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Background
Iontophoresis is the introduction of ionizable drugs through intact skin by the administration of continuous, direct electrical current into the tissues of the body. The sweat test by pilocarpine iontophoresis is the only practical and reliable laboratory test for confirmation of the diagnosis of cystic fibrosis. Localized sweating is stimulated pharmacologically, the amount of sweat is measured, and sodium and chloride levels determined. In patients with a suggestive clinical picture or a positive family history of cystic fibrosis, a chloride concentration greater than 60 mEq/L confirms the diagnosis. Iontophoresis can be tried for intractable disabling primary hyperhidrosis when antiperspirants or pharmacotherapy are not effective (see CPB 504 - Hyperhidrosis (Hyperhydrosis)). Iontophoresis has been reported to provide relief in cases of primary hyperhidrosis of the hands and feet. A specialized electrode can be used to apply iontophoresis to the axillae. The procedure is repeated regularly, initially in 20-minute sessions several times a week, gradually stretching out the interval between treatments to 1-2 weeks. The Drionic® device (General Medical Co., Los Angeles, California) is an iontophoretic device that can be purchased for home use. There is insufficient evidence that iontophoresis of corticosteroids is effective in treating musculoskeletal disorders. Hasson et al (1992) evaluated the pain alleviating effect of dexamethasone iontophoresis on delayed onset muscle soreness (DOMS) produced via an eccentric exercise bout, and to determine the effect on muscle function. Baseline data were collected on 18 female subjects for maximum isometric knee extension contraction (MVC), knee extension peak torque (PT), knee extension work (W), and muscle soreness perception (SP). All values were subsequently reassessed 24 and 48 hours after a 10-min bout of bench stepping. Immediately following the 24-hr reassessment, the experimental (E) (n = 6) and placebo (P) (n = 6) groups received iontophoresis treatment while the control (C) group (n = 6) received no treatment. Percent deviation from baseline of SP was significantly less at 48 hours for the E group compared to P and C groups. However, MCV, PT, and W were no different between the three groups at 48 hours post muscle soreness bout. Moreover, this study evaluated an experimentally induced condition (DOMS), thus it has little bearing on clinical musculoskeletal disorders. Schiffman and colleagues (1996) evaluated the short-term effect of iontophoretic delivery of dexamethasone (DEX) on the signs and symptoms of temporomandibular disorders in patients who had concurrent temporomandibular joint disc displacement without reduction and capsulitis. Twenty-seven patients with this clinical diagnosis were randomized to one of three groups: (i) treatment group (DEX and lidocaine hydrochloride); (ii) control group (lidocaine hydrochloride); and (iii) placebo group (pH-buffered saline). The authors reported that iontophoretic delivery of DEX and lidocaine was effective in improving mandibular function, but not in reducing pain, in temporomandibular disorders patients who had concurrent temporomandibular joint capsulitis and disc displacement without reduction. Li and associates (1996) examined the effectiveness of DEX iontophoresis for the treatment of rheumatoid arthritis (RA) of the knee in a pilot study. Ten subjects with RA were randomly assigned to either the experimental or placebo group. Iontophoresis treatments were given to both groups on days 1, 3, and 5. Five subjects in the experimental group received a mixture of 1 ml of DEX (4 mg/ml) and 1 ml of injectable sterile water; those in the placebo group received 2 ml of saline solution. Pain on movement, at rest, and on pressure, active joint count, and active range of motion, were evaluated on days 1, 5, and 20. The results suggested that DEX iontophoresis is more effective than placebo in relieving pain at rest and on movement in the RA knee. The finding of this small study needs to be verified by studies with larger sample size and longer follow-ups. Gudeman and co-workers (1997) investigated whether iontophoresis of DEX in conjunction with other traditional modalities provides more immediate pain relief than traditional modalities alone. Forty affected feet were randomly assigned to one of two groups. In Group I, feet were treated with traditional modalities and placebo iontophoresis. In Group II, feet received the traditional modalities plus iontophoresis of dexamethasone. Both groups were treated 6 times over a 2-week period. The authors reported that although traditional modalities alone are ultimately effective, iontophoresis in conjunction with traditional modalities provides immediate reduction in symptoms. Most studies of iontophoresis for other indications are not well designed. The studies have small sample sizes, lack appropriate control groups, and usually do not have objective outcome measures. As a result, it is still unclear whether iontophoresis (of a certain drug/agent) is clinically effective or that iontophoresis of the drug/agent is more effective than other forms of treatment. More research, especially randomized, controlled studies with large sample sizes and sound statistical analysis, is needed to ascertain the effectiveness of iontophoresis for the treatment of such conditions as temporomandibular joint disorders, musculoskeletal/soft tissue injuries, herpes labialis, and post-herpetic neuralgia. Baskurt et al (2003) reported that iontophoresis and phonophoresis of naproxen are equally effective electrotherapy methods in the treatment of lateral epicondylitis (n = 61 patients). The main drawback of this study is the lack of a placebo control group. Furthermore, the findings of this study are confounded by the fact that both groups were treated by other physiotherapy methods such as cold pack, progressive strengthening and stretching exercises. Thus, it is unclear whether the improvement is due to iontophoresis/phonophoresis or other physiotherapy methods. Neeter et al (2003) evaluated the effects of iontophoresis with dexamethasone (n = 14) to iontophoresis with saline solution (n = 11) on patients who had acute (less than 3 months) pain from the Achilles tendon, in terms of range of motion, muscular endurance, pain and symptoms. Patients were evaluated before and after 2 weeks of treatment with iontophoresis, as well as after 6 weeks, 3 and 6 months and 1 year. Both groups then followed the same rehabilitation program for 10 weeks. Good reliability was found for the toe-raise and range of motion tests. Poor reliability was, however, found for the pain on palpation test, which was excluded. No difference was found between or within groups for the toe-raise test. Several significant improvements were seen in the experiment group but not in the control group, in the range of motion test, pain during and after physical activity, pain during walking and walking up and down stairs, morning stiffness and tendon swelling. These investigators concluded that iontophoresis with dexamethasone were found to have a positive effect in the treatment of patients with acute Achilles tendon pain. This was a small study (n = 25), albeit it a randomized one. The small sample size limited the possibilities to draw definite conclusions from the present findings. Nirschl et al (2003) studied the effects of iontophoretic administration of DEX in controlling pain in patients with medial or lateral elbow epicondylitis. A total of 199 patients with elbow epicondylitis received 40 mA-minutes of either active or placebo treatment. Dexamethasone produced a significant 23-mm improvement on the 100-mm patient visual analog scale (VAS) ratings, compared with 14 mm for placebo at 2 days and 24 mm compared with 19 mm at 1 month. More patients treated with DEX than those treated with placebo scored moderate or better on the investigator's global improvement scale (52 % versus 33 %) at 2 days, but the difference was not significant at 1 month (54 % versus 49 %). Investigator-rated pain and tenderness scores favored DEX over placebo at 2 days. Patients completing six treatments in 10 days or less had better results than those treated over a longer period. The authors concluded that iontophoresis treatment was well tolerated by most patients and was effective in reducing symptoms of epicondylitis at short-term follow-up. There appears to be little difference in VAS rating at 1 month between the two groups which corresponded with the investigator's global improvement scale (54 % versus 49 %). Thus, iontophoretic administration of DEX does not appear to have any long-term effect on elbow epicondylitis. In a Cochrane review, Kroeling, et al. (2005) stated that no definitive statements on iontophoresis or other types of electrotherapy for mechanical neck disorders can be made. The current evidence on iontophoresis, galvanic current (direct or pulsed), transcutaneous electrical nerve stimulation, electronic muscle stimulation, low- or high-frequency pulsed electromagnetic stimulation, and permanent magnets is lacking, limited, or conflicting. Possible new trials on these interventions should have larger patient samples and include more precise standardization and description of all treatment characteristics. The BlueCross BlueShield Association Technology Evaluation Center (TEC) assessment of iontophoresis for medical indications (BCBSA, 2003) concluded that iontophoretic administration of non-steroidal anti-inflammatory drugs (NSAIDs) or corticosteroids for musculoskeletal inflammatory disorders does not meet the TEC criteria. The TEC assessment found that randomized controlled clinical studies have not consistently found better outcomes from corticosteroids delivered by iontophoresis compared to placebo iontophoresis. In addition, the TEC assessment found no randomized controlled clinical studies comparing iontophoresis of NSAIDs and corticosteroids to these drugs delivered by another route, which is the comparison essential to this assessment. The TEC assessment explained: "In order to demonstrate the effectiveness of iontophoresis for drug delivery, there must be adequate evidence on both of the following questions: whether the effects of iontophoresis exceed placebo effects; and how iontophoretic drug delivery compares with alternative treatments, usually other routes of drug administration (e.g., topical, oral, injection). Evidence showing iontophoresis of an active drug to be superior to iontophoresis of placebo is necessary, but not sufficient. The crucial issue to this assessment is whether iontophoretic drug delivery is at least as beneficial as other treatments." Osborne and Allison (2006) determined if, in the short term, acetic acid and DEX iontophoresis combined with LowDye (low-Dye) taping are effective in treating the symptoms of plantar fasciitis. A total of 31 patients with medial calcaneal origin plantar fasciitis were recruited from three sports medicine clinics. All subjects received 6 treatments of iontophoresis to the site of maximum tenderness on the plantar aspect of the foot over a 2-week period, continuous LowDye taping during this time, and instructions on stretching exercises for the gastrocnemius/soleus. They received 0.4 % DEX, placebo (0.9 % NaCl), or 5 % acetic acid. Stiffness and pain were recorded at the initial session, the end of 6 treatment sessions, and the follow-up at 4 weeks. Data for 42 feet from 31 subjects were used in the study. After the treatment phase, all groups showed significant improvements in morning pain, average pain, and morning stiffness. However for morning pain, the acetic acid/taping group showed a significantly greater improvement than the DEX/taping intervention. At the follow-up, the treatment effect of acetic acid/taping and DEX/taping remained significant for symptoms of pain. In contrast, only acetic acid maintained treatment effect for stiffness symptoms compared with placebo (p = 0.031) and DEX. The authors concluded that 6 treatments of acetic acid iontophoresis combined with taping gave greater relief from stiffness symptoms than, and equivalent relief from pain symptoms to, treatment with DEX/taping. For the best clinical results at 4 weeks, taping combined with acetic acid is the preferred treatment option compared with taping combined with DEX or saline iontophoresis. There are several drawbacks with the findings of this study: (i) small sample size (n = 31), (ii) no long-term follow-up (patients were only followed for 4 weeks), and (iii) all groups showed significant improvements in morning pain, average pain, and morning stiffness -- i.e., placebo (saline) iontophoresis (plus taping) is effective in reducing pain and stiffness. It is also interesting to note that in a randomized controlled study (n = 92), Radford et al (2006) reported that LowDye taping (by itself) provided improvement in heel pain. Brown et al (2006) stated that various strategies have emerged over recent years to enhance transdermal drug delivery, and these can be categorized into passive and active methods. The passive approach entails the optimization of formulation or drug carrying vehicle to increase skin permeability. Passive methods, however do not greatly improve the permeation of drugs with molecular weights >500 Da. In contrast active methods that normally involve physical or mechanical methods of enhancing delivery have been shown to be generally superior. Improved delivery has been shown for drugs of differing lipophilicity and molecular weight including proteins, peptides, and oligonucletides using electrical methods (iontophoresis, electroporation), mechanical (abrasion, ablation, perforation), and other energy-related techniques such as ultrasound and needless injection. However, for these novel delivery methods to succeed and compete with those already on the market, the prime issues that require consideration include device design and safety, efficacy, ease of handling, and cost-effectiveness. Andres and Murrell (2008) performed a systematic review to determine the best treatment options for tendinopathy. These researchers evaluated the effectiveness of NSAIDS, corticosteroid injections, exercise-based physical therapy, physical therapy modalities, shock wave therapy, sclerotherapy, nitric oxide patches, surgery, growth factors, and stem cell treatment. Corticosteroid injection and NSAIDS appear to provide pain relief in the short-term, but their effectiveness in the long-term has not been demonstrated. These researchers identified inconsistent results with shock wave therapy and physical therapy modalities (e.g., ultrasound, iontophoresis and low-level laser therapy). Current data support the use of eccentric strengthening protocols, sclerotherapy, and nitric oxide patches, but larger, multi-center trials are needed to confirm the early results with these treatments. Preliminary work with growth factors and stem cells is promising, but further study is needed in these fields. Surgery remains the last option due to the morbidity and inconsistent outcomes. The ideal treatment for tendinopathy remains unclear. Well-designed studies (randomized controlled trials with large sample size and long-term follow-up) are needed to ascertain the clinical value of iontophoresis in the treatment of musculoskeletal disorders. There is insufficient evidence to support the use of verapamil iontophoresis for the treatment of patients with Peyronie's disease.Cabello Benavente and colleagues (2005) assessed the effects of transdermal iontophoresis with verapamil and dexamethasone in patients with Peyronie's disease of less than 1 year of evolution. These researchers had treated 10 patients twice a week during 6 consecutive weeks using iontophoresis with a Miniphysionizer dispositive. This device generates a 2 mA electric current during 20 mins, which triggers the transdermal penetration of medication. In every session dexamethasone (8 mg) and verapamil (5 mg) were administered inside a small self-adhesive receptacle on the penile skin overlying the fibrosis plaque. To evaluate the efficacy, penile curvature was measured by Kelami's test, while the plaque size was assessed by penile ultrasound. Other parameters like pain, erectile function and ability for vaginal intercourse were recorded using questionnaires. Safety parameters were also assessed during treatment. No improvement or progression in penile curvature was evidenced in any of the patients. The hardness of the plaque was reduced in 5 patients, becoming impalpable in 2 of them. Decrease in plaque volume was observed by penile ultrasound in 6. Pain improved in 8 patients, disappearing in 6 of them. One patient recovered his erectile function at the end of the treatment; whereas 3 referred that their ability for intercourse enhanced while 2 reported that treatment improved their sexual life in general. These investigators did not record any significantly side effects, except for a transitory and slight dermal redness on the site of electrode placement. The authors concluded that transdermal iontophoresis is an effective treatment for pain control in early stages of Peyronie's disease. Efficacy in reducing penile curvature seems to be limited. They noted that controlled clinical trials are needed to obtain more relevant clinical effects. Greenfield et al (2007) performed a double-blind, placebo controlled trial to determine the effectiveness of verapamil delivered through electromotive drug administration. A total of 42 men with Peyronie's disease volunteered to participate in this study, which was approved by our institutional review board. A genitourinary examination was performed on all patients, including plaque location, stretched penile length, objective measurement of curvature after papaverine injection and duplex ultrasound. Each subject was randomized to receive 10 mg verapamil in 4 cc saline or 4 cc saline via electromotive drug administration. A Mini-Physionizer (Physion, Mirandola, Italy) device was used at a power of 2.4 mA for 20 minutes. Treatments were performed 2 times weekly for 3 months. After 3 months each patient was re-evaluated with physical examination and duplex ultrasound by a technician blinded to the treatment received. A modified erectile dysfunction index of treatment satisfaction questionnaire was also completed by each patient. A total of 23 patients were randomized to the verapamil treatment group (group 1) and 19 were randomized to the saline group (group 2). There were no significant differences between patient groups with respect to patient age, disease duration or pretreatment curvature. In group 1, 15 patients (65 %) had measured improvement (mean 9.1 degrees, range 5 to 30), 5 (22 %) had no change and in 3 (13 %) the condition worsened. In group 2, 11 patients (58 %) had measured improvement (mean 7.6 degrees, range 5 to 30), 7 (37 %) showed no change and in 1 (5 %) the condition worsened. To better evaluate effectiveness the total number of patients experiencing significant improvement (20 degrees or greater) was calculated and compared. Seven patients (30 %) in group 1 and 4 (21 %) in group 2 achieved this criterion. Although a greater percentage of patients treated with verapamil had improved curvature, the results were not statistically significant. The authors concluded that although a greater percentage of patients treated with verapamil in their electromotive drug administration protocol had a measured decrease in curvature, the results were not statistically significant. Further research is needed to determine if electrical current may have a role in the treatment of Peyronie's disease as well as if verapamil delivered via electromotive drug administration may have a role as effective treatment. Akin-Olugbade and Mulhall (2007) stated that there are a wide variety of medical treatments that are available to the practicing urologist, including oral agents, topical creams and gels with or without iontophoresis, intralesional injection therapy, radiation therapy, extracorporeal shockwave therapy, and laser therapy for the treatment of Peyronie's disease. Medical management of Peyronie's disease might be a valuable treatment option for this debilitating disorder, especially in the early symptomatic stages of the disease. Although no single modality has been demonstrated to have superior efficacy, intralesional therapy appears to confer some benefit. Multi-center, large-scale, randomized, controlled studies are needed to fully establish the effectiveness of the available treatments. Sasso et al (2007) noted that the etiopathogenesis of Peyronie's disease is not yet clearly understood, no medical therapy is fully effective, and surgery remains the gold standard in patients with severe deformity and/or erectile dysfunction. Iontophoresis has been used for the delivery of local anesthetic before skin puncture or painful dermal procedures. An assessment by the BlueCross BlueShield Association Technology Evaluation Center (BCBSA, 2003) concluded that iontophoresis to administer local anesthetic before skin puncture or dermal procedures meets the TEC criteria. This use of iontophoresis is most useful in emergent situations, as iontophoresis results in more rapid dermal anesthesia than topical anesthetic agents. Topical anesthetic agents (e.g., lidocaine/prilocaine (EMLA) cream) take approximately 30 minutes to achieve maximal effect, and are sufficient for dermal anesthesia in non-emergent situations. Turner and colleagues (2008) noted that effective assessment of endothelial function is an important tool for ascertaining individuals at risk of development and progression of cardiovascular disease. As an alternative to invasive tests of endothelial function, several non-invasive methods have been developed such as the use of laser Doppler flowmetry to measure cutaneous perfusion accompanied by iontophoresis of acetylcholine and sodium nitroprusside. It is evident from published reports that this approach not only provides a validated and reproducible method for evaluating and monitoring of endothelial function in patients with various pathological conditions, it may also be employed to examine disease progression and responsiveness to treatment; thus facilitating clinical trials. Moreover, a standardization of protocols would aid to reduce the apparent controversy observed in the literature. With its increasing use by other groups, it is anticipated that further published studies will help to provide a better understanding of the development and progression of cardiovascular disease.
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