Iontophoresis

Iontophoresis is defined as the passing of an ionized substance through intact skin by the application of a direct electrical current.[134] Tap water iontophoresis is considered by many dermatologists to be the first line of treatment for hyperhidrosis of the palms and soles.[7,134] Although more cumbersome, iontophoresis can be used to treat axillary hyperhidrosis as well.[7] In addition to simple tap water iontophoresis, clinicians have also used iontophoresis to deliver anticholinergics and other drugs to areas affected by hyperhidrosis.[4] Two iontophoresis devices currently available in the US, the Drionic and the Fischer Model MD-1a Iontophoresis unit, have received US Food and Drug Administration approval for treating hyperhidrosis.

See the following area for specific information on iontophoresis

Not long after it was discovered, electricity was tried as treatment for human disease during the 18th century. Pivati is reported to have used iontophoresis to treat arthritis in 1740.[7] Research during the late 19th century and the 20th century demonstrated that iontophoresis is an efficient method for the delivery of drugs into the body through the skin. Interestingly, the sweat glands are the main portal of entry for any drugs delivered through the skin, since electrical resistance is lowest by that route.[7,47] Dermatologists have tried iontophoresis for a host of conditions, including vitiligo and scleroderma.[7] Currently hyperhidrosis is said to be the only clear indication for iontophoresis, because use of this therapy in hyperhidrosis has been both successful and popular.[7,131]

In 1936, Ichikasa discovered that iontophoresis of drugs led to a reduction of sweating in the affected area.[7] In the 1940s, Takata and Shelley independently found that anhidrosis could be obtained by iontophoresis with tap water. The treatment became increasingly popular after Levit published his paper on a practical device for iontophoresis in 1968.[7,85]Mechanism of action

One of the physical principles of electricity is that molecules with the same charge repel, and those with opposite charge attract, one another. In iontophoresis, a charged molecule is delivered across the skin, by placing it near the electrode of like charge, while the electrode of opposite charge is placed elsewhere on the body.[7] This physical explanation for how drugs are transported across skin does not explain the mechanism of action of tap water iontophoresis in reducing sweat output, however. Although the mechanism of action is currently not understood, there have been several theories advanced.[7]

An early theory was that iontophoresis leads to a plugging of sweat gland ducts. This concept was based on the development of iatrogenic miliaria when iontophoresis was done on the back, chest, or arms of patients. Microscopic analysis showed keratin plugs obstructing sweat ducts. However, light and electron microscopy of sweat glands in a patient with palmar hyperhidrosis did not show ductal obstruction.[56] This finding led to the theory that iontophoresis may cause a functional impairment of the sweat gland, either by completely blocking sympathetic nervous system transmission to the gland, raising the threshold for transmission of sympathetic nerve impulse, or changing the cellular secretory physiology.[7] However, neurotransmitter levels in the eccrine gland or surrounding microcirculation do not change after iontophoresis.[147]

Decreased pH in the sweat duct due to an increase in H+ ions during tap water iontophoresis may contribute to eccrine gland dysfunction.[121] Anodal current has a better inhibitory effect on sweating than cathodal current, and this may be due to the lowering of pH. Use of saline in iontophoresis is not as effective as use of tap water; Sato and colleagues also found that the pH of anodal water did not drop during saline iontophoresis.

Recommended regimen
The regimen recommended for iontophoresis will vary with the device used, the areas to be treated, and whether the treatment is to be carried out in the clinic or at home.[3,7,86,134]. Some general advice:

Scratches and cuts on the surface to be treated should be covered with a thin layer of petro-
latum.[86,134] Coat the skin around the axilla with petrolatum if treating that area.[7]
Use nondeionized tap water (from the faucet).[7]
Fill the trays with just enough water to cover the hands (or feet).[134]
After placing the body part in the device tray, or after applying the device or wet pads attached to an electrode to the axilla, turn the machine on. Slowly increase the amperage until a tingling that is not unpleasant is felt in the affected area,[86,145] or to a maximum of 20 mA.[4,134,145]
Treat for 20 minutes a session every two to three days[134] or for ten minutes three to five times a week.[7]
Halfway through the 20-minute session, reverse current flow to switch anode site to opposite side,[134] or keep one side in anodal pan each session until euhidrosis is reached and then switch sides.[7]
Can do hands and feet simultaneously, with hands and feet going into separate trays.[7]
Maintenance treatment frequency will vary, but one to three times a week is usually necessary.[7,86] If mineral content of tap water is low, insufficient current flow may occur. This can be corrected by adding a teaspoon of baking soda to each tray.[134]
Do not treat pregnant patients or those with pacemakers or arrhythmias.[86,134]
If patient fails to respond to tap water iontophoresis alone, one can add an anticholinergic. Glycopyrrolate 2-mg tablets can be crushed and added to each tray (see section on use of anticholinergics in iontophoresis).[134]
Irritation developing along the water line can be treated with 1% hydrocortisone cream.[134]
Children can be treated with iontophoresis, but some may not be able to tolerate the same current levels used by adults.[86,130]

Clinical studies

Observational studies in palmar sweating

An early observational study of iontophoresis in 113 patients with palmoplantar hyperhidrosis published in 1952 demonstrated a response rate of 91% for palmoplantar hyperhidrosis and showed that adding ionizable agents to the water did not improve the results.[22]

Using different current configurations

In another study, 30 patients with palmoplantar hyperhidrosis were successfully treated, using different pan and electrode configurations, current, and duration of sessions.[130] Treated 6 days a week until sweating stopped, patients required 2 to 3 weeks to reach that endpoint and remained in remission for an average 6.3 months. Observing that some patients could not tolerate the usual current level when the electrodes were placed in separate pans, one group of patients was treated with both electrodes in the same pans. This configuration required longer times to reach anhidrosis despite higher current levels.

A group of 18 patients with palmar hyperhidrosis had iontophoresis of one hand with the other serving as control.[133] Patients were treated with 12 to 20 mA for 20 minutes 3 times a week for 3 weeks. Fifteen of 18 had markedly reduced sweat production in their treated hands.

Controlled studies in palmar sweating
A double-blind study of 11 patients with palmar hyperhidrosis used a sham treatment of one involved hand as placebo.[31] After a median of 10 treatments using current from 2 to 10 mA, sweat production was measured by gravimetry and compared to baseline. A median reduction of 38% from baseline was found for the treated hands. After maintenance treatment every other week for 3 months, there was an 81% median reduction of sweat production (P<0.05). br=""> Study of portable device for home use A portable iontophoretic device, the Drionic unit (General Medical Company, Los Angeles, California), has been on the market since 1984. This battery-operated device allows patients to treat their hyperhidrosis at home. A study of the device’s efficacy was carried out on 27 treatment sites in 22 patients: 10 palms, 9 feet, and 8 axillae.[<a href="references#3">3] Patients used the device on the involved area, using the opposite side as control, for 30 minutes twice a day for 5 days followed by 30 minutes daily. Sweat production was assessed using a computerized image analysis of chemically treated paper applied to the involved area. Two axillae and one foot did not respond to treatment. It took 2 weeks for 80% of palms to respond, and by 20 days 100% of hands, 78% of feet, and 75% of axillae responded. Of the 24 sites that had at least a 50% improvement in subjective symptoms, there was a statistically significant decrease in mean sweat production after 1 month of treatment compared to controls (P<0.001 for palms and soles and P<0.01 for axillae). Follow-up 1 month after therapy was stopped found a continued statistically significant difference in sweat production only for palms. The authors concluded that the device has a role in treating hyperhidrosis but may require twice-daily treatment for more than 2 weeks for some patients and that retreatment is necessary 2 weeks after stopping treatment.

Study with gravimetric follow-up

To investigate whether a current other than the standard direct current (DC) would lessen side effects of iontophoresis, 25 patients with palmar hyperhidrosis were treated in a double-blind manner with standard DC, alternating current (AC), or an alternating current with a DC offset (AC/DC).[110] Patients were treated 4 times a week until resolution, and then once weekly as maintenance. Gravimetric measurement of sweat production was done. Those treated with standard DC had improvement in hyperhidrosis after an average of 11 treatments, as well as the usual side effects, including the occasional mild shock with incorrect technique (ie, moving hands in or out of the bath too quickly). Those on AC treatments had no resolution of hyperhidrosis after a total of 25 treatments. Those on the AC/DC protocol improved at the same rate as those on DC, but there were no signs of skin irritation or discomfort. The authors concluded that the AC with a DC offset “should become the treatment of choice.”

A recent study of 112 patients with palmoplantar symptoms had treatment of their hands with the standard direct current tap water iontophoresis method.[70]

Side effects

Several side effects are seen during tap water iontophoresis but usually are not severe enough to lead to discontinuation of treatment.[<a href="/references#3" >3,133] Some effects can be prevented by proper preparation. Open wounds (cuts, abrasions, hangnails) on the treated surface can be covered with petrolatum to minimize discomfort during the procedure.[133] Proper education in use of the device will prevent mild shocks from occurring. For instance, moving the hands out of the tray or touching the electrodes can lead to a small shock.[134]

In series of patients treated with iontophoresis, a few side effects were commonly reported. Vesiculation in the effected area has been reported, but is usually transient.[133] Eight of 112 patients reported vesiculation in a recently published series.[70] Redness of the skin, often along the water line, is also commonly reported.[133] Twelve of 122 patients reported erythema.[70] Discomfort, either as a burning sensation or “pins and needles,” is also common.[70,133] All patients in one series complained of “pins and needles,” and 20 of 112 complained of the burning sensation.

Both erythema and vesiculation can be treated with 1% hydrocortisone cream should these symptoms persist.[134] Sometimes the skin becomes dry and cracked or fissured, necessitating the use of moisturizers or decreasing the frequency of iontophoresis sessions.[134]

Studies of iontophoresis and other agents

Since sweat glands are the main route for absorption of drugs delivered by iontophoresis, using this method to deliver agents to treat hyperhidrosis is a logical approach. Several studies compared tap water iontophoresis to iontophoresis of anticholinergic medication, and another compared combined iontophoresis of aluminum chloride and an anticholinergic to tap water iontophoresis.

Poldine methylsulfate
Glycopyrronium bromide
Glycopyrrolate and aluminum chloride

Poldine methylsulfate

The anticholinergic agent poldine methylsulfate or tap water was delivered by iontophoresis to the palms, soles, and axillae of 13 patients, using one side either as placebo control or for the other treatment.[47] Poldine was more effective than tap water overall, and two patients with sweating unresponsive to tap water had an excellent response to poldine iontophoresis. The greatest effect of poldine was on the palms, and the worst response was in the axillae, where only 2 of 5 patients had a response. Systemic side effects were seen, most commonly dry mouth. Similar to tap water iontophoresis, continued treatment once or twice weekly with poldine was needed, as only a few patients had longer remissions.

Another study evaluated the use of a 0.1% solution of glycopyrronium bromide delivered by iontophoresis to 27 patients with various combinations of palmar, plantar, and axillary hyperhidrosis.[1] Treatment results for tap water iontophoresis in 26 other patients were reported for comparison. The group treated with tap water all responded after a variable number of treatments, but most required continued weekly or twice-weekly treatment to maintain dryness. Patients with planter and axillary symptoms required more treatments to reach sufficient dryness. Those treated with glycopyrronium fared better, however. Except for those with axillary hyperhidrosis, a prolonged period of hypohidrosis was achieved—an average of 33.7 and 47.2 days between treatments for palmar and plantar hyperhidrosis, respectively. Axillary patients continued to need treatment about once per week. All patients had signs of systemic absorption of the anticholinergic. Dryness of the mouth usually persisted for 6 to 24 hours after therapy. Occasional visual, GI, and urinary difficulties were reported. The reason for the prolonged effect with glycopyrronium is unknown, and the author speculated that the drug is held in the epidermis and slowly released.

Glycopyrrolate and aluminum chloride

In a third study, the combination of 0.01% glycopyrrolate and 2% aluminum chloride was delivered by iontophoresis to patients with palmar hyperhidrosis.[129] One group had the opposite hand treated with tap water in a double-blind study, and a second group received the combined treatment to both hands. Combined iontophoresis used changing periods of time for delivery of glycopyrrolate and aluminum chloride over 4 days: on the first day the anticholinergic alone was given over 30 minutes, and on the second day 20 minutes were used for delivery of glycopyrrolate and 10 minutes for aluminum chloride. This ratio was reversed for the third day, and on the fourth day the patients received aluminum chloride alone. Using this approach, the investigators hoped to suppress sweating with the anticholinergic in order to enhance the absorption of aluminum chloride into the sweat gland. Each day the treatment was repeated with reversed polarity, leading to an overall treatment duration of 1 hour. In the double-blind study, the decrease in severity as measured by iodine-starch paper patterns was higher in the palms treated with combination therapy (P=0.084). The mean remission duration after the 4-day treatment was 3.5 days for tap water iontophoresis and 20 days for combination therapy (P=0.098). In the observational study, 87% of patients responded to the treatment and had a mean remission duration of 32 days. Only 1 patient complained of mouth dryness. Although no specific data on treatment of the axillae by this method are reported, the authors state that the axillary hyperhidrosis responded as well as palmar symptoms. Two patients had 5 months of remission of axillary sweating after a single 4-day treatment.