iontophoresis

Iontophoresis

Prepared by Ryan Hansen, Pharm D. CandidateEdited by Mike Pavlovich, Pharm D.

Produced by Robert Nickell, Pharmacist

Veratti originally described the process of drivingmolecules across the skin using electrical charges in 1748. Early reported experiments with this processinvolved the euthanizing of rabbits with differentpolar chemicals. The observers of the experimentcould determine which ion was applied to the patchby the type of death to which the rabbit succumbed.This concept of introducing ionic substances throughthe integument has since been refined and modifiedfor use in several specialties. Currently more thanfive manufacturers market devices specifically forthis task, iontophoresis.

This method of drug delivery is novel in that it avoidsfirst-pass metabolism by the liver, allows for theremoval of inter-subject variability in drugabsorption, removes the pain associated withinjections, and can be initiated and terminatedrapidly. However, due to the unique mechanism and the fact that it relies solely on electricity, only smallmolecules of less than 5000 daltons may be utilizedby this method.

Iontophoresis involves the use of low voltage(typically less than 10 volts) and continuous constant(DC) current of 0.5mA/cm2 or less. With this currentmay be placed solutions of ionic molecules that maybe attracted either to the anode or cathode. However,only one polarity may be delivered at a time as theparticular electrode must be placed over the intended treatment site in order for it to be delivered.

The theories behind iontophoresis arestraightforward. Coulomb’s Law states that “likecharges repel” which means that by placing a cationicsolution under the anode (+), when a current isapplied the positive ions will be drawn toward thecathode (-) electrode. The human body conductselectrical signals very well, as demonstrated byneuronal action. Thus, when an electrode is appliedto the skin, the current flows down the path of leastresistance (i.e. through the skin) and the ionicsubstance is drawn into the body.

Table 1: Common Iontophoresis Drugs and their charges.

Drug ChargeEpinephrine +

Gentamicin +

Hyaluronidase +

Hydrocortisone +

Lidocaine +

Acetic Acid -

Dexamethasone -

Ketoprofen -

Ketorolac -

Penicillin -

Sodium Salicylate -

SportPharm Pharmaceuticals381 Van Ness Ave, Suite 1507 Torrance, Ca 90501 1-800-272-4767

Local and systemic drug levels may be achievedwhen delivering drugs via iontophoresis. However,these levels depend greatly upon the solubilitycharacteristics of each drug and local dermal blood flow. Molecules with more hydrophiliccharacteristics have been shown to produce systemiclevels through their ability to traverse the dermiscompletely and enter the vasculature. However,lipophilic molecules tend to be attracted to thesubcutaneous layer and thus do not move past thisstage of the integument. Studies of severaltherapeutic classes have shown that a class can bestratified by their relative lipophilicity and that overall iontophoresis success follows thatstratification.

Doses of iontophoretically delivered medications aremeasured in milliamp-minutes (mA min) units.

Where the milliamps of current are delivered over aperiod of minutes and these are multiplied to give atotal dose. These measurements are used becauseseveral studies have shown that the pathway ofdelivery is “saturable” in that increasing theconcentration of the ionic solution does not increasethe amount of drug delivered over a certainpercentage (usually 4-5%). Most studies performedhave found efficacy ranges in the 20-80mA min dose range.

There are many problems faced by healthcare professionals that do not require systemic treatments.Some of these may be easily treated usingiontophoresis (ref. Tables 2 and 3).

Table 2:

Iontophoresis Drugs and Typical Uses

Table 3:Specific Inflammatory Conditions

StudiedDrug Use Lateral epicondylagia

Acetic Acid Calcium Deposits Plantar fasciitis

Hyaluronidase Deep Tissue Hematomas, Edema Rheumatic knee

Epinephrine Excipient to vasoconstrict Shoulder tendonitis

Dexamethasone Inflammation Superficial Masseter

Hydrocortisone Inflammation Tarsals

Gentamicin Ear Chondritis, Burn Infection Temporomandibular joint

Ketoprofen InflammationKetorolac InflammationLidocaine PainPenicillin Burn InfectionSalicylate Pain

This treatment option is obviously not withoutpotential side effects. However, these side effects have been well studied. The potential forexperiencing an adverse event can be greatlydiminished by checking the patient’s skin forimperfections at the intended iontophoresis site. Scars, moles and broken skin can all influencechanges in the way that current will flow through thetissue and thus increase the chance that an burn mayoccur. Also, many patients may react to certainmolecules and not others. Thus, it is important for thepractitioner to maintain close proximity to the patientduring initial uses of iontophoresis monitoring forskin changes around the electrodes.

The most obvious potential side effect is skinirritation by either acidic or basic reactions at the respective electrodes. A randomized controlled trial to investigate skin pH changes found that significantchanges only occurred in treatment doses of 80mAmin without a buffer solution. Furthermore, nosignificant differences were found between bufferedand non-buffered treatments at doses of 20 and 40mA

min.10 Therefore, treatments may be given atreasonable doses without regard to buffer with littleor no concern for burning the skin. Physicochemicalanalysis of changes in the skin’s impedence(resistance to electrical charge) has found thatalthough the impedence of the skin changes duringiontophoresis. Subsequent analysis determined thatthis is more a marker that charges are beingexchanged rather than a manifestation of damage.15

Furthermore, another randomized, crossover trialfound that hydrocortisone (a more or less neutralmolecule) added to metoclopramide solutionproduced significant decreases of erythema andedema at the iontophoresis site.11 Using thiscorticosteroid may be unnecessary in patients whoare being treated with dexamethasone. However, given the long half-life of dexamethasone and itsionic state that allows it to be driven into tissues, theuse of hydrocortisone for routine site irritationsshould be considered optimal. Therefore, in patientswho require iontophoresis but experience local

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Copy right protected, all rights reserved, HNP Pharmaceuticals, 2003 et al.

irritant reactions, hydrocortisone may be successfullyadded to the iontophoresis solution.

Comparisons to other Methods/Options ofTransdermal Delivery

A double-blind, placebo-controlled crossover trialcompared the delivery of lidocaine usingelectroporation, electroincorporation andiontophoresis using 10 randomized healthyvolunteers found that all three methods producedsimilar anesthesia. However, when a 27-gauge needlewas used to measure depth of anesthesia,iontophoresis was found to have significantadvantages.13

For larger molecules, up to 5000 daltons, a combination of iontophoresis and electroporationpulses has been successfully employed.16 This is anarea of current research that may prove fruitful in thefuture when therapeutic problems may require thetransdermal delivery of larger molecules.

Some researchers have suggested the use ofcombinations of several kinds of transdermaldelivery, such as an iontophoresis treatment followedby a session of ultrasound therapy over the sametreatment area. It is theorized that these types of combinations may utilize multiple mechanisms inorder to achieve local penetration of therapeuticmolecules.42,56

Donor Salt/Vehicle

One study comparing deionized water to 5% salinefound that less microvascular reactivity could beachieved by using sodium chloride as the vehicle foriontophoresis solutions.15 The recovery rate of skinimpedence has also been shown to be increased bythe use of sodium chloride.53 Furthermore, anotherstudy found significant increases in the penetration ofan insulin product by changing the donor salt fromcalcium chloride to sodium chloride.52 This is an areaof research that should be a focus of continueddevelopment.

Specific Drugs

LidocaineLidocaine has been extensively studied for treatmentand prophylaxis of local pain. Using iontophoresis as the method of delivery reduces systemic exposure tothis antiarrythmic agent, thus lowering the possibilityfor cardiac side effects. One common problem is a short duration of action, which is explained by thevasodilation that lidocaine causes, increasing its ownclearance. In order to alleviate this problem,combination with epinephrine is indicated to cause

local vasoconstriction and thus hold the lidocaine inthe tissues in close proximity to the electrode.

The efficacy of lidocaine in providing dermalanesthesia has been proven by several randomizedcontrolled clinical trials.5,8,13,27,35,36,37,39,40,46,47

Studies comparing the efficacy of eutectic mixture of local anesthetics (EMLA) to iontophoresis withlidocaine for pre venipuncture analgesia have foundmixed results. Most studies find either equivalence35

or superiority36,37 of iontophoresis in the quality ofpain relief. These findings support the use of iontophoresis as a viable alternative to EMLA.5,8,13,27

Several studies have evaluated the cost effectivenessof delivering medications (mostly lidocaine) viaiontophoresis. One study comparing the use ofiontophoresed lidocaine versus general or spinalanesthesia found that the cost of iontophoresis was half that of other anesthesia for performing bladdersurgeries.32 Other studies have compared the costs ofusing EMLA versus iontophoresis and all have foundiontophoresis to be a more cost effective method ofdrug delivery.

DexamethasoneDexamethasone is an extremely effective corticosteroid with strong anti-inflammatory effects and a long half-life. Using this medication viaiontophoresis enables steroids to be delivered to joints and tissues, while bypassing the variousunwanted side effects that accompany systemic treatment with corticosteroids. Its use for treatingjoint, fascia and tendon inflammation has been wellstudied.33,34,43,44

One double-blind, randomized controlled trialinvolving 39 patients suffering from plantar fasciitis found significant benefit from the addition ofdexamethasone 0.4% iontophoresis to the standardtreatment regimen during the 2-3 week treatment.However, the duration of increased effect was lost at the four-week follow-up. Therefore, althoughiontophoresis may not provide a long-term benefit, it does provide for accelerated improvement crucial to performance athletes and highly active patients.33

Another interesting application involves combinationtherapy with dexamethasone and lidocainecombination solution applied at the positiveelectrode. When the electrical current is turned on,lidocaine is driven into the tissues, toward thenegatively charged electrode. Although the dexamethasone in solution is not repelled by thepositive electrode, the solution flow into the tissues,driven by the lidocaine is sufficient to draw asubstantial amount of dexamethasone into the tissuesas well.

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NSAIDsThe efficacy of NSAIDs has been documented for along period of time. However, many patientsexperience routine gastro-intestinal side effects after taking them systemically. Topical preparations areavailable in compounded form. Deeper penetrationmay be facilitated by preparation of an iontophoresissolution.22

One randomized controlled trial involving 40 patientscompared the pain relief produced byiontophoretically delivered sodium salicylatecompared to diclofenac for lateral epicondylitis andfound that pain in both resisting wrist extension andpressure were more significantly decreased in thediclofenac group.12

Ketoprofen and Ketorolac solutions have also beensuccessfully used with iontophoresis.20,21

AntibioticsThe use of antibiotics has been historicallydocumented for various dermatologic infections, earchondritis and burn infections. Reports of the usepenicillin and gentamicin as well as the antisepticeffects of zinc and iodine are available.

The available data on the use of this gentamicin viaiontophoresis are conflicting. Historical data presentsthis use as a productive application of iontophoresis.The theory of attempting to deliver antibiotics to a tissue with limited vascularity appears strong.However, in a randomized trial comparing patientswho received gentamicin with those who only received standard ear care, there were no differencesother than the gentamicin group developinggentamicin resistant organisms.45

HyaluronidaseThe enzymatic action of hyaluronidase has been usedfor a variety of indications. Its ionic nature andability to promote fluid resorption makes it an idealmolecule for iontophoresis. Historically this drug was available as the product, Wydase? . However, thisproduct has been discontinued by the manufacturerand thus is only available through compoundingpharmacies. The mechanism should decrease thedamage involved with hematomas and edema. It isimportant to remember that hyaluronidase requires a special buffer solution and also has limited shelf life. Also, this product requires refrigeration when it is in solution.

Acetic AcidThe acetate ion in this chemical is believed to reducecalcium deposits. The published studies and casereports on this application are unfortunately

conflicting with regard to both acetate penetrationand clinical efficacy. One study found reductions inboth the size and density of calcium deposits as confirmed by x-ray.49 Another case report foundcomplete absorption of deposits at 3 months.50 And astudy involving 35 patients with heel pain found“significant” decreases in pain with 27 months offollow-up.55 However, a small (n=21) randomizedcontrolled trial found no significant differences incalcium density or range of motion.42 Therefore, thesuccess of this treatment may be questionable but is not out of the realm of possibility and should be keptin the armamentarium.

Evidence Limitations

Having elucidated the various uses of iontophoresis,it is also important to recognize that the quality ofevidence for all applications is lacking from what isnormally required in today’s medical literature. Mostrecommendations must be made on the basis of verysmall, sometimes not well randomized andsometimes not controlled trials, case-control studiesand worse yet case reports. This is not to say that iontophoresis is not effective but rather that it is difficult to characterize the placebo effect, validatethe measures and reproduce the author’s data.However, the cost of iontophoresis is not prohibitiveto attempting such delivery when other treatmentshave failed or if the potential side effects from a systemic medication warrant alternative modes ofdrug delivery.

Potential Future Uses/Target Patient Populations

Iontophoresis has been studied/attempted in treatingand or diagnosing the following conditions (see table4).

Table 4:Potential Iontophoresis Conditions

Cystic Fibrosis detection Kaposi’s Sarcoma

LupusMigraine

Peyronie’s disease Raynaud’s disease

The following specialties/drug classes have beenevaluated for applications involving iontophoresis as the method of drug delivery (see table 5).

Table 5:Potential Iontophoresis Applications

Antiarrythmic TherapyAntiviral Therapy

DentalDermatology

OncologyOphthalmology

Veterinary

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Appendix I:

Sample Iontophoresis Administration Instructions

• Carefully read the instructions for your specific manufacturers’ device• Both electrode pads must be in clean contact with skin, clean areas before applying current• Do not wrap electrodes with tape for extra adhesion• Treat patient with anode (+) delivered medications first• Skin under electrode will normally turn white for up to an hour post use• Daily use is not recommended, attempt to limit to 3 episodes per week

Patient Preparation

1. Prepare skin (clip excess hair, DO NOT SHAVE), check for moles and other skin imperfections which maylead to alterations in safety/efficacy

2. Clean skin with an alcohol wipe to remove excess oils3. Prepare electrodes: depending on manufacturer and drug this may involve loading electrode with ionic

solution or placing a water-based cream under the electrode4. Place electrodes 4-6 inches apart, attaching electrode containing the ionic drug over the area of treatment5. Attach lead wires (unless using a self contained system without leads) 6. Ensure that both the return buffer and delivery solutions have been instilled into electrodes7. Turn on device

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Appendix II: HNP Pharmaceuticals “Iontosol™” Reference

Iontosol Name Drug(s) Common Solution Concentration(s)%

Lidonephrine-1™ Lidocaine/Epinephrine 1% / 1:50,000Lidonephrine-2.5™ Lidocaine/Epinephrine 2.5% / 1:100,000Lidonephrine-4™ Lidocaine/Epinephrine 4% / 1:100,000

Dexion-4™ Dexamethasone 0.4%Dexion-8™ Dexamethasone 0.8%Dexion-16™ Dexamethasone 1.6%Dexicaine™ Dexamethasone/Lidocaine 0.4% / 1-2%Bruision™ Hyaluronidase 150U/ml (add to buffer solution)Ketorion™ Ketorolac 0.6%-3%Profion™ Ketoprofen 5-10%

Diclofion™ Diclofenac 0.7%Sodsalion™ Sodium Salicylate 2%Reactisol™ Hydrocortisone 10%Acetion™ Acetic Acid 2%

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Appendix III: Drug Reference

Drug Use Charge Solution% NotesAcetic Acid Calcium Deposits - 2-5%Calcium chloride Skeletal muscle spasms + 2%Dexamethasone Inflammation - 0.4%-1.6% Diclofenac Inflammation - 0.7%

Epinephrine Excipient to vasoconstrict + 1:10,000-1:100,000-Studied with lidocaine for increased efficacy

GentamicinEar Chondritis, Burn Infection + 0.8%

Hyaluronidase

Deep Tissue Hematomas, Local Edema + 150U/ml

-Stable for 90 days (3-7 daysafter mixing with buffer soln)-Refrigerate

Hydrocortisone Inflammation +/- 0.5-1%-Addition to solutions that cause local irritation is useful

Iodine Adhesions, infection - 5-10% -May use ointmentKetoprofen Inflammation -Ketorolac Inflammation - 0.3%-0.6%

Lidocaine Pain + 0.4-4%-Mix with epinephrine for sustained effect

Magnesium sulfateMyositis, Skeletal muscle spasms + 2% -May use ointment

Penicillin Burn Infection - 2-5% Sodium Salicylate Pain/Inflammation - 2%Zinc Oxide Skin ulcers + 20% -Ointment

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