] If the pH is lowered below 3, this effect can happen at the cathode.[12]

Effect of pH

The pH is a critical variable in iontophoresis because, as was noted, it affects skin charge and electroosmotic flow.[8,13,14] During iontophoresis, as a result of ionic exchange between the electrode and the body fluids, oxidation and reduction reactions take place at the anode and cathode, respectively. These reactions produce a lowering of the pH at the anode and an increase of the pH at the cathode.[15] In his dissertation, Mandleco reported that at the cathode, following direct current flow of 2 or 4 mA for up to 30 minutes, the pH changed from 7 to 10.1.5 Changes in the pH are also considered responsible for the discomfort and skin irritation sometimes associated with iontophoresis.[16] Histamine release probably mediates the redness of the skin that usually occurs after treatment.[16]

These pH changes at the electrodes can alter the transfer of medications due to changes in the electroosmotic effect. The pH also alters the degree of ionization of organic compounds, which usually exist in a solution in a pH-dependent equilibrium between their ionized and nonionized states.[13-15] An optimal iontophoretic effect occurs when a material is maximally ionized.[17,18] Other conditions may also be pH dependent. For example, Chien et al[2] showed that iontophoretic transfer of insulin is greatest at a pH of 3.7, because at higher values, the molecules aggregate.

Because of these effects of the pH, there has been interest in developing electrode systems that will provide a stable pH.[15,16] This research on electrode design will be discussed in later sections.

Pore Transport

The strurum corneum of human skin is normally quite impervious. This part of the epidermis, however, is punctured by pores, particularly those of the sweat glands, as well as those of the hair follicles and sebaceous glands. Electric current-mediated ion transfer occurs primarily through these pores. This ion transfer was first demonstrated by Morton in 1898.[19] More recent studies[20-24] have verified that electric current traverses the skin by passing primarily through sweat glands and, to a lesser extent, through hair follicles and sebaceous glands. Another interesting observation from these studies[19-22] is that the material delivered by iontophoresis stays in the skin for several days following treatment. There also appears to be some physical narrowing or plugging of these skin pores, which begins to resolve after about 5 days.[25]

Permselectivity

The ability of the skin, when iontophoresis is applied, to allow the passage of some ions and to restrict that of others reflects the "permselective" properties of the skin. Studies[7-9,26,27] have shown that transport across the skin is dependent on the valence of the ion, its polarity, and its transport number (related to its size). Small, monovalent cations pass through the skin most readily. Larger ions and anions pass through the skin less readily. Bivalent ions (both anions and cations) appear to bind to receptors on the walls of the pores and thus do not traverse the skin.

Concentration and Mixture of Solutes

If the concentration of ions in a solution is too great, it causes a bottleneck effect as the ions attempt to pass through the available pores.[26,28] If several ions or other substances are mixed in the solution, the ions compete, and those that are best capable of carrying the charge will be transported preferentially across the skin.[24,26,29]

Penetration and Distribution of Ions

The physical therapy use of iontophoresis is largely based on the penetration and distribution of ions. Some researchers[30-32] have proposed that all the material delivered through the skin with iontophoresis is removed by the subcutaneous circulation and distributed around the body (ie, there is no local concentration). Other researchers[33-35] have shown with animal studies and direct measurement that ions and other substances do penetrate and concentrate in the deeper tissues under the medication electrode. In addition, several studies[28,36-38] have indicated sufficient penetration of ions to produce deep cutaneous anesthesia. Other studies on humans[39-42] have indicated that ions penetrate and have therapeutic effects on deeply situated structures.

Costello recently reported, in his dissertation, on his in vivo studies of lidocaine iontophoresis with an animal (rabbit) model.[35] He reported penetration of lidocaine to at least 1 cm into the gluteal muscles. He found that the ideal variables for depth of ionic penetration were a current of 4 mA, applied for 10 minutes, with a 4% lidocaine solution.[35]

Skin Injury

The pH changes that occur with direct currents have long been considered the cause of the skin injuries associated with treatments using such currents.[5] Bums under the cathode generally are more serious, being deeper and slower to heal than burns under the anode.[32] Molitor and Fernandez[43] found that bums occurred in areas of high current density, even though the electrode solution was continuously replaced (so that the pH did not change). Lewis and Zotterman[44] and Leeming et al[45] reported that gas bubbles disrupt the stratum corneum, causing areas of higher current density where the pH changes occur to the greatest degree. Because twice as much hydrogen is produced at the cathode, compared with oxygen at the anode, the disruption is greater there.45 Gas bubbles seem to occur mostly at the periphery of electrodes, because pressure under the center of the electrodes appears to trap the gas and impedes the current flow there, reducing the electrolytic effect.[45]

The likelihood of skin injury with direct current can be decreased by thoroughly cleansing the skin prior to treatment, using only well-saturated absorbent pads (or other material) for electrodes, ensuring that there is no contact between the metal or carbon-rubber components and the skin, ensuring even skin contact with no skin blemishes (any small skin lesions should be protected with petroleum jelly), and keeping the current density at the cathode at less than 1 mA/[in.sup.2].[6]

Instrumentation

Currents Used in Iontophoresis

Constant direct current has been used in iontophoresis applications, but we contend that a constant-current generator should be used to provide consistent current flow while the skin resistance is changing. Because of concerns about skin charge accumulation and skin irritation and bums due to pH changes, however, modulated currents have been used with success in in vitro and in vivo studies on laboratory animals for the transdermal delivery of drugs for a systemic effect.[2,46-52] Pulsed currents have proved to be as effective or more effective in the delivery of small, yet systemically effective, quantities of drugs, including insulin.[2,46-50] Okabe et al[46] reported drug transfer with pulse durations as short as 4 microseconds. In all of these studies, very low amplitude currents, as low as 25 [mu]A,[50] were used. We believe the amplitude of the currents used in these studies is too small to meet the needs of physical therapists to cause primarily a local effect. The results of these studies, however, indicate the need for physical therapists to consider the use of currents other than the traditional continuous monophasic current for iontophoresis.

Su et al,[52] for example, reported recently on a study involving in vivo iontophoresis of tetraethylanunonium (TEA). By placing the TEA in both electrodes and reversing the 100-[mu]A current every 6 hours over a 24-hour period, the pH change was only 0.2 at both electrodes, compared with changes of 0.55 at the anode and 1.3 at the cathode without current reversal.[52]

Electrodes

There have been few published studies concerning the construction of electrodes for iontophoresis. Until manufacturers started marketing specific iontophoretic drug delivery systems, therapists and others made their own electrodes from lint cloth, orthopedic felt, paper towels, or gauze. These electrodes were then connected by a soft metal or alloy electrode to the direct-current generator. In an attempt to maintain a stable pH, Phipps et al[15] used a buffer solution separated from the medication solution by an anion-permeable membrane in their electrode. Sanderson et al[16] used a silver anode, which reacted with chloride ions from the body to form insoluble silver chloride. Both these studies demonstrated a stable pH and an increased rate of drug transfer. The buffer ions must be restrained, because if they were mixed in solution with the medication, the buffer ions would compete with the medication ions for transport across the skin.

Another type of electrode available today is the gel electrode. Although it appears that this type of electrode may provide a more even distribution of current, 53 the hydrophilic nature of the gel of these electrodes binds the solvent, thus inhibiting the electroosmotic effect and reducing the total amount of drug transferred at the anode, compared with other electrode designs.26,54

Pore Dilation 

Because of the relatively impervious nature of the stratum corneum, and because drug transport through the skin occurs primarily via pores, it appears logical that the use of a pore dilator may enhance iontophoretic transport across the skin. However, little has been published about the use of pore dilation in combination with iontophoresis. In his dissenation,[35] Costello reported that with lidocaine iontophoresis, using menthol as a pore dilator, there was no enhancement of the amount of drug transferred or depth of penetration into the tissues. There was a reduced tendency for the lidocaine to pool in the skin, probably secondary to the enhanced blood flow due to the vasoactive effects of the menthol.

Su et al[52] reported enhanced drug delivery with use of a skin permeation enhancer. The plasma levels of the drug more closely followed the theoretical prediction and the plasma levels with tape-stripped skin (with the stratum corneum removed). The authors also reported that the drug was delivered with less voltage needed to generate the current.

Applications in Physical Therapy

Corticosteroids (Glucocorticosteroids)

Pharmacology. Corticosteroids are the primary drugs used with iontophoresis in physical therapy. Corticosteroids are widely used because they possess a profound anti-inflammatory effect and are available in relatively inexpensive forms designed both for oral and topical administration. Several corticosteroids are available as water-soluble salts, rendering the corticosteroid molecule negatively charged and therefore available to move under the influence of a negative current field.

Two water-soluble steroids have gained widespread popularity in physical therapy: dexamethasone sodium phosphate (Decadron and various generic forms) and methylprednisolone sodium succinate (Solu-Medrol and various generic forms). Methylprednisolone must be reconstituted immediately before use. Dexamethasone is available in a somewhat more stable, dissolved form. In either case, corticosteroid solutions should be kept at room temperature to ensure stability. Methylprednisolone must be used within 48 hours of mixing, according to the manufacturer's instructions, because the solution loses stability after that time.

Dissolution of the sodium phosphate salt results in formation of positively charged sodium ions and negatively charged dexamethasone molecules. Decadron injectable solutions contain both bisulfite and paraben preservatives and should not be administered to patients with sensitivity to either substance (bisulfite sensitivity is occasionally seen in steroid-dependent persons with asthma). Solu-Medrol, in its powder form, contains no preservatives and can be used with patients who are allergic to preservatives. The solvent provided with some forms of powdered medlyl prednisolone, however, should be substituted by distilled water when used with iontophoresis, because this solvent may contain other competing ions.

Corticosteroids inhibit the inflammatory process, in part by reducing the migration of neutrophils and monocytes into the inflamed area and reducing the activity of these white blood cells.[56] Corticosteroids have recently been shown to reduce "sprouting" that occurs in sensory nerves in association with tissue injury.[57] This "sprouting" may be one factor increasing the sensitivity of inflamed tissues to painful stimuli. However, corticosteroids should not be applied to infected areas or to open wounds, because steroids tend to inhibit the immunologic defense process.

Clinical applications. In selecting patients for treatment with steroids, the therapist must determine that the patient has a condition that is amenable to relief by application of a corticosteroid and that the patient is not allergic to the medications or their preservatives. In the case of joint pain, one additional factor should be considered: steroid resistance. This condition is seen in a small number of patients with rheumatoid arthritis and other conditions treated by long-term steroid use.[58] In cases in which patients are being treated with systemic corticosteroids, the patients' physician should to consulted prior to the administration of any additional form of steroid to minimize any further adrenocortical suppression.

Dexamethasone is often administered by iontophoresis, in combination with lidocaine, in the treatment of musculoskeletal disorders. This corticosteroid has frequently been administered from the positive electrode (it presumably is carried through the skin by the electroosmotic effect, because it is a negatively charged ion). DeLacerda[40 used dexamethasone (1 mL of 0.4% dexamethasone mixed with 2 mL of 4% lidocaine in aqueous solution administered from the anode at a dosage of 5 mA for 10 minutes) to treat patients with myofascial shoulder girdle syndrome and found that iontophoresis produced the most rapid improvement in range of motion, compared with treatment with ultrasound or muscle relaxants. He used a current of 5 mA for 15 minutes, applied over trigger points.

Bertolucci[41] reported reduction of pain and increased range of motion in a group of patients with shoulder tendinitis treated with the same mixture of dexamethasone and lidocaine iontophoresis, applied for 10 minutes at 2 mA, for 5 minutes at 3 mA, and for 5 minutes at 4 mA, compared with a control group. He reported that the results were similar to those seen with steroid injections. He used a current of 2 to 4 mA, progressed over a 20-minute treatment period. Similarly, Hasson and colleagues have reported a delay in the onset of postacute exercise muscle soreness with the use of dexamethasone iontophoresis,[59] and an improvement in knee joint range of motion and a reduction in knee circumference following dexamethasone iontophoresis, applied using the same protocol as Bertolucci.[60]

Other glucocorticoids administered by iontophoresis have been used in the treatment of patients with temporomandibular trismus and paresthesia[61] and for Peyronie's disease.[62]

Lidocaine

Pharmacology. Lidocaine is an injectable, amide-type local anesthetic that is widely used in medicine and dentistry. In its injectable form, it is a hydrochloride salt that dissociates into a positively charged molecule. Therefore, lidocaine is applied iontophoretically under the anode. When applied in this manner, lidocaine produces dilation of blood vessels and a rather profound topical anesthesia of the skin, to depths of several millimeters.[28,36-38] Because the amounts of drug administered in this manner are rather small, the systemic effects of lidocaine are not seen. In certain conditions (eg, facial pain syndrome with trigger points), the application of local anesthesia prior to administration of the corticosteroid appears to be beneficial. Because lidocaine and other local anesthetics dilate blood vessels, however, they enhance their own clearance from the tissues being treated, requiring the addition of a drug to constrict blood vessels and localize subsequent drugs to the treated area. Gangarosa[28] reported increased depth of penetration and longer duration of anesthesia when epinephrine (epinephrine:total solution dilution of 1:50,000) was coad-ministered with 2% lidocaine in iontophoresis. Recently, Silcox et al[63] confirmed that cutaneous vasoconstriction with iontophoresis enhanced the accumulation of topically applied, radiolabeled compounds.

Clinical applications. Russo et al[64] reported that lidocaine applied by iontophoresis was more effective for producing skin anesthesia than when it is applied by swabbing. Iontophoresis, however, was not as effective as injection.[64] Although these investigators examined skin anesthesia for injection or minor surgical procedures, they demonstrated that lidocaine had a deeper, longer-lasting effect when applied by iontophoresis than when it was swabbed on. The method of application could be a consideration when cutaneous anesthesia is used in physical therapy to modulate kinesthesia from skin or superficial joint receptors.

Epinephrine

Epinephrine is the vasoconstrictor most widely used in conjunction with lidocaine. In dentistry, where the local anesthetic is injected, relatively small amounts of the vasoconstrictor are used (eg, epinephrine:total solution dilutions of 1:50,000-1:200,000, or 0.02-0.005 mg/mL). In iontophoresis, higher concentrations are required to produce sufficient vasoconstriction and to counteract the rapid deterioration of epinephrine after it is mixed and exposed to oxygen, light, and body temperatures. Epinephrine acts on alpha- and beta-adrenergic receptors throughout the body, producing a number of sympathomimetic effects when administered systemically.[65] These effects are well known and include cardiovascular stimulation, elevations in blood glucose, and dilation of bronchioles. In some patients, even small amounts of epinephrine may produce uncomfortable and potentially harmful side effects, such as cardiovascular stimulation and palpitations, and this drug should not be used in such patients. Epinephrine is only available in a water-soluble, injectable form and must be diluted prior to use. Because epinephrine is also positively charged in this form, it can be administered along with lidocaine under the positive iontophoretic electrode.

Historical Uses in Physical Therapy

Although use of lidocaine and dexamethasone represents the majority of clinical applications of iontophoresis currently used in physical therapy, there are reports on the use of other materials, particularly inorganic anions and cations. Much of the historical applications of these are well summarized by Harris.[13] Other published reports are discussed in the following sections. Readers must realize, however, that most of these reports are poorly substantiated or are reports of clinical trials that lacked controls. The reported results of these studies, therefore, should be viewed with caution.

Hyaluronidase 

Hyaluronic acid, a gelatinous substance that exists in many body tissues, is a major constituent of the "ground substance" of connective tissue. It restricts diffusion of certain substances through the tissues. Hyaluronidase is an enzyme that hydrolyses hyaluronic acid, reducing its viscosity.[66] Hyaluronidase carries a positive charge and migrates most rapidly at a pH of 5.4. For these reasons, it is applied in 0.1-mol/L solution with an acetate buffer by iontophoresis to an edematous limb.[66-68]

Hyaluronidase has been shown to be effective in reducing acute66 and chronic[66,68] edema. it has also been used to reduce joint swelling due to hemarthrosis.[66,69] Additionally, Popkin[67] reported on two patients with scleroderma to whom he applied hyaluronidase iontophoresis. These patients improved by having increased skin softness and flexibility and reduced cold sensitivity.

In spite of the apparent clinical effectiveness of hyaluronidase, we encourage caution in its use because it is indiscriminate in breaking down the intercellular ground substance matrix. In so doing, it may open a path for infection or other toxins, and may damage articular cartilage. Until further studies support its safe use, we contend that hyaluronidase should not be used routinely as a component of iontophoretic therapy. This caution, however, does not rule out the careful use of hyaluronidase in selected cases.

Vasodilators 

Two potent vasodilators, histamine and mecholyl (acetyl-beta-methylcholine chloride), have been administered by iontophoresis for a variety of disorders.[70-73] Kling and Sashin[70] compared the efficacy of these two vasodilators and determined that mecholyl produced less vasodilation. They also used histamine iontophoresis for patients with a number of conditions, particularly arthritis. The authors reported reduced pain and increased range of motion. Because there was no change in joint swelling, it is possible that the improvements noted were largely due to pain modulation. Kling and Sashin also reported improvement in patients with conditions associated with vasospasm, such as Raynaud's disease.

Kovacs,[71] using mecholyl, and later Abramson et al,[72] using histamine, reported enhanced healing of longstanding, trophic ulcers. More recently, DeHaan and Stark[73] experimented with using histamine iontophoresis to improve the viability of large, composite skin grafts. Histamine enhanced venous flow, but apparently did not improve overall blood flow or the establishment of new circulation that would allow the grafts to "take" sooner.

Inorganic Cations

Inorganic cations carry a positive charge and are delivered from the anode. Zinc has been used in the treatment of patients with ischemic ulcers, applied from a 0.1-mol/L solution of zinc oxide.74 in this case presentation, zinc appeared to promote healing and prevent infection.

Silver ions were used in the treatment of a series of patients with osteomyelitis.[75] The ions were from a silver wire electrode, connected to the wound through saline-soaked gauze. Because this was a case report, however, there were no controls to determine whether the beneficial effects were due to the use of silver ions or merely the passage of a low-intensity direct current. Silver iontophoresis has also been used with some success in the treatment of patients with rheumatoid arthritis.[13]

Copper iontophoresis has been used to treat chronic fungal infections of the feet.[76] A 0.2% solution of copper sulphate was used. Most patients were cured, without recurrence of the infection, following an average of six to seven treatments.

Weinstein and Gordon[77] reported on the use of magnesium iontophoresis from a solution of 2% magnesium sulphate in the treatment of a series of 50 patients with subdeltoid bursitis. Thirty-four of the patients showed good results (resolution of all clinical signs and symptoms and restoration of full active range of motion), and another 14 patients were improved. The authors felt that these results were satisfactory, better than could be achieved by other methods available.

Kahn[78] reported a case study that showed improvement in a patient with gout following treatment with lithium iontophoresis. The rationale was that the lithium would replace the insoluble sodium urate in the joint with soluble lithium urate. The patient reported hours of relief after the first treatment and complete relief after four weekly treatments. There was no change in rudiologic signs, although no gouty tophi developed and swelling was reported to decrease. The author reported that previous, similarly treated patients did demonstrate reduction of tophi. Given the time period of the study, during which remission is likely to occur, and that other pain-reducing treatments were administered, however, the conclusions can be questioned.

Inorganic Anions

Inorganic anions are administered under the cathode. Acetic acid iontophoresis has been described in case reports for the treatment of patients with calcium deposits around the shoulder[79] and for myositis ossificans affecting the quadriceps femoris muscle.[80] In both case reports, the authors reported resolution of the calcium deposition, with reduction in symptoms and improved function.

Coyer[81] reported on the use of citrate iontophoresis for patients with an exacerbation of rheumatoid arthritis affecting the hands. He used a 2% solution of sodium citrate and reported increased grip strength in these patients, compared with similar control groups treated with anodal or cathodal galvanism, with tap water electrodes.

Salicylate, ions from a 2% solution of sodium salicylate have been shown to be effective in treating a series of five patients with plantar warts.[82] The warts disappeared after two or three weekly treatments.

Iodide iontophoresis, using "Iodex" ointment, has been reported as useful in the management of problems related to scar tissue, such as Dupuytren's contracture,[83] and release of scar adhesion of tendon to bone.84

Clinical Applications in Other Disciplines

Dentistry

Dentistry, probably to an even greater extent than physical therapy, has used iontophoresis. Beginning in the late 19th century, dentists applied local anesthetics to their patients prior to oral surgical procedures. Gangarosa[85] described the use of iontophoresis for three basic applications in dentistry: (1) treatment of hypersensitive dentin (eg, in teeth sensitive to air and cold liquids) using negatively charged fluoride ions; (2) treatment of oral ulcers ("canker sores") and herpes orolabialis lesions ("fever blisters") using negatively charged corticosteroids and antiviral drugs, respectively; and (3) the application of local anesthetics to produce profound topical anesthesia, as is done in some physical therapy applications.[86,87]

Dermatology

A review of iontophoresis in dermatology was provided by Sloan and Soltani.[88] Many of the uses of iontophoresis discussed in this article are also used in physical therapy and dentistry. Except for the use of lidocaine for anesthesia and the treatment of patients with hyperhidrosis, however, most uses of iontophoresis in dermatology have largely been abandoned. Iontophoresis with tap water or anticholinergic compounds has been used for the treatment of patients with hyperhidrosis of the palms, feet, and axillae.[89-94]

In patients with bums, iontophoresis of antibiotics has been shown to be more effective for treating superficial infections than systemically administered antibiotics that would not penetrate eschar.[95]

Otorhinolaryngology

Iontophoresis is a preferred method for obtaining anesthesia of the tympanic membrane prior to simple surgical procedures involving that structure.[96,97] Iontophoresis of zinc has also been used for the treatment of patients with allergic rhinitis.[13,98]

Ophthalmology

Iontophoresis has been used experimentally to deliver antibiotics into the eye.[99] The principal disadvantage of this technique is the time required for direct contact of the electrode with the eye.

Diagnostic Applications

Iontophoretic application of the drug pilocarpine produces intense sweating, allowing sufficient amounts of sweat to be collected and analyzed. This is now accepted as the primary test in the diagnosis of cystic fibrosis.[100-102]

Conclusions and Future Applications

For the reasons outlined by Chien et al,[2] the use of iontophoresis in medicine is likely to increase, because it offers a convenient, safe, noninvasive route for the administration of many compounds that are capable of penetrating the skin, but are difficult to administer in other ways. This applies particularly to the administration of hormones and other polypeptide medications.[47,48] Other recent applications are for the systemic management of pain. Thysman and Preat,[103] for example, reported on the iontophoretic administration of fentanyl and sufentanil (opiate analgesics) in rats, with the production of analgesia for up to 4 hours. It is questionable to what extent physical therepists will be involved in this expanded use of iontophoresis for the delivery of systemically active drugs.

Miniaturized, unit-dose iontophoretic systems may become available for the long-term administration of medically useful drugs that are effective at low plasma concentrations and that would otherwise be ineffective or produce serious side effects if given orally or by injection. The "minisets" would likely be self-contained, with a built-in battery. They would provide low current levels for sustained administration. The currents may be pulsed to reduce skin irritation and charge accumulation,[2,46-50] or the current may be reversed intermittently, with the medication in both electrodes, to provide continuous administration while lessening the pH changes associated with unidirectional flow.[52] It may even be possible for the patient to selectively apply different drugs from the same iontophoretic delivery system ("Dial A Drug").[17] A permeation enhancer will most likely be used to reduce skin resistance and accumulation of the drug in the skin. Much work, however, still needs to be done to validate the clinical efficacy of this form of drug administration.

For most physical therapy applications, we recommend treatment with a current of 4 mA for 10 minutes. This current is needed to penetrate into the deeper tissues; treatment times greater than 10 minutes are not likely to achieve any greater tissue concentration due to circulatory removal of the medication (possibly unless a vasoconstrictor were used). An electrode system that uses a silver or silver-silver chloride electrode would probably be the most cost effective to minimize pH changes.[16]

In spite of the many years that iontophoresis has been used by physical therapists, very little has been done in the way of research to demonstrate the efficacy of this treatment. There are strong indications that this treatment technique is clinically effective, but this effectiveness must be proven by controlled studies, both in the clinic and the laboratory. These studies should include demonstration (where possible) of the ability of the medications to penetrate to the target tissues in sufficient quantity to produce a clinical effect, as well as controlled trials of clinical efficacy. There are several applications of iontophoresis that have been used in the past and that are believed based on clinical judgment and experience to be effective. it would be worthwhile to subject these applications to scientific scrutiny in controlled trials to determine whether they can meet the criteria of being more clinically effective and cost efficient compared with alternative treatment techniques.

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CT Costello, PhD, PT, CHT, is Assistant Professor, Department of Physical Therapy, The University of Texas Medical Branch, Galveston, TX 77555-1028 (USA). Address all correspondence to Dr Costello.

AH Jeske, PhD, DMD, is Professor, Department of Basic Sciences/Pharmacology, Dental Branch, The University of Texas, Houston-Health Science Center,