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1995; 75:554-563.PHYS THER.Charles T Costello and Arthur H JeskeMedication DeliveryIontophoresis: Applications in Transdermal

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harmacology eriesIontophoresis: Applications in TransdermalMedication Delivery

Key Words: Contmlled drug delivery, Drug delivery, EElectmosmos Iontophoresis,Pharmacology, Transdermal drug delivery.

This article presents a review of the literature relating to iontophoresis. Thistechnique has been used i n physical therapy to introduce ionic medicationsthrough the skin, primarily for a local effect. Recently, there has been increasedinterest in using this technique for the transdermal delivery of medications,

Iontophoresis is the introduction ofvarious ions into the skin by means ofe1ectricity.l This definition, however,should be expanded because manynonionic materials such as polypep-tides can be delivered into the bodyby iontophoresis. Physical therapistsuse iontophoresis with the objective ofdelivering a locally higher, therapeuticconcentration of an ion or other medi-cation, while minimizing the systemicconcentration caused by circulatoryremoval of the material from the area.The use of iontophoresis has fluctu-ated over the years, partly due toconcerns about chemical burns of theskin that can accompany iontophore-

Charles T CostelloArthur H Jeske

sis treatment and the lack of researchdemonstrating the efficacy of the tech-nique. Recently, there has been aresurgence in the use of iontophoresis,particularly for the delivery of anti-inflammatory medications. Interest hasalso grown in the use of iontophoresisfor the percutaneous delivery into thebody of systemically active drugs andmaintenance of therapeutic levels. Thisapproach has been termed controlledrelease.

both ionic and nonionic. This article includes an ovenjiew of the histov ofiontophoresis and a discussion of thephysico-chemical and biological factorsaffecting iontophoretic drug transfer or both local and systemic effects. Factorsaffecting skin injury and techniques or optimizing iontophoretic drug deliverythrough the use of current modulation, electrode construction, and skin perme-ation enhancers are also discussed. Clinical applications of iontophoresis inphysical therapy and the pharmacology of selected medications are presented.Thoughts or future potential uses of this technique and needs for further re-search are also discussed. [Costello CT, Jeske AH Iontophoresis: applications intransdermal medication delivery. Phys Ther. 1995; 753554-563.1

According to Chien et a1,2 here areseveral advantages of an effective,controlled percutaneous drug deliverysystem such as iontophoresis. These

advantages are listed in the Table. Useof iontophoresis easily overcomessome of the major impediments toother passive transdermal drug deliv-ery mechanisms, including require-ments such as low molecular weight,low dose, and balanced oil-waterpartition coefficient (implying that thematerial is equally soluble in bothwater and organic solvents).3The interests of the pharmaceuticaland physical therapy professions iniontophoresis are often dlferent. Manymedical practitioners are interestedprimarily in the delivery of medicationto achieve a systemic concentrationsufficient for a desired effect (althoughmedication uptake may occur prefer-entially in a specific target organ),

CT Costello, PhD, PT, CHT, is Assistant Professor, Deparrm ent of Physical Therap y, Th e University whereas physical therapists are inter-of Texas Medical Branch, Galveston, TX 77555-1028 USA). Address all correspondence to Dr ested in directing larger quantities of aCostello. medication into a localized treatmentAH Jeske, PhD, DMD, is Professor, Deparrment of Basic Sciences/Pharmacology, Dental Branch, region (under the electrode) and mini-The University of Texas, Houston-Health Science Center, Houston, TX 77225.

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Table Advantages of an Effective Controlled Percutaneous Drug Delivery System Such as ~o ntophoresi?1 Avoids the risks and inconveniences of parenteral (injection/intravenous) herapy2. Prevents the variation in the absorption and metabolism seen with oral administration3 ncreases therapeutic efficacy by bypassing hepatic first-pass elimination-the reduction n the amount of the drug entering the systemic circulation,

due to metabolism by the liver as the drug passes through the hepatic circulation after absorption from the gastrointestinal tract4 Reduces the chance of overdosing or underdosing by providing continuous delivery of the drug, programmed at the required therapeutic rate5. Permits the use of a drug with a short biological half-lifebecause 1) the drug is delivered directly to the target organ without the need to circulate andrecirculate in the blood or (2)the drug is delivered directly into the bloodstream without delays due to absorption through the gastrointestinal ract6. Provides a simplified therapeutic regimen, leading to better patient compliance7. Permits a rapid termination of administration of the medication, f needed, by simply turning off the iontophoretic delivery system

mizing systemic levels of themedication.The purposes of this article are topresent what is known about themechanisms of iontophoresis and toreview the past and present clinicalapplications of this technique.History of lontophoresisA comprehensive historical review ofelectrotherapy until 1965, includingiontophoresis, is provided by Licht4; amore recent overview has been pub-lished by Chien and Banga.3 Accord-ing to Chien and Banga,3 claims ofmedication transfer by electricity havebeen made as early as 1745. Not until1879, however, did Munck truly dem-onstrate the ability to deliver ions, bydelivering strychnine into a rabbit withan electric current.* few years later,in 1898, hlorton published a book inwhich he described an experiment inwhich he drove finely powderedgraphite into his slun.3The first scientific experiments relatingto the mechanism of iontophoresiswere performed by LeDuc in 1908.3Using two rabbits placed in series, heintroduced strychnine into one andcyanide into the other, each depend-ing on the polarity. He was able todetermine which ions were introducedby observing the signs precedingdeath.Experimental and clinical trials havecontinued to establish a role for ionto-phoresis in clinical practice, in physi-cal therapy and other health-related

disciplines, most notably dermatology,otorhinolaryngology,ophthalmology,and dentistry.5 Iontophoresis is alsoused in some research methods, par-ticularly in neuroscience either toadminister small quantities of neuroac-tive substances or to create small le-sions within the central nervoussy~ tem.~Factors InfluencinglontophoresisIonization and Electm sisThe primary factors in iontophoresisrelate to the movement of ions. Inaqueous solution, an inorganic com-pound dissociates into positivelycharged cations and negativelycharged anions. When a direct electriccurrent is passed through this solution,the cations move toward the negativeelectrode (the cathode) and the anionsmove toward the positive anodewhere the ion either picks up or re-leases electrons. When a direct currentis passed through the body, electroly-sis of sodium chloride takes place.This electrolysis results in the forma-tion of sodium hydroxide and a rise inthe pH at the cathode and in the for-mation of hydrochloric acid and alowering of the pH at the anode.6When the electrodes contain solutionsof ions, negatively charged anions arerepelled from the cathode into thebody. Positively charged cations arerepelled into the body from the an-ode. This effect is specific for ions ofthe same polarity as the electrode.Ions of the opposite polarity are nottransferred into the body. If ionto-

phoretic medication delivery weredependent solely on this mechanism,nonionized drugs, including mostorganic compounds, would not beappropriate for delivery with thistechnique.ElectmosmosisAnother primary means by which ionsand other substances traverse the skinduring iontophoresis is via the passageof a solvent, carrying with it otherdissolved substances, through the skinunder the Influence of direct current.This process been termed iontohydm-kinesis.8 This effect and its depen-dence on the pH were first demon-strated by Rein.9 The relevance of thiseffect to medical iontophoresis waslater discussed by HarpuderloJ andwas more recently studied byPraissman et all2 and Gangarosa et al.8The skin is isoelectric (cames nocharge) at a pH of between 3 and4.13914 At a physiologic pH (around 7 ,the slun cames a negative charge,which enhances the migration of cat-ions at the an0de. ~,9, ~his greatermigration seems to drag the solventthrough the skin, carrying with it anydissolved su bs ta nc e~ .~ ~9 ~~ ~f the pH islowered below 3, this effect can hap-pen at the cathode.12Effect of pHThe pH is a critical variable in ionto-phoresis because, as was noted, itaffects skin charge and electroosmoticf l o ~ . ~ J ~ 1 ~ ~uring iontophoresis, as aresult of ionic exchange between the

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electrode and the body fluids, oxida-tion and reduction reactions take placeat the anode and cathode, respec-tively. These reactions produce a low-ering of the pH at the anode and anincrease of the pH at the cathode.15 Inhis dissertation, Mandleco reportedthat at the cathode, following directcurrent flow of or rnA for up to 30minutes, the pH changed from 7 to10 .1 .~ hanges in the pH are alsoconsidered responsible for the discom-fort and skin irritation sometimes asso-ciated with iontophoresis.l'j Histaminerelease probably mediates the rednessof the skin that usually occurs aftertreatment.I6These pH changes at the electrodescan alter the transfer of medicationsdue to changes in the electroosmoticeffect. The pH also alters the degree ofionization of organic compounds,which usually exist in a solution in apH-dependent equilibrium betweentheir ionized and nonionizedstates.lS15An optimal iontophoreticeffect occurs when a material is maxi-mally ionized.17J8 Other conditionsmay also be pH dependent. For exam-ple, Chien et a12 showed that ionto-phoretic transfer of insulin is greatestat a pH of 3.7, because at hlgher val-ues, the molecules aggregate.Because of these effects of the pH,there has been interest in developingelectrode systems that will provide astable pH.15J6 This research on elec-trode design will be discussed in latersections.ore Transport

The stratum comeum of human skin isnormally quite impervious. This partof the epidermis, however, is punc-tured by pores, particularly those ofthe sweat glands, as well as those ofthe hair follicles and sebaceous glands.Electric current-mediated ion transferoccurs primarily through these pores.This ion transfer was first demon-strated by Morton in 1898.l9 Morerecent studies20-24 have venfied thatelectric current traverses the skin bypassing primarily through sweatglands and, to a lesser extent, throughhair follicles and sebaceous glands.

Another interesting observation fromthese st~ die sl7 -~~s that the materialdelivered by iontophoresis stays in theskin for several days following treat-ment. There also appears to be somephysical narrowing or plugging ofthese skin pores, which begins toresolve after about 5 days.25

The ability of the skin, when ionto-phoresis is applied, to allow the pas-sage of some ions and to restrict thatof others reflects the permselectiveproperties of the skin. Studies7-9-26327have shown that transport across theskin is dependent on the valence ofthe ion, its polarity, and its transportnumber (related to its size). Small,monovalent cations pass through theskin most readily. Larger ions andanions pass through the skin lessreadily. Bivalent ions (both anions andcations) appear to bind to receptorson the walls of the pores and thus donot traverse the skin.

oncentration and Mixtureof SdutesIf the concentration of ions in a solu-tion is too great, it causes a bottleneckeffect as the ions attempt to passthrough the available pores.26~28fseveral ions or other substances aremixed in the solution, the ions com-pete, and those that are best capableof carrying the charge will be trans-ported preferentially across theskin.24.26,29Penetration and Distributionof IonsThe physical therapy use of ionto-phoresis is largely based on the pene-tration and distribution of ions. Someresearchers3O-32 have proposed that allthe material delivered through the skinwith iontophoresis is removed by thesubcutaneous circulation and distrib-uted around the body (ie, there is nolocal concentration). Other research-ers3535 have shown with animal stud-ies and direct measurement that ionsand other substances do penetrate andconcentrate in the deeper tissues un-der the medication electrode. In addi-

tion, several studies2 36-38 have indi-cated sufficient penetration of ions toproduce deep cutaneous anesthesia.Other studies on h~rnans39-~2aveindicated that ions penetrate and havetherapeutic effects on deeply situatedstructures.Costello recently reported, in his dis-sertation, on his in vivo studies oflidocaine iontophoresis with an animal(rabbit) model.35 He reported penetra-tion of lidocaine to at least 1 cm intothe gluteal muscles. He found that theideal variables for depth of ionic pene-tration were a current of rnA ap-plied for 10 minutes, with a 4 lido-caine solution.35Skin InjuryThe pH changes that occur with directcurrents have long been consideredthe cause of the skin injuries associ-ated with treatments using such cur-rents.5 Bums under the cathode gener-ally are more serious, being deeperand slower to heal than burns underthe anode.s2Molitor and Femandez43found that burns occurred in areas ofhigh current density, even though theelectrode solution was continuouslyreplaced (so that the pH did notchange). Lewis and Zottermanbl andLeerning et a145 reported that gas bub-bles disrupt the stratum comeum,causing areas of higher current densitywhere the pH changes occur to thegreatest degree. Because twice asmuch hydrogen is produced at thecathode, compared with oxygen at theanode, the disruption is greaterthere. Gas bubbles seem to occurmostly at the periphery of electrodes,because pressure under the center ofthe electrodes appears to trap the gasand impedes the current flow there,reducing the electrolytic effe~t.~5The likelihood of skin injury withdirect current can be decreased bythoroughly cleansing the s h rior totreatment, using only well-saturatedabsorbent pads (or other material) forelectrodes, ensuring that there is nocontact between the metal or carbon-rubber components and the skin,ensuring even skin contact with noskin blemishes (any small skin lesions

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should be protected with petroleumjelly), and keeping the current densityat the cathode at 1es.s than 1 mA/in2.6InstrumentationCurrents Used in lontophoresisConstant direct curr~mt as been usedin iontophoresis applications, but wecontend that a constant-current gener-ator should be used to provide consis-tent current flow while the skin resis-tance is changing. Eiecause of con-cerns about skin chiarge accumulationand skin irritation and bums due topH changes, however, modulatedcurrents have been used with successin in vitro and in vivo studies on labo-ratory animals for the transdermaldelivery of drugs for a systemic ef-fect. .G-j2 Pulsed currents have provedto be as effective or more effective inthe delivery of small, yet systemicallyeffective, quantities of drugs, includinginsulin.2-45-5O Okabe et a146 reporteddrug transfer with pulse durations asshort as 4 microsecc>nds.In all ofthese studies, very low amplitudecurrents, as low as :25 pA,50wereused. We believe the amplitude of thecurrents used in these studies is toosmall to meet the needs of physicaltherapists to cause primarily a localeffect. The results of these studies,however, indicate the need for physi-cal therapists to consider the use ofcurrents other than the traditionalcontinuous monophasic current foriontophoresis.Su et al,52 for example, reported re-cently on a study involving in vivoiontophoresis of tetraethylammoniumTEA). By placing tlne TEA in both

electrodes and reversing the 100-pAcurrent every 6 hours over a 24-hourperiod, the pH change was only 0.2 atboth electrodes, compared withchanges of 0.55 at the anode and 1.3at the cathode without currentreversal j2ElectrodesThere have been few published stud-ies concerning the construction ofelectrodes for iontophoresis. Untilmanufacturers started marketing spe-

cific iontophoretic drug delivery sys-tems, therapists and others made theirown electrodes from lint cloth, ortho-pedic felt, paper towels, or gauze.These electrodes were then connectedby a soft metal or alloy electrode tothe direct-current generator. In anattempt to maintain a stable pH,Phipps et allj used a buffer solutionseparated from the medication solu-tion by an anion-permeable mem-brane in their electrode. Sanderson etall6 used a silver anode, which reactedwith chloride ions from the body toform insoluble silver chloride. Boththese studies demonstrated a stablepH and an increased rate of drugtransfer. The buffer ions must be re-strained, because if they were mixedin solution with the medication, thebuffer ions would compete with themedication ions for transport acrossthe skin.Another type of electrode availabletoday is the gel electrode. Although itappears that this type of electrode mayprovide a more even distribution ofcurrent,53 he hydrophilic nature of thegel of these electrodes binds the sol-vent, thus inhibiting the electroosmoticeffect and reducing the total amount ofdrug transferred at the anode, com-pared with other electrode de ~i gn s. ~~ ,i 4Pore DilationBecause of the relatively imperviousnature of the stratum corneum, andbecause drug transport through theskin occurs primarily via pores, itappears logical that the use of a poredilator may enhance iontophoretictransport across the slun. However,little has been published about the useof pore dilation in combination withiontophoresis. In his dissertation,35Costello reported that with lidocaineiontophoresis, using menthol as a poredilator, there was no enhancement ofthe amount of drug transferred ordepth of penetration into the tissues.There was a reduced tendency for thelidocaine to pool in the skin, probablysecondary to the enhanced blood flowdue to the vasoactive effects of thementhol.

Su et alj2 reported enhanced drugdelivery with use of a skin permeationenhancer. The plasma levels of thedrug more closely followed the theo-retical prediction and the plasma lev-els with tape-stripped skin (with thestratum corneum removed). The au-thors also reported that the drug wasdelivered with less voltage needed togenerate the current.

pplications in PhysicalTherapyCorticostemidsGlucocorticostemids)Pharmacology Corticosteroids arethe primary drugs used with ionto-phoresis in physical therapy. Cortico-steroids are widely used because theypossess a profound anti-inflammatoryeffect and are available in relativelyinexpensive forms designed both fororal and topical administration. Severalcorticosteroids are available as water-soluble salts, rendering the corticoste-roid molecule negatively charged andtherefore available to move under theInfluence of a negative current field.Two water-soluble steroids havegained widespread popularity in phys-ical therapy: dexamethasone sodiumphosphate (Decadron and variousgeneric forms) and methylpred-nisolone sodium succinate (Solu-Medrol and various generic forms).Methylprednisolone must be reconsti-tuted immediately before use. Dexa-methasone is available in a somewhatmore stable, dissolved form. In eithercase, corticosteroid solutions shouldbe kept at room temperature to ensurestability. Methylprednisolone must beused within 48 hours of mixing, ac-cording to the manufacturer s instruc-tions, because the solution loses stabil-ity after that time.Dissolution of the sodium phosphatesalt results in formation of positivelycharged sodium ions and negativelycharged dexamethasone molecules.Decadron injectable solutions containboth bisulfite and paraben preserva-tives and should not be administeredto patients with sensitivity to eithersubstance (bisulfite sensitivity is occa-

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sionally seen in steroid-dependentpersons with asthma). Solu-hledrol, inits powder form, contains no preserva-tives and can be used with patientswho are allergic to preservatives. Thesolvent provided with some forms ofpowdered methyl prednisolone, how-ever, should be substituted by distilledwater when used with iontophoresis,because this solvent may contain othercompeting ions.Corticosteroids inhibit the inflarnma-tory process, in part by reducing themigration of neutrophils and mono-cytes into the inflamed area and re-ducing the activity of these whiteblood cells.56 Corticosteroids haverecently been shown to reducesprouting hat occurs in sensory

nerves in association with tissue inju-ry.57 This sprouting may be onefactor increasing the sensitivity ofInflamed tissues to painful stimuli.However, corticosteroids should notbe applied to infected areas or toopen wounds, because steroids tendto Inhibit the immunologic defenseprocess.Clinical applications In selectingpatients for treatment with steroids,the therapist must determine that thepatient has a condition that is amena-ble to relief by application of a corti-costeroid and that the patient is notallergic to the medications or theirpreservatives. In the case of joint pain,one additional factor should be con-sidered: steroid resistance. This condi-tion is seen in a small number of pa-tients with rheumatoid arthritis andother conditions treated by long-termsteroid u ~ e . 5 ~n cases in which pa-tients are being treated with systemiccorticosteroids, the patients' physicianshould be consulted prior to the ad-ministration of any additional form ofsteroid to minimize any further adre-nocortical suppression.Dexamethasone is often administeredby iontophoresis, in combination withlidocaine, in the treatment of musculo-skeletal disorders. This corticosteroidhas frequently been administered fromthe positive electrode (it presumably iscamed through the skin by the elec-troosmotic effect, because it is a nega-

tively charged ion). DeLacerda40useddexamethasone (1 mL of 0.4% dexa-methasone mixed with m of 4%lidocaine in aqueous solution adminis-tered from the anode at a dosage of 5mA for 10 minutes) to treat patientswith myofascial shoulder girdle syn-drome and found that iontophoresisproduced the most rapid improvementin range of motion, compared withtreatment with ultrasound or musclerelaxants. He used a current of 5 mAfor 15 minutes, applied over triggerpoints.Bertolucci41 eported reduction of painand increased range of motion in agroup of patients with shoulder tendi-nitis treated with the same mixture ofdexamethasone and lidocaine ionto-phoresis, applied for 10 minutes at 2mA for 5 minutes at 3 mA and for 5minutes at 4 mA, compared with acontrol group. He reported that theresults were similar to those seen withsteroid injections. He used a current of2 to 4 mA progressed over a 20-minute treatment period. Similarly,Hasson and colleagues have reporteda delay in the onset of postacute exer-cise muscle soreness with the use ofdexamethasone iontophoresis,59 andan improvement in knee joint range ofmotion and a reduction in knee cir-cumference following dexamethasoneiontophoresis, applied using the sameprotocol as Berto1ucci.mOther glucocorticoids administered byiontophoresis have been used in thetreatment of patients with temporo-mandibular trismus and paresthesiab'and for Peyronie's disease.62

drug administered in this manner arerather small, the systemic effects oflidocaine are not seen. In certain con-ditions (eg, facial pain syndrome withtrigger points), the application of localanesthesia prior to administration ofthe corticosteroid appears to be bene-ficial. Because lidocaine and otherlocal anesthetics dilate blood vessels,however, they enhance their ownclearance from the tissues beingtreated, requiring the addition of adrug to constrict blood vessels andlocalize subsequent drugs to thetreated area. Ga n g ar ~s a~ ~eportedincreased depth of penetration andlonger duration of anesthesia whenepinephrine (epinephrine:total solu-tion dilution of 1:50,000)was coad-ministered with 2% lidocaine in ionto-phoresis. Recently, Silcox et a163confirmed that cutaneous vasoconstric-tion with iontophoresis enhanced theaccumulation of topically applied,radiolabeled compounds.Clinical applications Russo et aF4reported that lidocaine applied byiontophoresis was more effective forproducing skin anesthesia than whenit is applied by swabbing. Iontophore-sis, however, was not as effective asinjection.@Although these investiga-tors examined skin anesthesia forinjection or minor surgical procedures,they demonstrated that lidocaine had adeeper, longer-lasting effect whenapplied by iontophoresis than when itwas swabbed on. The method ofapplication could be a considerationwhen cutaneous anesthesia is used inphysical therapy to modulate kinesthe-sia from skin or superficial jointreceptors.

LidocaineEpinephrinePharmacology Lidocaine is an inject-

able, arnide-type local anesthetic thatis widely used in medicine and den-tistry. In its injectable form, it is ahydrochloride salt that dissociates intoa positively charged molecule. There-fore, lidocaine is applied iontophoreti-cally under the anode. When appliedin this manner, lidocaine producesdilation of blood vessels and a ratherprofound topical anesthesia of theskin, to depths of several millime-t e r ~ . ~ ~ , % - %ecause the amounts of

Epinephrine is the vasoconstrictormost widely used in conjunction withlidocaine. In dentistry, where the localanesthetic is injected, relatively smallamounts of the vasoconstrictor areused (eg, epinephrine:total solutiondilutions of 1:50,000-1:200,000, or0.02-0.005 mg/mL). In iontophoresis,higher concentrations are required toproduce sufficient vasoconstriction andto counteract the rapid deterioration ofepinephrine after it is mixed and ex-

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posed to oxygen, light, and bodytemperatures. Epinephnne acts onalpha- and beta-adrenergic receptorsthroughout the body, producing anumber of syrnpathmnimetic effectswhen administered ~ystemically.~5These effects are well known andinclude cardiovascular stimulation,elevations in blood glucose, and dila-tion of bronchioles. In some patients,even small amounts of epinephrinemay produce uncomfortable and po-tentially harmful side effects, such ascardiovas~ular timulation and palpita-tions, and this drug should not beused in such patients. Epinephnne isonly available in a water-soluble, in-jectable form and must be dilutedprior to use. Because epinephrine isalso positively charged in this form, itcan be administered along with lido-caine under the positive iontophoreticelectrode.istorical Uses iin PhysicalTherapy

Although use of lidocaine and dexa-methasone represents the majority ofclinical applications of iontophoresiscurrently used in physical therapy,there are reports on the use of othermaterials, particularly inorganic anionsand cations. Much of the historicalapplications of these are well surnrna-rized by Harris.'3 Other publishedreports are discusse:d in the followingsections. Readers must realize, how-ever, that most of these reports arepoorly substantiated or are reports ofclinical trials that lacked controls. Thereported results of these studies, there-fore, should be vie-wed with caution.HyalumnidaseHyaluronic acid, a gelatinous sub-stance that exists in, many body tis-sues, is a major constituent of theground substance of connective

tissue. It restricts dihsion of certainsubstances through the tissues. Hyalu-ronidase is an enzyme that hydrolyseshyaluronic acid, reducing its viscos-ity.66 Hyaluronidast?carries a positivecharge and migrates most rapidly at apH of 5.4. For these reasons, it isapplied in 0.1-mol/L solution with an

acetate buffer by iontophoresis to anedematous limb.&-GBHyaluronidase has been shown to beeffective in reducing acute66 andchroni@@ edema. It has also beenused to reduce joint swelling due tohemarthro~is.@.~9dditionally, Pop-kinG7 reported on two patients withscleroderma to whom he appliedhyaluronidase iontophoresis. Thesepatients improved by having increasedslun softness and flexibility and re-duced cold sensitivity.In spite of the apparent clinical effec-tiveness of hyaluronidase, we encour-age caution in its use because it isindiscriminate in breaking down theintercellular ground substance matrix.In so doing, it may open a path formfection or other toxins, and maydamage articular cartilage. Until furtherstudies support its safe use, we con-tend that hyaluronidase should not beused routinely as a component ofiontophoretic therapy. This caution,however, does not rule out the carefuluse of hyaluronidase in selected cases.

Two potent vasodilators, histamineand mecholyl (acetyl-beta-methyl-choline chloride), have been adrninis-tered by iontophoresis for a variety of~iisorders.~0-73ling and Sashin70 com-pared the eficacy of these two vasodi-lators and determined that mecholylproduced less vasodilation. They alsoused histamine iontophoresis for pa-tients with a number of conditions,particularly arthritis. The authors re-ported reduced pain and increasedrange of motion. Because there wasno change in joint swelling, it is possi-ble that the improvements noted werelargely due to pain modulation. Klingand Sashin also reported improvementin patients with conditions associatedwith vasospasm, such as Raynaud'sdisease.K o ~ a c s , ~ ~sing mecholyl, and laterAbrarnson et using histamine,reported enhanced healing of long-standing, trophic ulcers. More recently,DeHaan and Stark73 experimentedwith using histamine iontophoresis to

improve the viability of large, compos-ite skin grafts. Histamine enhancedvenous flow, but apparently did notimprove overall blood flow or theestablishment of new circulation thatwould allow the grafts to takesooner.Inorganic ationsInorganic cations carry a positivecharge and are delivered from theanode. Zinc has been used in thetreatment of patients with ischemiculcers, applied from a 0.1-moVL solu-tion of zinc In this case pre-sentation, zinc appeared to promotehealing and prevent infection.Silver ions were used in the treatmentof a series of patients with osteomyeli-tk75 The ions were from a silver wireelectrode, connected to the woundthrough saline-soaked gauze. Becausethis was a case report, however, therewere no controls to determinewhether the beneficial effects weredue to the use of silver ions or merelythe passage of a low-intensity directcurrent. Silver iontophoresis has alsobeen used with some success in thetreatment of patients with rheumatoidarthritis. 3Copper iontophoresis has been usedto treat chronic fungal mfections of thefeet.76A 0.2 solution of copper sul-phate was used. Most patients werecured, without recurrence of the infec-tion, following an average of six toseven treatments.Weinstein and Gordon77 eported onthe use of magnesium iontophoresisfrom a solution of 2 magnesiumsulphate in the treatment of a series of50 patients with subdeltoid bursitis.Thirty-four of the patients showedgood results (resolution of all clinicalsigns and symptoms and restoration offull active range of motion), and an-other 14 patients were improved. Theauthors felt that these results weresatisfactory, better than could beachieved by other methods available.Kahn78 reported a case study thatshowed improvement in a patient withgout following treatment with lithium

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iontophoresis. The rationale was thatthe lithium would replace the insolu-ble sodium urate in the joint withsoluble lithium urate. The patientreported hours of relief after the firsttreatment and complete relief afterfour weekly treatments. There was nochange in radiologic signs, althoughno gouty tophi developed and swell-ing was reported to decrease. Theauthor reported that previous, similarlytreated patients did demonstrate re-duction of tophi. Given the time pe-riod of the study, during which remis-sion is likely to occur, and that otherpain-reducing treatments were admin-istered, however, the conclusions canbe questioned.Inorganic nionsInorganic anions are administeredunder the cathode. Acetic acid ionto-phoresis has been described in casereports for the treatment of patientswith calcium deposits around theshoulder79 and for myositis ossdicansaffecting the quadriceps femoris mus-cle.80 In both case reports, the authorsreported resolution of the calciumdeposition, with reduction in symp-toms and improved function.CoyeP1 reported on the use of citrateiontophoresis for patients with anexacerbation of rheumatoid arthritisaffecting the hands. He used a 2solution of sodium citrate and re-ported increased grip strength in thesepatients, compared with similar con-trol groups treated with anodal orcathodal galvanism, with tap waterelectrodes.Salicylate ions from a 2 solution ofsodium salicylate have been shown tobe effective in treating a series of fivepatients with plantar warts.e2 Thewarts disappeared after two or threeweekly treatments.Iodide iontophoresis, using "Iodex"ointment, has been reported as usefulin the management of problems re-lated to scar tissue, such as Du-puytren's contracture,B3 and release ofscar adhesion of tendon to bone.*

Clinical pplications in OtherDisciplinesDentistryDentistry, probably to an even greaterextent than physical therapy, has usediontophoresis. Beginning in the late19th century, dentists applied localanesthetics to their patients prior tooral surgical procedures. Gangarosa85described the use of iontophoresis forthree basic applications in dentistry:(1) treatment of hypersensitive dentin(eg, in teeth sensitive to air and coldliquids) using negatively charged fluo-ride ions; 2) treatment of oral ulcers("canker sores") and herpes orolabialislesions ("fever blisters") using nega-tively charged corticosteroids andantiviral drugs, respectively; and (3)the application of local anesthetics toproduce profound topical anesthesia,as is done in some physical therapya p p l i ~ a t i o n s . ~ , ~ ~

A review of iontophoresis in dermatol-ogy was provided by Sloan andS ~ l t a n i . ~ ~any of the uses of ionto-phoresis discussed in this article arealso used in physical therapy anddentistry. Except for the use of lido-caine for anesthesia and the treatmentof patients with hyperhidrosis, how-ever, most uses of iontophoresis indermatology have largely been aban-doned. Iontophoresis with tap wateror anticholinergic compounds hasbeen used for the treatment of patientswith hyperhidrosis of the palms, feet,and a~illae.~9-9"In patients with bums, iontophoresisof antibiotics has been shown to bemore effective for treating superficial~nfectionshan systemically adminis-tered antibiotics that would not pene-trate eschar.95

Iontophoresis is a preferred methodfor obtaining anesthesia of the tym-panic membrane prior to simple surgi-cal procedures involving that struc-ture.Ns97 Iontophoresis of zinc has also

been used for the treatment of patientswith allergic rhiniti~.l3 9~OphthalmologyIontophoresis has been used experi-mentally to deliver antibiotics into theeye." The principal disadvantage ofthis technique is the time required fordirect contact of the electrode with theeye.Diagnostic pplicationsIontophoretic application of the drugpilocarpine produces intense sweating,allowing sufficient amounts of sweatto be collected and analyzed. This isnow accepted as the primary test inthe diagnosis of cystic f i b r o s i ~ . ~ ~ ~Conclusions and FuturepplicationsFor the reasons outlined by Chien eta1,2 he use of iontophoresis in medi-cine is likely to increase, because itoffers a convenient, safe, noninvasiveroute for the administration of manycompounds that are capable of pene-trating the skin, but are difficult toadminister in other ways. This appliesparticularly to the administration ofhormones and other polypeptidemedications.47.48 Other recent applica-tions are for the systemic managementof pain. Thysman and Preat,13 forexample, reported on the ionto-phoretic administration of fentanyl andsufentanil (opiate analgesics) in rats,with the production of analgesia forup to 4 hours. It is questionable towhat extent physical therapists will beinvolved in this expanded use of ion-tophoresis for the delivery of systemi-cally active drugs.

Miniaturized, unit-dose iontophoreticsystems may become available for thelong-term administration of medicallyuseful drugs that are effective at lowplasma concentrations and that wouldotherwise be ineffective or produceserious side effects i given orally or byinjection. The "minisets" would likelybe self-contained, with a built-in bat-tery. They would provide low currentlevels for sustained administration. Thecurrents may be pulsed to reduce skin

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irritation and charge accumula-ti0n,~, -50r the current may be re-versed intermittently, with the medica-tion in both electrodes, to providecontinuous administration while less-ening the pH changes associated withunidirectional fl0w.5~t may even bepossible for the patient to selectivelyapply different drugs from the sameiontophoretic delivery system (''Dial ADrugn).174 permeation enhancer willmost likely be used to reduce skinresistance and accumulation of thedrug in the skin. Much work, how-ever, still needs to be done to validatethe clinical efficacy of this form ofdrug administration.For most physical therapy applica-tions, we recommend treatment with acurrent of 4 rnA for 10 minutes. Thiscurrent is needed to penetrate into thedeeper tissues; treatment times greaterthan 10 minutes are not likely toachieve any greater tissue concentra-tion due to circulatory removal of themedication (possibly unless a vaso-constrictor were used). n electrodesystem that uses a silver or silver-silverchloride electrode would probably bethe most cost effective to minimize pHchanges.16In spite of the many years that ionto-phoresis has been used by physicaltherapists, very little has been done inthe way of research to demonstratethe efficacy of this treatment. Thereare strong indications that this treat-ment technique is clinically effective,but this effectiveness must be provenby controlled studies, both in theclinic and the laboratory. These stud-ies should include demonstration(where possible) of the ability of themedications to penetrate to the targettissues in sufficient quantity to producea clinical effect, as well as controlledtrials of clinical efficacy. There areseveral applications of iontophoresisthat have been used in the past andthat are believed based on clinicaljudgment and experience to be effec-tive. It would be worthwhile to subjectthese applications to scientific scrutinyin controlled trials to determinewhether they can meet the criteria ofbeing more clinically effective and cost

efficient compared with alternativetreatment techniques.

References1 Thomas CL, ed. Tubers Cyclopedic MedicalDictionary. 13th ed. Philadelphia, Pa: FADavis Co; 19773-47.2 Chien YW, Siddiqui 0 , Shi W-M, et al. Di-rect current iontophoretic transdermal deliveryof peptide and protein drugs. J Phann Sci.1989;78:376-383.3 Chien YW, Banga AK. lontophoretic (trans-dermal) delivery of drugs: overview of histori-cal development. J Phann Sci. 1989;78:35>354.4 Licht S. History of electrotherapy. In: LichtS, ed. Therapeutic Electricity an d UltravioletRadiation. New Haven, Conn: Elizabeth LichtPublisher; 1967:l-70.5 Mandleco CF. Application of Zontophoresisfor Noninvasive Administration of Lidocaine~ ~ d r o c h l o r i d en the Ionized FO . SaltLake City, Utah: University of Utah; 1978.Dissertation.6 Shriber WJ. A Manual of Electrotherapy. 4thed. Philadelphia, Pa: Lea Febiger; 1975:chap 11.7 O Malley EP, Oester YT Warnick EG. Ex-perimental iontophoresis: studies with radio-isotopes. Arch Phys Med Rehabil. 1954;35:500-507.8 Gangarosa LP ark N-H, Wiggins CA, HillJM. Increased penetration of nonelectrolytesinto mouse skin during iontophoretic watertransport (iontohydrokinesis). J PhannacolTher. 1980;212:377-381.9 Rein H. Experimentalle studien iiber elek-troendosmose an iiberiebender menschlicherhaut. Z Biol. 1924;81:124-130.10 Harpuder K. Electrophoresis in physicaltherapy. Arch Phys Ther X-Ray Radium . 1937;18:221-225.11 Harpuder K. Electrophoresis in physicaltherapy. N m York JMed . 1938;38:176-180.12 Praissman M, Miller IF, Berkowitz JM. Ion-mediated water flow, I: electroosmosis.JMe mbr Biol. 1973;11:139-151.13 Harris R. Iontophoresis. In: Licht S, ed.7bera peutic Electricity and Ultraviolet Radia -tion. New Haven, Conn: Elizabeth LichtPublisher; 1967:156-178.14 Tyle P. Iontophoretic devices for drug de-livery. Phannacol Res. 1986;3:318-326.15 Phipps JB, Padmanabhan RV, Lanin GA.Iontophoretic delivery of model inorganic anddrug ions. J Phann Sci. 1989:78:365-369.16 Sanderson JE, DeRiel S, Dixon R. Ionto-phoretic delivery of nonpept ide drugs: formu-lation optimization for maximum skin perme-ability.J Phann Sci. 1989;78:361-364.17 Behl C, Kumar S, Malick WA, et al. Ionto-phoretic drug delivery: effects of physiochemi-cal factors on the skin uptake of nonpeptidedrugs.J Phann Sci. 1989;78:355-360.18 Siddiqui 0 , Roberts MS, Polack AE. Theeffect of iontophoresis and vehicle pH on thein vitro permeation of lignocaine through hu-man stratum corneum. Phann Phannacol.1985;37:732-735.

19 Morton WJ. Cataphoresis or Electrical Me-dicam ental Surgery. New York, NY: AmericanTechnical Book Co; 1898.20 Abramson HA, Gorin MH. Skin reactions,MI: relationship of skin permeability to elec-trophoresis of biologically active materials intothe living human skin. Phys C h a . 1939;43:335-346.21 Abramson HA, Gorin MH. Skin reactions,IX. the electrophoretic demonstration of thepatent pores of the living human skin; its rela-tion to the charge of the skin. Phys Chem.1940;44:1094-1102.22 Abramson HA, Engel MG. Skin reactions,XII: patterns produced in the skin by electro-phoresis of dyes. Arch Dennatol Syphilol.1941;44:190-200.23 Grimnes S. Pathways of ionic flow throughhuman skin in vivo. Acta Denn Vmereol(Stockh). 1984;64:93-98,24 Burnette RR, Ongpipananakul B. Charac-terization of pore transport properties of ex-cised human skin during iontophoresis.J Phann Sci. 1988;77:132-137.25 Dobson RL Lobitz WC. Some histochemi-cal observations on the human eccrine sweatglands. Arch Dennatol Syphilol. 1957;75:653-666.26 O Malley EP, Oester YP. Influence of somephysical chemical factors on iontophoresisusing radio-isotopes. Arch Phys Med Rehabil.1955;36:310-315.27 Burnette RR Marrero D. Comparison be-tween the iontophoretic and passive transportof thyrotropin releasing hormone across nudemouse skin. JPha nn Sci . 1986;75:738-745.28 Gangarosa LP. Defining a practical solu-tion for iontophoretic local anesthesia of theskin. Methods Find E q Clin Phannacol. 1981;3:83-94.29 Abramson HA. Alley A. Mechanisms ofhistamine iontophoresis from aqueous media.Arch Phys Ther X-Ray Radiu m. 1937;18:327-333.30 Turrell WJ. The therapeutic action of con-stant current. Proc R Soc Med. 1920-1921;14(1-2):41-52.31 Turrell WJ. The action of the constant cur-rent with special reference to its action on thesubcutaneous tissues. Arch Radiol E lecttother.1922-1923;27:130-135.32 Challiol MM, Laquierriere. Action of theconstant galvanic current on tissues in healthand disease. Arch Radiol Electrother. 1922-1923;27:135-139,33 Finzi NS. Cited by: Turrell WJ. The thera-peutic action of constant current. Proc R SocMed. 1920-1921;14 1-2):41-52.34 Glass JM, Stephen RI acobsen SC. Thequantity and distribution of radiolabeled dexa-methasone delivered to the tissues by ionto-phoresis. Znt J Dermatol. 1980;19:519-525.35 Costello CT. Optim ization of Drug D eliv-ery With Zontophoresis.Houston, Tex: TexasWoman s University; 1993. Dissertation.36 Morton WJ. Guaiacol-cocaine cataphoresisand local anesthesia: a new cataphorecic elec-trode and the Wheeler fractional volt selector.Dental Cosmos. 1896;38:48-53.37 Druffel C, Fox A, Sabbahi M. Do jointreceptors change h e excitability of motorneurons. Phys Ther. 1986;66:796-797.Abstract.

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38 Sabbahi MA, Fox AM Druffle C. Do jointreceptors modulate motoneuron excitability?Electromyogr Clin Neuropbysiol. 1990;30:387-3 .39 Kahn J. Acetic acid iontophoresis forcalcium deposits. Pbys Ther. 1977;57:658-660.40 DeLacerda FG. A comparative study ofthree methods of treatment for shoulder girdlemyofascial syndrome.J Orrhop Sports PhysTher. 1982;4:51-54.41 Bertolucci LE. Introduction of anti-inflammatory drugs by iontophoresis: double-blind study.J O rtbop Sports Pbys Ther. 1982;4:103-108.42 Hams PR. Iontophoresis : clinical researchin n~usculoskeletal nflammatory conditions.J Orthop Sports Pbys Ther. 1982;4: 09-1 12.43 Molitor H Fernandez L. Studies on ionto-phoresis, I: experimental studies on thecauses and prevention of iontophoretic bums.Am J Med Sci. 1939;198:778-785.44 Lewis T, Zotterman Y. Vascular reactionsof the skin to injury, part VIII: the resistanceof the human skin to constant currents, in re-lation to injury and vascular response.J Pbysiol. 1926-1927;62:280-288.45 Leeming MN, Cole R Howland WS. Lowvoltage direct-current bums. JAMA. 1970;214:1681-1684.46 Okab e K, Yamaguchi H Kawai Y. Newiontophoretic transdermal administration ofthe beta blocker metoprolol. Journal of Con-trolled Release. 1986:4:79-85.47 Siddiqui 0 , Sun Y, Liu J-C, Chien YW. Fa-cilitated transdermal transport of insulin.J Pbarm Sci. 1987;76:341-345.48 Chien YW, Siddiqui Y, Shi WM, Liu JC.Transdermal iontophoretic delivery of thera-peutic peptides/proteins. Ann NYAcad Sci.1987;507:32-51.49 Burnette RR Bagniefski TM. Influence ofconstant current iontophoresis on the imped-ance and passive Naf permeability of excisednude mouse skin. J Pbarm Sci. 1988;77:492-497.50 Bagniefski TM, Burnette RR A comparisonof pulsed and continuous current iontophore-sis.Journal of Controlled Release. 1990;ll:113-122.51 Sabbahi MA Costello CT, Ernran A. Amethod for reducing skin irritation by ionto-phoresis. Pbys Ther 1 4;74(suppl):S156.Abstract.52 Su M-H, Srinivasan V, Ghanem A-H, Higu-chi WI. Quantitative in vivo iontophoreticstudies. J Pbarm Sci. 1994;83:12-17.53 Iorned Inc. Visualizing uneven DC currentdistribution by fiber electrodes. Pborum.1992:5.54 Petelenz TJ, Buttke JA, Bonds C, et al. Ion-tophoresis of dexamethasone: laboratory stud-ies. Journal of Controlled Release. 1992;20:5566.55 Bush RK Taylor SL, Holden K, et al. Prev-alence of sensitivity to sulphiting agents inasthmatic patients. Am JMed. 1986;81:816-820.56 Wingard LB, Brody TM, Larner J. SchwartzA. Glucocorticoids and other adrenal steroids.In: Human Pbanac ology . St Louis, Mo:Mosby-Year Book; 1991:484-493.57 Hong D, Byers MR, Oswald RJ. Dexameth-asone treatment reduces sensory neuropep-

tides and nerve sprouting reactions in injuredteeth. Pain. 1993;55:171-181.58 Bames PJ, Adcock I. Anti-inflammatoryactions of steroids: molecular mechanisms.Trends Pb an ac ol Sci. 1993;14:436-441.59 Hasson SM, Wible CL, Reich M, et al.Dexamethasone iontophoresis: effect on de-layed muscle soreness and muscle function.Can JSport Sci. 1992;17:8-13.60 Hasson SH, Henderson GH, Daniels JC,Scheib DA. Exercise training and dexametha-sone iontophoresis in rheumatoid arthritis: acase study. Physiotherapy Canada. 1991;43:11-14.61 Kahn J. Iontophoresis and ultrasound forpostsurgical temporomandibular trismus andparesthesia. Phys Ther. 1980;60:307-308.62 Rothfield SH, Murray W. The treatmentof Peyronie's disease by iontophoresis ofesterified glucocorticoids. J CTrol. 967;97:874-875.63 Silcox G, Parry G, Bunge A, et al. Percuta-neous absorption of benzoic acid across hu-man skin, 11: prediction of an in vivo, skinflap system using in vitro parameters. PbarmRes. 1990;7:352-358.64 Russo J, Lipman AG, Cornstock TJ, et al.Lidocaine anesthesia: comparison of ionto-phoresis, injection and swabbing. Am J HospPbarm. 1980;37:843-847.65 Weiner N. Norepinephrine, epinephrine,and the sympathomimetic amines. In: GilmanAG, Goodman LS, Rall TW Murad F eds.Goodman an d Gilman s The Pathologic Basisof Therapeutics. 7th ed. New York, NY: Mac-millan Publishing Co; 1985:145-180.66 Magistro CM. Hyaluronidase by iontophoresis in the treatment of edema. PbysTher. 1964;44:169-175.67 Popkin R. The use of hyaluronidase byiontophoresis in the treatment of generalizedscleroderma.JInues t De na to l . 1951;16:97-102.68 Schwartz MS. Use of hyaluronidase by ion-tophoresis in treatment of lymphedema. ArcbIntern Med. 1955:95:662-668.69 Boone DC. Hyaluronidase iontophoresis.Pbys Ther. 1969;49:139-145.70 Kling DH, Sashin D. Histamine ionto-phoresis in rheumatic conditions an d deficien-cies of peripheral circulation. Arcb Pbys TherX-rav Radium. 1937;18:333-338.71 Kovacs J. Iontophoresis of varicose ulcers.Arcb Phys Ther X-ray Rad ium. 1937;18:103-106.72 Abramson DI, Tuck S, Chu LS Buso E.Physiologic and clinical basis for histamineiontophoresis. Arcb Pb-ys Med Rebabil. 1967;48:583-591.73 DeHaan CR, Stark RB. Changes in efferentcirculation of tubed pedicles and in the trans-plantability of large composite grafts producedby histamine iontophoresis. Plast ReconsaSurg. 1961;28:577-583.74 Comwall MW. Zinc iontophoresis to treatischemic skin ulcers. Pbys Ther. 1981;61:359-360.75 Becker RO, Spadaro JA. Treatment of or-thopedic infections with electrically generatedsilver ions. J Bone Joint Surg /A m/. 1978;60:871-881.76 Haggard HW, Strauss MJ, Greenberg LA.Fungous infections of the hands and feet

treated by iontophoresis of copper. JAMA.1939;112:1229-1232.77 Weinstein MV, Gordon A. The use of mag-nesium sulphate iontophoresis in the treat-ment of subdeltoid bursitis. Pbys Ther Rev.1958;38:96-98.78 Kahn J. A case report: lithium iontophore-sis for gouty arthritis. J Orthop Sports PhysTher. 1982;4:113-114.79 Kahn J. Acetic acid iontophoresis forcalcium deposits. Pbys Ther. 1977;57:658-660.80 Wieder DL. Treatment of traumatic myosi-tis ossificans with acetic acid iontophoresis.Pbys Ther. 1992;72:133-137.81 Coyer AB. Citrate iontophoresis in rheu-matoid arthritis of the hands. Ann Pbys Med.1955;2:16-19.82 Gordon AH Weinstein MV. Sodium salicy-late iontophoresis in the treatment of plantarwarts. Pbys Ther. 1969;49:869-870.83 Kovacs R. Electrotherapy an d Light Ther-a p y . 3rd ed. Philadelphia, Pa: Lea Febiger;1938: chap X.84 Tannenbaum M. Iodine iontophoresis inreducing scar tissue. Pbys Ther. 1980;60:792.85 Gangarosa LP. Iontophoresis in DentalPractice. Chicago, Ill: Quintessence PublishingCO; 198317-20.86 Gangarosa LP. Iontophoresis in pain con-trol. Pain Digest. 1993;3:162-174.87 Henley-Cohn T, Hausfeld JN. Ionto-phoretic treatment of oral herpes. h r y n g o -scope. 1984;94:118-121.88 Sloan JB, Soltani K. Iontophoresis indermatology: a review. Am Acad Dermatol.1986;4:671-684.89 Grice K, Sattar H, Baker H. Treatment ofidiopathic hyperhidrosis with iontophoresis oftap water and poldine methosulphate. BrJDermatol. 1972;86:72-78.90 Abell E Morgan K. The treatment of idio-pathic hyperhidrosis by glycopyrronium bro-mide and tap water iontophoresis. B r J D e r -matol. 1974:91:87-90.91 Shrivastava SN, Singh G. Tap water ionto-phoresis in palmo-plantar hyperhidrosis. Br JDermatol. 1977;96:189-195.92 Morgan K. The technique of treating hy-perhidrosis by iontophoresis. P b y s i o t b e r a ~ .1980;66:45.93 Midtgaard K. A new device for the treat-ment of hyperhidrosis by iontophoresis. BrJDermatol. 1986;114:48 488.94 Akins DL, Meisenheimer JL, Dobson RL.Efficacy of the Drionic unit in the treatment ofhyperhidrosis. J Am Acad De na to l . 1986;16:828-832.95 Rapperport AS, Larson DL, Henges DF,et al. Iontophoresis: a method of antibioticadministration in the bum patient. Plast Re-constr Surg. 1965;36:547-552.9 Comeau M, Brummett R, VernonJ. Localanesthesia of the ear by iontophoresis. ArcbOtolaryngol. 1973;98:114-120.97 Echols DF, Noms CH, Tabb HG. Anesthe-sia of the ear by iontophoresis of lidocaine.Arcb Otolaryngol. 1975;101:418-421.98 Vaudin J. Ionization and rhinitis. Physio-therapy. 1973;59:222.

Fellner R, Glawogger F. Penicillin-iontophoresis in der augenheikunde. KlinMontasbl Augenbeilkd. 1972;160:300-303.

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100 Gibson LE Cooke RE. A test for con-centration of electrolytes in sweat in cysticfibrosis of the pancreas utilizing pilocarpineby iontophoresis. Pediatrics 1959;23:545-549.101 Shwachman H Mahmoodian A. Pilo-carpine ionrophoresis sweat testing: results of

seven years exper ience. Bihlio Pediatr 1967; 103 Thysman S Preat V. In vivo iontophore-86:158-182. sis of fentanyl and sufentanil in rats: phama-102 Report o the Committee for a Study for cokinetics and acute antinociceptive effects.Evaluation of Testing for Cystic Fibrosis. Anesth Analg 1993;77:61-66.Pediatr 1976;88:711-750.

P H A R M A C O L O G YFor an in-depth understanding of howmedications influence your patient s I Bv PHONE all 1-800/999-2782, ext 3395, Monday-Fri-day between 8:30 am and 5:30 pm Eastern time. Pleasehave your Mastercard or VISA information ready.

I Bv FAX Fax a copy of this coupon to 703/706-3396.This collection of 13 articles, from a two-part BV E MAIL:-mail your order and credit card informationspecial series published in Physical Therapy, I to US via Internet:SVCCTR@APTA ORG

such as iontophoresis and phonophoresis; phar- clrvmacologic techniques used to manage pain and DAMIME PHONEreflex activity; and practice issues related to the nEc Em os Eo PAvABLr To APTA o MASTERCARD ISAprescription of medications by therapists in a CREDIT ARDGUESTDITED BY CICCONE, ITH 3 CONTRIBUTORS.APPROXIMATELY32 PACES, 3 ARTICLES, 1995 .

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1995; 75:554-563.PHYS THER.Charles T Costello and Arthur H JeskeMedication DeliveryIontophoresis: Applications in Transdermal

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