REVIEW
Iontophoresis: An Overview of the
Mechanisms and Clinical Application
Linda C. Li and Roger A. Scudds
HISTORY OF IONTOPHORETIC
DRUG DELIVERY
The biomedical application of electricity can be
traced back to the Golden Age of Greek civilization.
According to Chien and Banga [l], shocks of the Tor-
pedo fish were prescribed by the Greek physician &tius
for the treatment of gout at that time. However, the
value of electricity in the medical field was not rec-
ognized until the mid-eighteenth century. Static elec-
tricity, the major source of medical electricity at that
time, was used in various conditions, such as muscle
weakness and paralysis, arthritic conditions, mental
illnesses, and many more [Z].
After the discovery of direct current (DC] by Luigi
Galvani in 1791 [l],attention focused on the possibility
of using electricity as a mode of drug delivery. It had
long been known that medicines could be introduced
into the human body by way of the skin. This tech-
nique is known as transdermal drug delivery (TDD].
Massage, inunction (an act of rubbing an oily sub-
stance into the skin], and moxa (a mode of TDD that
involves burning dried leaves of Asian medical herbs
[3]) are examples of the older forms of TDD [4].
Although clinicians have a considerable amount of
experience with the practice of traditional TDD, not
all drugs can be delivered in this manner due to the
unique structure of human skin. The skin has a selec-
Linda C. Li, BSc (PT), MSc, is from the Arthritis Society and the
Department of Physical Therapy; Roger A. Scudds. PhD. PT, is an
Assistant Professor of the Department of Physical Therapy, The
University of Western Ontario, London, Ontario, Canada.
Address correspondence to Roger A. Scudds, PhD, PT, Depart-
ment of Physical Therapy, Elborn College, The University of West-
ern Ontario, London, Ontario N6H 1H1,Canada.
Submitted for publication December 14, 1993;accepted October
4,1994.
0 1995 by the American College of Rheumatology.
0893-7524/95/$5.00
tive permeability to lipophilic (lipid soluble] chemi-
cals, and acts as a barrier to hydrophilic (water soluble]
substances. This affects the practicality of TDD
because many drugs, such as corticosteroids and non-
steroidal anti-inflammatory drugs (NSAIDs], are hy-
drophilic. Thus, local administration of anti-inflam-
matory agents was not a favorable treatment for
rheumatoid arthritis (RA] and other musculoskeletal
conditions. In 1747, Veratti suggested that hydrophilic
drugs might be introduced to the subcutaneous tissue
through human skin by the application of a direct
current [l]. This mode of TDD is known as iontopho-
resis (meaning ion transfer).
Iontophoresis has been used frequently in dentistry
[5]and dermatology [6,7] for the delivery of a variety
of drugs. It has also been suggested that iontophoretic
delivery of anti-inflammatory drugs may be an effec-
tive treatment for acute and chronic musculoskeletal
conditions (8-151. Table 1shows a list of ions that have
been used by practitioners in iontophoresis treatments
for various pathological conditions.
The purpose of this paper is to discuss the mecha-
nisms of iontophoresis and to explore its application
in RA and other musculoskeletal conditions. First, the
structure of human skin and its effect on TDD will be
discussed. Next, a brief review on the physics of ion-
tophoresis will be presented. Then the possible routes
of iontophoretic drug delivery will be discussed. Some
factors that may affect the efficiency of iontophoresis
will also be examined. Finally, a critical review of the
literature on iontophoresis and its use in inflammatory
conditions will be given.
THE EFFECTS OF SKIN STRUCTURE ON
TRANSDERMAL DRUG DELIVERY
The skin is a multicomponent, multifunction organ
that is involved in the body’s interaction with, and
51
52 Li and Scudds Vol. 8,No.1, March 1995

TABLE 1
A Partial List of Suitable Ions for Iontophoresis

D w Polarity Solution Condition Reference

1. Acetic acid Negative 2% Solution Myositis ossificans [50,511

2. Aspirin Negative 1.8 g/5 ml Lysine soluble aspi- Rheumatic diseases ~ 4 1
rin
3. Dexamethasone and Negative/positiveO 4 mg/ml Dexamethasone sodi- Tendinitis, bursitis, shinsplints, [8-10,15,45,46,49]
lidocaine um phosphate, 4% lidocaine rheumatoid arthritis
hydrochloride
4. Dexamethasone and Negative/positive" 4 mg/ml Dexamethasone sodi- Delayed muscle soreness Pi1
lidocaine um phosphate, 4% lidocaine
hydrochloride
5. Diclofenac sodium Negative 150 mg Solution Scapulo-humeral periarthritis,
elbow epicondylitis
6. Iodine Negative "Iodex"ointment Fibrosis, adhesions, scar tissue,
trigger finger
7. Lidocaine Positive 4% Lidocaine hydrochloride Local anesthesia
8. Lithium Positive 2% Lithium chloride solution Gouty arthritis
9. Morphine Positive - Postoperative analgesia
10. Pilocarpine Positive - Sweat test (cystic fibrosis)
11. Pirprofen Negative 400 mg/4 ml Solution Rheumatic diseases
12. Potassium citrate Negative 2% Solution Rheumatoid arthritis
13. Potassium iodide Negative 10% Solution Scar tissue
14. Silver Positive - Chronic osteomyelitis
15. Salicylate Negative 2% Sodium salicylate solution Plantar warts, scar tissue
16. Sodium fluoride Negative 2% Solution Tooth hypersensitivity
17. Water Positive/negative Tap water Hyperhidrosis

Dexamethasone sodium phosphate has a negative charge, and lidocaine hydrochloride has a positive charge.

adaptation to, the environment. It is composed of the
dermis and epidermis [16]. The dermis makes up the
lower level of the skin and constitutes the majority of
the skin mass. The thickness of the dermis varies from
1 mm on the scalp to 4 mm on the back. Blood vessels,
lymphatic vessels, nerve endings, hair follicles, se-
baceous glands, and sweat glands are all located in
the dermis. The latter three structures open directly
into the environment at the skin surface and provide
entry for substances that are administered topically.
The epidermis is the superficial layer of skin and pro-
vides the outer covering of the body. In humans, the
epidermis ranges from 0.075 to 0.15 mm in thickness,
except on the palm and the sole where it can be up
to 0.6 mm thick [16].
The epidermis has four distinct layers [16]. The out-
ermost cornified layer, or stratum corneum, is a mul-
ticellular, metabolically inactive surface layer of the
skin. In its nonhydrated state, the stratum corneum is
about 10 pm thick. It contains 10 to 15 layers of flat-
tened, stacked cells called corneocytes. The corneo-
cytes are the intact remains of the cells once found in
the other three layers of epidermis [17].
The stratum corneum has a unique biochemical
structure. It has a water content of about 20% as com-
pared with the 70% in most physiologically active tis-
sues [I]. The corneocytes are mainly composed of the
protein fibrils keratin and filaggrin. These protein sub-
stances form a network that provides cell integrity.
This is in contrast to the typical plasma membrane,
which requires lipid for structural integrity [16].Within
the cell envelope and between the cells, the corneo-
cytes are separated by free fatty acids [16,18]. This
creates a lipid-rich environment in the stratum cor-
neum, and thereby allows it to be an effective barrier
to water and other ionic substances. Thus, water can
be kept within the body and foreign compounds are
kept outside the body [19].
The unique structure of the skin has caused some
problems in TDD. Many lipophilic drugs, such as sco-
polamine for motion sickness, clonidine for hyperten-
sion, and nitroglycerin for the treatment of angina, can
be readily delivered through human skin. With these
drugs, the concentration gradient between the drug-
loaded reservoir and the body is sufficient enough to
drive the drug through the skin at therapeutic dosage
rates [2O]. However, this is not the case for hydrophilic
drugs.
Delivery of Hydrophilic Drugs
Because topical application fails to deliver thera-
peutic dosages of hydrophilic drugs, more traditional
Arthritis Care and Research
Figure 1. Movement of ions in an electrolytic solution. A,
direction of electron flow; B, battery; C, cathode (-); D,
anode [ +); E, electrolytic solution.
methods, such as oral drug delivery, have been fa-
vored. However, these methods have several disad-
vantages. First, systemic administration leads to mas-
sive “first-pass” inactivation of the drugs as a result
of the enzymatic action of the liver [20,21]. Also, oral
drug administration can cause peaks and valleys in
the concentration of the drug in the systemic circu-
lation. This may in turn result in toxic or subthera-
peutic blood levels of the drug [l].
These problems can be counteracted by the use of
iontophoresis. Using electric current as an external
driving force, hydrophilic drugs can be readily intro-
duced through the epidermal level. This technique
greatly reduces the first-pass hepatic inactivation and
provides more constant blood levels [22]. Also, ion-
tophoresis allows for continuous administration of
drugs for a long period (up to 4 days [23]). Thus, drugs
with short half-lives are well suited for iontophoresis
[201.
MECHANISM OF IONTOPHORESIS
Physics
Distilled water is not a good conductor of electricity
because it only has small number of charged ions.
However, when inorganic salts, such as acids, bases,
salts, or alkaloids, are dissolved in water, the sub-
stances dissociate into charged ions. This process is
known as ionization. The resulting solutions become
conducting liquids called electrolytes [8,24].
Electric current passes through an electrolytic so-
Iontophoresis 53
lution by way of ion migration. This phenomenon is
known as electrolysis. When two electrodes are placed
in an electrolytic solution, the positive ions will be
attracted to the negative electrode, and the negative
ions to the positive pole (Figure 1). This observation
follows the basic principle of physics, that is, “like
poles repel, and unlike poles attract” [25]. this is also
applicable to iontophoresis. During the passage of
electric current, positively or negatively charged drug
particles are repelled into the skin by an identical
charge on the electrode surface placed over it.
Various types of drugs are potential candidates for
iontophoresis. Hydrophilic drugs with relatively low
molecular weight are the most suitable for the pro-
cedure, although the delivery of some large peptides
and hormones by this technique has also proven to be
successful [1,26,27].Once the drug ions reach the sub-
dermal level, they form a new compound by combin-
ing with existing ions and radicals floating in the
bloodstream. This new compound will then provide
the desired therapeutic action in the underlying tissue
The Choice of Current
Direct current, or galvanic current, is the current of
choice for iontophoresis. DC is defined as a continu-
ous, unidirectional current. Theoretically, DC allows
the maximum ion transfer per unit of applied current,
because its course is uninterrupted [24]. Therapeutic
DC can be obtained from battery-powered units. Most
of the commercial available units deliver a constant
current. According to Ohm’s law:
V = IR,
(Eq. 1)
where V = voltage, I = current, and R = resistance,
the voltage generated within the system is therefore
dependent on the resistance of the skin during the
treatment.
It should be remembered that the actual iontopho-
retic treatment is provided by the drug ions introduced
into the subcutaneous tissues, instead of the direct
current itself. The selection of ions and the use of
correct polarity for the delivery electrode are therefore
crucial factors for successful treatment.
Possible Routes of Ionic Transport
The pathway of skin penetration during iontopho-
retic drug delivery is obscure. Two dominant theories
have been postulated to account for this. These are
the shunt pathway theory and the “flip-flop gating
mechanism.”
The Shunt Pathway Theory. It has been suggested
by many investigators that penetration of hydrophilic
54 Li and Scudds
substances occurs mainly by way of sweat ducts, se-
baceous glands, and perhaps hair follicles and im-
perfections in the skin [26,29-321. Abramson and Gorin
[29] and Burnette and Marrero [26] have shown that
iontophoresis of ionic dyes, such as methylene blue,
results in the development of a blue dot pattern on
the epidermal surface. They conclude that the dye
migrates through the skin via sweat and sebaceous
glands. These routes are known as the “shunt” path-
way.
Numerous studies have investigated the role of the
shunt pathway. Although many have demonstrated
support for this theory, several factors may have in-
fluenced the findings. The first is the choice of chem-
icals. In order to make the pattern of delivery easily
observable, dyes were used in many in vivo human
studies [26,29,30]. A few studies also used other drugs,
such as thyrotropin-releasinghormone [26] and insulin
[31], to examine the pathways of ionic flow. Although
the results are generally supportive of the presence of
the shunt pathway, this does not rule out the possibility
that some chemicals can be delivered through the cel-
lular structure of the stratum corneum.
Secondly, many studies employed in vitro models
[26,32]. A two-compartment diffusion cell model was
commonly used. The apparatus consists of a donor
compartment,which contains the drug to be delivered,
and a receptor compartment, which is filled with nor-
mal saline. The excised skin (usually consisting of all
of the epidermis and part of the dermis) is secured
between the two compartments, with the stratum cor-
neum facing the donor side, and the dermis facing the
receptor side. Two electrodes are placed in either com-
partment, and the polarity of the electrodes is deter-
mined by the charge of the drug. This arrangement is
different from that of therapeutic iontophoresis, in
which both electrodes are placed on the epidermal
side. Therefore, the results of the in vitro studies are
questionable.
Finally, the choice of skin samples is also an im-
portant factor in the elucidation of this theory. Opti-
mally, skin uptake research should employ a human
in vivo model. However, this is not a practical ap-
proach. To deal with this problem, many investigators
replace human skin with cadaver skin 1321 or animal
skin [26,31]. According to Behl et al. [33], the most
suitable animal for passive skin uptake studies is be-
lieved to be the hairless guinea pig. As compared to
the furry animals, the skin of hairless animals shows
more resemblance to the structure of human skin, be-
cause they also have some residual hair follicles in
the skin [34]. Much less is known about appropriate
animal models for iontophoretic studies, in contrast to
passive skin uptake trials. A suitable animal for ion-
tophoretic trials has not yet been identified.
Vol. 8, No. 1, March 1995
In summary, the shunt pathway theory suggests that
during iontophoresis,drugs are introduced through the
skin by way of glands, follicles, and/or imperfections
in the skin structure. The results of several studies
supported this theory. However, they have not ruled
out the possibility that ion transfer can take place
through alternative pathways.
The “Flip-flop Gating Mechanism.” It has been sug-
gested that the permeability of skin may be altered as
a result of the application of an electric potential across
the skin [1,27]. This evolved from the findings of Jung
et al. in 1983 (351.These investigatorsstudied the ability
of several natural and synthetic polypeptides to induce
potential-dependent pores in lipid bilayer mem-
branes. They found that the only structural require-
ment for pore formation was the presence of alpha-
helical polypeptides.
Jung et al. [35] suggested that during the noncon-
ducting state, the alpha helices of the polypeptides of
physiological membranes attract and arrange them-
selves in an antiparallel fashion within the lipid bi-
layers. This is a result of the strong dipole moments
of the protein molecules. However, when an electric
potential is applied across the membrane, a voltage-
dependent “flip-flop” of the helices occurs. This caus-
es a rearrangement of the helices to a parallel fashion.
All the partially negatively charged oxygen is then
attracted to the positive site of the membrane. This
leads to repulsion between the neighboring dipoles
within the structure of the polypeptides. In this man-
ner, voltage-dependent pores are formed.
The “flip-flop gating mechanism” is strongly sup-
ported by Chien and Banga [l]and Chien et al. [27],
who believe it could be the operating model in the
voltage-dependent pore formation in the stratum cor-
neum. It has already been mentioned that the stratum
corneum is rich in keratin, which is an alpha-helical
polypeptide. Therefore, it is possible that skin per-
meability can be enhanced by the formation of “ar-
tificial shunts” by the use of DC during iontophoresis.
However, the existence and the effect of voltage-de-
pendent pores during ion transfer has not yet been
determined. Further research to examine this theory
is warranted.
FACTORS AFFECTING
IONTOPHORETIC DRUG DELIVERY
Compared to drug delivery by passive absorption,
iontophoresis has received considerably less attention
with respect to understanding of its operational mech-
anism. Whereas work has been done to identify and
to understand the factors affecting this mode of drug
Arthritis Care and Research
TABLE 2
Factors that Affect Iontophoretic Skin Permeation
1. Drug lipophilicity and molecular weight
2. Current density
3. Skin impedance
4. Ion mobility/conductiivty
5. Ionic valance
6. pH of the drug solution
7. State of ionization
8. Duration of iontophoresis
9. Effect of iontophoresis on drug metabolism and degradation in
the skin
10. Concentration of the drug ion in the solution
uptake, only a limited level of understanding has been
attained [33]. A list of factors that may affect ionto-
phoretic drug delivery is provided in Table 2. Some
of these factors will be discussed briefly in the follow-
ing sections.
Size of the Ions
A few studies have examined the effect of molecular
size on iontophoretic drug delivery, with conflicting
results. Some investigators agree that the delivery ef-
ficiency of drugs, which is defined as the fraction of
all ions that cross the skin that are drug ions [36],
decreases with increasing molecular weight (MW).
Using a two-compartment diffusion cell, Phipps et al.
[ZO] examined the delivery efficiency of lithium (MW
= 6.9 g/mol), pyridostigmine (MW = 181 g/mol), and
propranolol (MW = 260 g/mol) across excised human
cadaver skin. Their results showed that the delivery
efficiency of lithium (32.2%) is the highest of the three
ions (pyridostigmine = 21.770, propranolol = 4.8%).
Similar results were found when studying the effi-
ciency of delivering sodium, magnesium, potassium,
and calcium across pig skin (Table 3).
In contrast to these findings, Siddiqui et al. [37] sug-
gested that the molecular weight of a drug does not
influence the rate of delivery by iontophoresis. In their
in vitro study, the steady-state flux of drug delivery
was evaluated. Steady-state flux is defined by Siddiqui
et al. [38] as “the slope of the linear portion of the plot
of cumulative amount (of the drug] permeated against
time.” Human skin, which was removed from the mid-
abdominal region of a male Caucasian cadaver within
48 hours of death, was used. Seven radiolabeled weak
electrolytes (salicylic acid, aspirin, ephedrine hydro-
chloride, pilocarpine hydrochloride, chlorpromazine
hydrochloride, chlorphreniramine maleate, and meth-
otrexate) were studied. They found the steady-state
flux to be largely affected by the amount of ions present
in the drug solution. However, the resuIts were not
influenced by the molecular weight of the drugs.
lontophoresis 55
TABLE 3
Summary of the Efficiencies of Drug Delivery for
Migration of Cations from 1.0 M Aqueous Solution
Through Excised Pig Skin
Molecular Delivery
weight efficiency
Ion Charge (g/molI ( 7 0 ) (SDI
Sodium +1 23.0 42.5 (3.1)
Magnesium +2 24.3 16.8 (1.3)
Potassium +1 39.1 39.6 (4.3)
Calcium +2 40.1 18.4 (3.0)
Data from this table were taken from Phipps et al. [36].
Based on the research cited above, it is difficult to
reach any conclusion regarding the effect of the mo-
lecular weight on iontophoretic drug delivery. The
differences in study methodologies and outcome mea-
sures are the major confounders. The types of skin
and drug solution, the current parameters, and the
method of obtaining measurements are some of the
factors that lead to difficulties in comparing the study
results.
Ionic Charge
Ionic charge, or valence, is the number of unpaired
electron(s) that determines the bonding and chemical
behavior of an atom. Only a few studies have exam-
ined the effects of ionic charge of drug molecules on
iontophoretic drug delivery. Phipps et al. [20,36] com-
pared the delivery efficiency of four ions of similar
size but different ionic charges (Table 3). They found
that monovalent molecules can be delivered more
readily than divalent molecules, even when their mo-
lecular weights were similar. This suggests that di-
valent ions may interact more strongly with charged
sites in the skin than do monovalent ions. Thus, di-
valent molecules may migrate more slowly.
Current Parameters
The current parameters required for iontophoretic
drug delivery are still speculative. Most of the ionto-
phoretic units that are available for clinical use op-
erate in a constant DC mode. The current parameter
of a treatment is measured in units called coulombs.
A coulomb is the quantity of electricity that is defined
as the product of current and time [39]:
quantity of electricity (coulombs)
= current (ampere) x time (seconds) (Eq. 2)
Many different parameters have been employed in
iontophoresis research, but the optimal parameters for
56 Li and Scudds Vol. 8, No. 1, March 1995

TABLE 4
A Summary of Studies on Iontophoresis in Musculoskeletal Inflammatory Conditions
~ ~~ ~~ ~~ ~~

Treatment and
Condition and number of subjects Outcome
Authors sample size Per group (4 variables Results

Bertolucci 191 0 Infraspinatis (7)
0 Supraspinatis (5)
Adhesive capsulitis (10)
Bicepital tendonitis (9)
0 Lateral epicondylitis (7)
0 Sacrolitis (6)
0 Others (9)
Delacerda Shoulder girdle myofascial
[491 syndrome (23)
Harris [8] Lateral epicondylitis (26)
0 Subacromial bursitis (5)
0 Bicepital tendonitis (9)
0 Anterior talofibular liga-
ment strain (2)
Patellar tendonitis (3)
Kahn [48] 0 Gouty arthritis (1)
Delacerda 0 Shinsplint (12 subjects, 18
[lo1 shinsplint cases)
Vecchini an- 0 Scapulo-humeral periar-
Grossi [13] thritis (12)
0 Elbow epicondylitis (12)
1. DEX & LID iontopho- 1. Pain 0 Twelve subjects in the DEX & LID
resis (n = 38) 2. Anterior flexion group reported “excellent” im-
2. NaCl iontophoresis of shoulder provement in pain and ROM.
(placebo) (n = 15) Six subjects reported “good” im-
provement
Subjects in the placebo group rat-
ed “poor” in both outcomes
1. DEX & LID iontopho- Pain-free ROM of No more than 10 treatments were
resis (n = 8) shoulder abduc- given to each subject
2. Hot packs and ultra- tion The DEX and LID group gained
sound (n = 8) full ROM on day 8 (average =
3. Antispasmodic and 120”). No subject reported pain
analgesic drugs by day 9.
(placebo) (n = 7) The group that received hot pack
and ultrasound showed some
improvement in ROM (average
= 105”).Two subjects reported
pain by day 10.
The placebo group showed little
improvement in ROM (average
= 68”).Three subjects reported
pain by day 10.
DEX and xylocaine ion- 1. Active ROM 0 75% of the subjects reported “ex-
tophoresis (n = 50) 2. Pain, swelling cellent” or “good” improvement
and tempera- in all three areas
ture 0 14% of the subjects reported pain
relief, and increase ROM and
3. Function
function
0 11%showed little or no relief of
symptoms
Lithium chloride ionto- Patient’s subjec- 0 Complete absence of pain on
phoresis (n = 1) tive report of weight bearing and ambulation
pain intensity after four treatments
1. Hydrocortisone ionto- Pain No more than 10 treatments were
phoresis (9 cases) given to each subject
2. Xylocaine iontophore- The hydrocortisone group reported
sis for the first complete pain relief after re-
three treatments, ceiving an average of 3.05 treat-
and hydrocortisone ment
iontophoresis for 0 The xylocaine group reported 1to
the rest of the treat- 6 hours of pain relief after each
ments (9 cases) treatment, but it returned to the
original intensity prior to the
next treatment
1. Declofenac sodium 1. Pain at rest, on 0 The diclofenac group showed a
iontophoresis (n = pressure and significant improvement in all
11) on movement the outcomes
2. NaCl iontophoresis 2. Functional im- The placebo group showed a sig-
(placebo) (n = 13) pairment nificant improvement in pain on
3. Swelling pressure and on movement, no
improvement in pain at rest and
swelling
Arthritis Care and Research Iontophoresis 57

TABLE 4
Continued

Treatment and
Condition and number of subjects Outcome
Authors sample size Per group (nl variables Results

Garagiola et al. Rheumatic diseases of var- 1. Pirprofen iontophore-
ious joints (SO] sis (n = 40)
2. Lysine soluble aspirin
iontophoresis (n =
401
Hasson et al. 0 RA of knees (11 1. DEX and LID ionto-
[461 phoresis (L side]
2. LID iontophoresis
(control] (R side]
Hasson et al. RA of knees (1) Phase 1: DEX & LID
~ 5 1 iontophoresis in L
knee, LID iontophore-
sis in R knee
Phase 2: DEX & LID
iontophoresis in both
knees
Phase 3: DEX & LID
iontophoresis com-
bined with an exercise
program for both
knees
1. Pain Significant improvements in pain
2. Function at rest and on movement were
3. Global efficacy reported after five treatments in
of treatment both groups. No significant dif-
ference was found between the
two groups.
0 80% improvement in function in
both groups
75% of the subjects in both groups
rated “excellent” or “good” in
global efficacy of treatment
1. Peak torque of Peak torque increased by 20.8% in
knee exten- the L knee and decreased by
sion 6.7% in the R side
2. Angular veloci- Angular velocity increased by
ty of knee ex- 22.3% in the L knee and 9.4%
tension in the R side.
3. Total work of 0 Total work increased by 54.0% in
knee exten- the L knee and 11.8% in the R
sion side
1. Maximum knee MKET Phase 1-decreased 3.5
extension Nm in R side, increased 5.2 nm
torque in L side. Phase %--increased an
(MKET) extra 7.9 nm in R side, and 1.3
2. Active ROM nm in L side. Phase 3-in-
creased 11.2 nm in L side and
3. Mid-patellar
circumfer- 13.6 nm in R side.
ence (MC) 0 Active ROM: Phase 1-increased
7“ in R side, 1l0 in L side. Phase
4. Cardio-
respiratory 2-increased 5” in R side, 0“ in
endurance L side. Phase %-increased an
extra 20 in both sides.
(VO, max)
0 MC: Phase 1-decreased 1 cm in
R side, 2.5 cm in L side. Phase
2-decreased an extra 5 cm in R
side, 4 cm in L side. Phase 3-
no change in both sides.
0 VO, max: Phase 1-increased 0.5
ml/kg/minute. Phase 2-in-
creased an extra 0.4 ml/kg/min-
ute. Phase 3-increased 4.1 ml/
kg/minute.

DEX, dexamethasone sodium phosphate: LID. lidocaine hydrochloride:RA. rheumatoid arthritis. L, left: R, right: ROM, range of motion.

the delivery of individual ions have not yet been es-
tablished. Therapeutically, a current density of less
than 1 mA per square inch of electrode surface is
recommended [24]. This is based on two criteria: (1)
the current is sufficient to provide a desired delivery
rate, and (2) the current does not produce any harmful
effects on the skin [33]. However, whether the rec-
ommended current density truly meets these two cri-
teria has not been extensively explored.
The effects of various current intensities on corti-
costeroid iontophoresis were investigated by Tu and
Allen [40]. Using a two-compartment diffusion cell,
they examined the permeability of ionizable [dexa-
methasone sodium phosphate [DEX], hydrocortisone
58 Li and Scudds
sodium succinate, and prednisolone sodium succinate)
and nonionizable corticosteroids (cortisone acetate]
through a synthetic membrane. Five current intensities
[O, 0.2, 0.4, 0.6, and 0.8 mA] were employed. The con-
centration of each drug in the receptor compartment
was measured every 5 minutes, over a 30-minute pe-
riod. They found that the enhancement of transmem-
brane permeation of the ionizable steroids was pro-
portional to the increase in current intensity. However,
iontophoresis did not increase the permeability of cor-
tisone acetate. These findings are in accord with Far-
aday’s First Law of Electrolysis, which states that
the mass of a substance liberated at (or dissolved from)
an electrode during electrolysis is directly proportional
to the quantity of electricity passed through the elec-
trolyte. [39]
Acidity and Alkalinity
A solution is described as acidic, neutral, or alkaline
depending on its hydrogen ion concentration, which
is measured by pH [39]. In an electrolytic solution, pH
is an essential factor in controlling the degree of ion-
ization of molecules. This phenomenon was demon-
strated by Siddiqui et al. 1381. They studied the effect
of iontophoresis and the pH of a solution on the rate
of lignocaine permeation through excised human stra-
tum corneum. They found that, during passive ab-
sorption, the penetration rate was greatest at the higher
pH levels (9.4 and 11.7), where Iignocaine is mainly
nonionized. On the other hand, lignocaine is mainly
in the ionized form at pH 3.4 and 5.2. As a result,
iontophoresis was most effective at the lower pH level.
A later study by Siddiqui et al. [37], using a range of
weak electrolytes, also supports the previous findings.
Their results indicate that weak electrolytes can be
readily introduced by iontophoresis, provided that the
drug is kept in a highly ionized form. They further
suggest that pH may be an important factor in facili-
tating iontophoresis.
THE USE OF IONTOPHORESIS IN
MUSCULOSKELETAL CONDITIONS
Iontophoretic treatments have been used in the
management of a variety of clinical conditions. Claims
of therapeutic success have been made for inflam-
matory disorders of the temporomandibular joint [41],
local anaesthesia delivery [42,43], otitis media [44], or-
thopedic infection [23], port-wine stains [7], shinsplints
[10,45], and RA [15,46]. Despite considerable clinical
experience in using this technique, many doubts re-
main as to the efficacy of iontophoresis for the treat-
ment of inflammatory musculoskeletal conditions.
Vol. 8, No. 1, March 1995
Coyer 1121 was one of the first to explore this area.
In 1954, he conducted a study to compare the efficacy
of citrate iontophoresis with anodal and cathodal gal-
vanism. Forty-five RA patients who were suffering
from an acute exacerbation in the small joints of the
hand were involved in the study. It was found that 13
out of the 15 patients in the iontophoresis group re-
ported a marked relief from pain and joint stiffness
up to 5 hours after each treatment. However, the effect
wore off as the day progressed. Improvement in grip
strength, which was measured by a rubber-bulb er-
gometer, was also observed. In contrast to the positive
results in the iontophoresis group, 18 of the 20 patients
who received plain galvanism felt little or no relief
of pain and stiffness after the treatments. Six patients
experienced more pain and swelling of the fingers.
Furthermore, the improvement of grip strength was
less noticeable compared to the iontophoresis group.
Unfortunately, a standardized measurement scale,
such as the visual analogue scale, was not available
at that time. Assessment of pain and joint stiffness
were solely dependent on the patients’ subjective re-
ports. Therefore, only limited quantitative results were
provided by this study.
In spite of the positive results reported by Coyer
[12], the study was not followed up, nor were the results
replicated by other groups. The use of this technique
for managing inflammatory conditions was not favored
by clinicians due to the limited knowledge of ionto-
phoresis, such as the optimal treatment parameters,
the practicality of this technique, and the safety issues
(i.e., skin irritation and burns]. Some of these issues
were addressed by Glass et al. [47], who conducted an
animal study to examined the depth of drug delivery
by iontophoresis to various joints. Combined DEX and
lidocaine [LID] iontophoresis was applied to the right
elbow, shoulder, hip, knee, and ankle joints of a rhesus
monkey, whereas the left side served as the control.
After applying a current of 5 mA to the right side and
0 mA to the left side for 20 minutes, the radiolabeled
DEX was detected to a maximal depth of 1.7 cm in
the right side, which was the location of the hip joint
capsule of the animal. This is in contrast with the
control site, where the amount of ions delivered by
passive diffusion was insignificant. Also, no signs of
electrolytic burn were observed after the 20-minute
procedure. The results of this study have stimulated
further research into the value of iontophoresis in
musculoskeletal conditions. A summary of the clinical
studies performed in the 1980s and early 1990s is pre-
sented in Table 4.
In 1982, Kahn [48] reported a successful case study
on the treatment of gouty arthritis with lithium ion-
tophoresis. Also, Delacerda [10,49],Harris [8],and Ber-
Arthritis Care and Research
tolucci [9] demonstrated favorable results using DEX
and LID iontophoresis for various inflammatory con-
ditions. However, their results were rendered ques-
tionable by some methodological problems. First, all
the studies included a small sample size, which af-
fected their statistical power. Second, some of the stud-
ies did not monitor the use of additional anti-inflam-
matory medications by the subjects [8,10,48]. The
observed effects might have been contaminated by the
additional treatments. Finally, statistical analyses were
not performed in these studies. Therefore, the claims
of high efficacy for iontophoretic treatment are still in
doubt.
More than 30 years after Coyer [12] claimed success
in using citrate iontophoresis for the treatment of RA,
Hasson et al. [15,46]further explored the value of DEX
and LID iontophoresis for treating this disease. In the
earlier case study [46], DEX and LID iontophoresis was
applied to the subject’s left knee while the right knee
served as the control (LID iontophoresis only]. In this
study, the peak torque, angular velocity, and total work
of knee extension were measured fortnightly over an
8-week period. It was found that the peak torque of
the left knee was improved by 20.870, whereas a 6.7%
decrease was observed in the right side. Furthermore,
the angular velocity and total work were increased
markedly in the left side. However, some improve-
ment was also shown in the contralateral side. A recent
case study by Hasson et al. [15] also suggests that a
combination of DEX and LID iontophoresis and ex-
ercise may be effective for improving muscle strength,
active range of motion (ROM), and swelling of RA
knees, as well as cardiorespiratory endurance of the
patient.
In these studies, Hasson et al. [15,46] employed a
unique protocol for current application. During the 20-
minute treatment, the current intensity was main-
tained at 2 mA for the first 5 minutes. It was then
increased to 3 mA for the next 5 minutes and remained
at 4 mA during the last 10 minutes. This was different
from the more commonly used protocol, which rec-
ommended a gradual increase of current intensity from
0 to 4 mA, and remained at 4 mA, for a 20-minute
treatment. In total, this protocol produced a current
dosage of about 80 mA/minute. In contrast, only 65
mA/minute was delivered according to Hasson’s pro-
tocol. Although the gradual increase of DC might min-
imize the possibility of skin irritation, the efficiency of
ion transfer would be diminished due to the lower
current dosage. Further research is thus required to
determine both the optimal current dosage and ap-
plication procedure that will increase the efficiency of
ion delivery as well as enhance patient comfort.
Although clinical studies seem to be in favor of the
Iontophoresis 59
use of iontophoresis in orthopedic conditions, the ef-
fectiveness of this technique compared to other treat-
ment modalities remains unclear. In 1986, Smith et al.
[45] compared the effects of four modalities (ice mas-
sage, ultrasound, hydrocortisone iontophoresis, and
phonophoresis) for the management of shinsplints.
They found that subjects who received any one of the
four modalities showed significant improvement in
pain and active ROM, as compared to those who re-
ceived control [no modality) treatment. However, none
of the modalities was superior to another.
In summary, research on the iontophoretic delivery
of drugs in musculoskeletal conditions is still at an
early stage. With the limited data, it is premature to
draw any conclusions about its efficacy. Further stud-
ies are needed to compare the effectiveness of ion-
tophoresis with other treatment modalities for various
orthopedic conditions. Also, well-designed clinical
studies are required to provide additional information
on the effect of using different drugs, and on the op-
timal treatment parameters.
CONCLUSIONS
Although iontophoresis has more than two centuries
of history, its role in medicine has not yet been con-
firmed. Limited information is available in terms of
the mechanisms and the factors that influence this
technique. Additional research to establish and un-
derstand its physical basis and clinical efficacy will
further encourage clinicians to utilize this mode of
drug delivery.
The use of iontophoresis in inflammatory muscu-
loskeletal conditions has received more attention since
the 1980s. Research effort has been dedicated to the
investigation of the efficacy of iontophoresis using dif-
ferent types of anti-inflammatory medications. How-
ever, the value of this technique as compared to other
treatment modalities, such as phonophoresis, as well
as the optimal treatment parameters, also needs fur-
ther research and understanding. The future status of
clinical iontophoresis will be greatly improved with
the answers to these problematic research questions.
REFERENCES
Chien YW, Banga AK: Iontophoresis [transdermal) de-
livery of drugs: overview of historical development. J
Pharm Sci 78:353-354, 1989.
Licht S: History of electrotherapy. In Licht S (ed]: Ther-
apeutic Electricity and Ultraviolet Radiation, 2nd ed.
Baltimore, Maryland, E Licht, 1967.
Stux G: Moxibustion. In Stux G, Pomeranz B [eds]:Acu-
puncture. New York, New York, Springer-Verlag, 1987.
60 Li and Scudds
4. Haller JS: Medical cataphoresis-electrical experimen-
tation and 19th century therapeutics. NY State J Med
85:257-261, 1985.
5. Kern DA, McQuade MJ, Scheidt MJ, Hanson B, Van
Dyke TE: Effectiveness of sodium fluoride on tooth hy-
persensitivity with and without iontophoresis. J Perio-
dontol 60:386-389, 1989.
6. Dahl JC, Glent-Madsen L: Treatment of hyperhidrosis
manuum by tap water iontophoresis. Acta Derm Vene-
reol (Stockh) 69:346-348, 1989.
7. Kennard CD, Whitaker DC: Iontophoresis of lidocaine
for anesthesia during pulsed dye laser treatment of port-
wine stains. J Dermatol Surg Oncol18:287-294, 1992.
8. Harris PR: Iontophoresis: clinical research in musculo-
skeletal inflammatoryconditions. J Orthopaed Sports Phys
Ther 4:109-112, 1982.
9. Bertolucci L E Introduction of antiinflammatory drugs
by iontophoresis: double blind study. J Orthopaed Sports
Phys Ther 4:103-107, 1982.
10. Delacerda FG: Iontophoresis for treatment of shinsplints.
J Orthopaed Sports Phys Ther 4:183-185,1982.
11. Hasson SM, Wible CL, Reich M, Barnes WS, Williams
JH: Dexamethasone iontophoresis: effect on delayed
muscle soreness and muscle function. Can J Spt Sci 17:
8-13, 1992.
12. Coyer AB: Citrate iontophoresis in rheumatoid arthritis
of the hands. Ann Phys Med 216-19,1954.
13. Vecchini L, Grossi E: Ionization with diclofenac sodium
in rheumatic disorders: a double-blind placebo-con-
trolled trial. J Int Med Res 12346-350, 1984.
14. Garagiola U, Decatra U, Braconaro F, et al: Iontophoretic
administration of pirprofen or lysine soluble aspirin in
the treatment of rheumatic diseases. Clin Ther 10:553-
558, 1988.
15. Hasson SM, Henderson GH, Daniels JC, Schieb DA
Exercise training and dexamethasone iontophoresis in
rheumatoid arthritis: a case study. Phys Can 43:ll-14,
1991.
16. Bissett DL: Anatomy and biochemistry of skin. In Ky-
donieu AF, Berner B (eds): Transdermal Delivery of
Drugs. Volume 1. Boca Raton, Florida, CRC Press, Inc,
1987.
17. Michniak-Mikolajczak BB, Barry BW: Interaction of
stratum corneum with water vapour. In Marks RM, Bar-
ton SP, Edwards C (eds]: The Physical Nature of the
Skin. Boston, Massachusetts, MTP Press Limited, 1988.
18. Elias PM: Epidermal lipids, membranes and keratini-
zation. Int J Dermatol 2O:l-19, 1981.
19. Brown L, Langer R: Transdermal delivery of drugs. Annu
Rev Med 39:221-229, 1988.
20. Phipps JB, Padmanabhan RV, Lattin GA: Transport of
ionic species through skin. Solid State Ionics 28-30: 1778-
1783, 1988.
21. Chien YW, Siddiqui 0, Shi WM, Lelawongs P, Liu JC:
Direct current iontophoretic transdermal delivery of
peptide and protein drugs. J Pharm Sci 78:376-383,1989.
22. Pannatier A, Jenner P, Testa B, Etter JC: The skin as a
drug-metabolizing organ. Drug Metab Rev 8:319-343,
1978.
Vol. 8, No. 1,March 1995
23. Becker RO, Spadaro J A Treatment of orthopaedic in-
fections with electrically generated silver ions. J Bone
Joint Surg 60-A:871-881, 1978.
24. Cumming J: Iontophoresis. In Nelson RM, Currier DP
(eds): Clinical Electrotherapy, 2nd ed. Norwalk, Con-
necticut, Appleton and Lange, 1991.
25. Harris R: Iontophoresis. In Licht S (ed): Therapeutic
Electricity and Ultraviolet Radiation, 2nd ed. Baltimore,
Maryland, E Licht, 1967.
26. Burnette RR, Marrero D: Comparison between the ion-
tophoretic and passive transport of thyrotropin releasing
hormone across excised nude mouse skin. J Pharm Sci
75~738-743,1986.
27. Chien YW, Siddiqui 0, Sun Y, Shi WM: Transdermal
iontophoretic delivery of therapeutic peptidedpro-
teins-I: insulin. Ann NY Acad Sci 507:32-51, 1987.
28. Kahn J: Iontophoresis. In Kahn J (ed): Principles and
Practice of Electrotherapy. New York, New York, Chur-
chill Livingstone, 1991.
29. Ambramson HA, Gorin MH: The electrophoretic dem-
onstration of the patent pores of the living human skin;
its relation to the charge of the skin. J Phys Chem 44:
1094-1102, 1940.
30. Grimnes S: Pathways of ionic flow through human skin
in vivo. Acta Derm Venereol (Stockh) 64:93-98, 1984.
31. Siddiqui 0, Sun Y, Liu JC, Chien YW: Facilitated trans-
dermal transport of insulin. J Pharm Sci 76:341-345,1987.
32. Burnette RR, Ongpipattanakul B: Characterization of the
pore transport properties and tissue alteration of excised
human skin during iontophoresis. J Pharm Sci 77:132-
137, 1988.
33. Behl CR, Kumar S, Malick AW, et a 1 Iontophoretic drug
delivery: effects of physicochemical factors on the skin
uptake of nonpeptide drugs. J Pharm Sci 78:355-360,
1989.
34. Behl CR, Kumar S, Malick AW, et al: Iontophoretic drug
delivery: effects of physicochemical factors on the skin
uptake of drugs. In Bronaugh RL, Maibach HI (eds):
Percutaneous Absorption: Mechanisms-Methodolo-
gy-Drug Delivery, 2nd ed. New York, New York, Mar-
cel Dekker Inc, 1989.
35. Jung G, Katz E, Schmitt H, et al: Conformational re-
quirements for the potential dependent pore formation
of the peptide antibiotics alamethicin, suzukacillin and
trichotoxin. In Spach G (ed): Physical Chemistry of
Transmembrane Ion Motion. New York, New York, El-
sevier, 1983.
36. Phipps JB, Padmanabhan RV, Lattin GA. Iontophoretic
delivery of model inorganic and drug ions. J Pharm Sci
78:365-369, 1989.
37. Siddiqui 0,Roberts MS, Polack AE: Iontophoretic trans-
port of weak electrolytes through the excised human
stratum corneum. J Pharm Pharmacol41:430-432, 1989.
38. Siddiqui 0, Roberts MS, Polack AE: The effect of ion-
tophoresis and vehicle pH on the in-vitro permeation of
lignocaine through human stratum corneum. J Pharm
Pharmacol 37:732-735, 1985.
39. Cheng E, Chow J: Electrolysis. In Cheng E, Chow J (eds):
Arthritis Care and Research
Chemistry-A Modern View. Hong Kong, Taiwan, Wil-
son Welsh Publications Ltd, 1987.
40. Tu YH, Allen LVJ: In vitro iontophoretic studies using
a synthetic membrane. J Pharm Sci 78:211-213, 1989.
41. Lark MR, Gangarosa LP: Iontophoresis: an effective mo-
dality for the treatment of inflammatory disorders of the
temporomandibular joint and myofascial pain. J Cra-
nioman Prac 8:108-119, 1990.
42. Russo J, Lipman AG, Comstock TJ, Page BC, Stephen
RL: Lidocaine anesthesia: comparison of iontophoresis,
injection and swabbing. Am J Hosp Pharm 373343447,
1980.
43. Zeltzer L, Regalado M, Nichter LS, et al: Iontophoresis
versus subcutaneous injection: a comparison of two
methods of local anesthesia delivery in children. Pain
44: 73-78, 1991.
44. Sato H, Takahashi H, Honjo I: Transtympanic ionto-
phoresis of dexamethasone and fosfomycin. Arch Oto-
laryngol Head Neck Surg 114:531-533.1988.
45. Smith W, Winn F, Parette R: Comparative study using
four modalities in shinsplint treatments. J Orthopaed
Sports Phys Ther 8:77-80, 1986.
46. Hasson SM, English SE, Daniels JC, Reich M: Effect of
iontophoretically delivered dexamethasone on muscle
performance in a rheumatoid arthritic joint. Arthritis
Care Res 1:177-182, 1988.
47. Glass JM, Stephen RL, Jacobson SC: The quantity and
distribution of radiolabeled dexamethasone delivered to
tissue by iontophoresis. Int J Derm 19:519-525, 1980.
48. Kahn J: A case report: lithium iontophoresis for gouty
arthritis. J Ortho Sports Phys Ther 4:113-114, 1982.
Iontophoresis 6 1
49. Delacerda FG: A comparative study of three methods of
treatment for shoulder girdle myofascial syndrome. J
Orthopaed Sports Phys Ther 4:51-54, 1982.
50. Wieder DL: Treatment of traumatic myositis ossificans
with acetic acid iontophoresis. Phys Ther 72:133-137,
1992.
51. Kahn J: Acetic acid iontophoresis for calcific deposits.
[abstract]. Phys Can 46:94, 1994.
52. Tannenbaum M: Iodine iontophoresis in reducing scar
tissue. Phys Ther 60:792, 1980.
53. Langley PL: Iontophoresis to aid in releasing tendon
adhesions. Phys Ther 64:1395, 1984.
54. Ashburn MA, Stephen RL, Ackerman E, et al: Ionto-
phoretic delivery of morphine for postoperative anal-
gesia. J Pain Symp Manage 7:27-33, 1992.
55. Gibson L, Cooke R: A test for the concentration of elec-
trolytes in sweat in cystic fibrosis of the pancreas utilizing
pilocarpine by iontophoresis. Pediatrics 23:545-549,1959.
56. Puttemans FJM, Massart DL, Gilles F, Lievens PC, Jon-
ckeer MH: Iontophoresis: mechanism of action studied
by potentiometry and X-ray fluorescence. Arch Phys Med
Rehabil 63:176-180, 1982.
57. Gordon AH, Weinstein M V Sodium salicylate ionto-
phoresis in the treatment of plantar warts. Phys Ther 49:
869-870, 1969.
58. Shrivastava S, Singh G: Tap water iontophoresis for pal-
mar hyperhidrosis. Br J Dermatol96:189-195, 1977.
59. Levit F Treatment of hyperhidrosis by tap water ion-
tophoresis. Cutis 26:192-194, 1980.