Description:
Iontophoresis is a method of transdermal local drug delivery using electrical current. A charged, ionic drug is placed on the skin with an electrode of the same charge, allowing direct current to drive the drug into the skin. Ultrasound transdermal delivery involves the use of ultrasonic energy to enhance delivery of solutes either simultaneously or via pretreatment, and is referred to as sonopheresis or phonophoresis.

Background
Iontophoresis may take advantage of sweat ducts, sebaceous glands, hair follicles and imperfections in the skin to achieve penetration. Alternatively, electrical potential across the skin could alter its permeability, possibly creating potential-dependent pores in lipid bilayer membranes. It has been proposed for numerous uses, including delivering local anesthetic before skin puncture or other painful dermal procedure, local drug delivery for agents such as nonsteroidal anti-inflammatory drugs or corticosteroids for musculoskeletal inflammatory disorders. In the treatment of musculoskeletal disorders, iontophoresis is often offered in the physical medicine and rehabilitation setting. The proposed mechanism for phonophoresis is to increase skin permeability by the formation of gaseous cavities within the intracellular lipids on exposure to ultrasound.

Regulatory Status
A number of iontophoresis devices have received 510(k) marketing clearance from the U.S. Food and Drug Administration (FDA) to "introduce ions of soluble salts or other drugs into the body." The FDA prohibits labeling or promoting their use with specific drugs prior to the FDA having specifically approved the drugs for iontophoretic administration. Two iontophoretic transdermal devices are being developed for patient-activated delivery of fentanyl for postoperative pain. The IONSYS^™ fentanyl iontophoretic transdermal system is manufactured by ALZA and marketed by Ortho-McNeil. Transdermal iontophoretic fentanyl (IONSYS) received FDA approval in May 2006. Janssen-Cilag EMEA is also investigating a patient-controlled fentanyl iontophoretic transdermal delivery system in Europe. These patch systems are intended for 24-hour use in hospitals, and allow patients to control the number of doses of fentanyl (40 mcg delivered over 10 minutes), with a maximum delivery of six doses per hour.

The SonoPrep^® (Echo Therapeutics Inc.) phonophoresis device is cleared by the FDA as class 2 electromedical equipment. SonoPrep^® uses low frequency ultrasound (55kHz) to enhance skin permeability.

Policy:
Iontophoresis may be considered MEDICALLY NECESSARY to administer local anesthesia prior to a venipuncture or dermatologic procedure.

Iontophoresis of fentanyl may be considered MEDICALLY NECESSARY for the short-term (i.e., less than 24 hours) management of acute postoperative pain in adult patients requiring opioid analgesia in a monitored facility (e.g., inpatient hospital, outpatient hospital, ambulatory surgical center).

Iontophoresis as a transdermal drug delivery technique for other medical indications is considered INVESTIGATIONAL.

Phonophoresis alone, or in combination with iontophoresis as a transdermal drug delivery technique, is considered INVESTIGATIONAL for any medical indication.

Policy Guidelines
Fentanyl administered with the IONSYS transdermal iontophoretic system (or other approved iontophoretic device) is not intended for home use and is, therefore, inappropriate for use in patients once they have been discharged from the hospital. It is not recommended for patients under the age of 18 years.

CPT code 97033 specifically describes iontophoresis. However, some providers may code for iontophoresis using CPT code 97039, Unlisted modality.

Phonophoresis is reported using CPT code 97035, Application of a modality to 1 or more areas; ultrasound, each 15 minutes.

Benefit Application
BlueCard/National Account Issues
When iontophoresis is used to apply local anesthetic prior to a venipuncture or prior to a dermatologic procedure, Plans may elect to consider iontophoresis as an integral component to the venipuncture or dermatologic procedure.

When iontophoresis is used in the treatment of musculoskeletal disorders, the procedure is often performed by physical therapists.

State or federal mandates (e.g., FEP) may dictate that all devices, drugs or biologics approved by the U.S. Food and Drug Administration (FDA) may not be considered investigational and, thus, these devices may be assessed only on the basis of their medical necessity.

Rationale
In general, for most indications, placebo-controlled studies demonstrated that iontophoretic delivery of a drug exceeded the effects of iontophoretic delivery of a placebo. While these studies are an important first step, they are considered insufficient to validate the efficacy of iontophoretic drug delivery compared to other methods, such as no drugs, topical applications of drug, oral, subcutaneous, intradermal injection, etc. The crucial issue is whether iontophoretic drug delivery is at least as beneficial as other treatments and other routes of drug administration. The benefit of iontophoresis for local drug delivery could be the avoidance of adverse effects of systemic administration of higher doses of drugs and possibly equivalent or greater therapeutic effects.

1. Administering local anesthetic before skin puncture or dermal procedures.

The 2000 TEC Assessment identified 12 controlled studies, and the 2003 TEC Assessment identified an additional controlled 15 studies, which demonstrated that the effects of iontophoretic administration of local anesthetics exceed placebo. Published and unpublished (studies submitted to the U.S. Food and Drug Administration [FDA]) showed improved self-reported Visual Analogue Scale (VAS) pain ratings, higher proportions of patients reporting pain-free dermatological procedures and fewer rescue injections of local anesthetics.

The comparison of iontophoresis to alternate interventions focused on the comparative effects of a topical anesthetic preparation called EMLA (eutectic mixture of local anesthetics; lidocaine and prilocaine). Studies showed that iontophoretic administration of local anesthesia is at least as beneficial as EMLA for reducing pain before venipuncture or dermatologic procedures. Iontophoresis can cause minor skin irritation, but it acts more quickly than EMLA: 15 minutes versus 45 minutes or more.

2. Treatment of musculoskeletal inflammatory disorders with nonsteroidal anti-inflammatory drugs (NSAIDs).

The 2000 TEC Assessment identified four placebo studies that suggested that iontophoretic delivery of NSAIDs exceed placebo effects. No additional placebo comparison trials were noted in 2003. No studies compared the relative effects of iontophoretic delivery to other routes of NSAID administration.

3. Treatment of musculoskeletal inflammatory disorders with corticosteroids.

The 2000 TEC Assessment identified five placebo studies with mixed results, and the 2003 TEC Assessment identified four additional placebo studies. Placebo studies did not consistently report significantly better outcomes for groups receiving corticosteroids compared to those receiving placebo. No studies compared the relative effects of iontophoretic delivery of corticosteroids to other routes of corticosteroid delivery.

A search of the MEDLINE database for articles published from 2003 through July 2007 identified five industry-sponsored randomized controlled trials on the use of the patient-controlled fentanyl transdermal system. Two ALZA-sponsored placebo-controlled trials with the IONSYS system have been published.^3,4 The most recent was a multicenter, randomized, double-blind, parallel-group study from 20 U.S. hospitals.⁴ Subjects admitted to the post-anesthesia care unit after major abdominal, orthopedic or thoracic surgery were randomized to fentanyl iontophoresis (n = 244) or a placebo system (n = 240). Bolus doses of intravenous (IV) fentanyl were allowed during the first three hours on patient request; no analgesics were allowed for the rest of the 24-hour study. Twice as many placebo patients (60 percent vs. 29 percent) withdrew from the study because of inadequate pain relief during the 24-hour monitoring period. Secondary outcome measures, including pain intensity scores, were improved with the active treatment (3.5 vs. 5.4 on a 10-point scale). Three patients in the active group withdrew due to adverse effects of treatment (nausea, pruritis). The most common adverse effect was mild-to-moderate erythema after system removal, occurring in 25 percent of patients treated with iontophoretic transdermal fentanyl.

Fentanyl iontophoresis was compared with patient-controlled IV morphine for postoperative pain in three industry-sponsored multicenter studies.^5,6,7 The studies were conducted at a total of 136 hospitals in the United States and Europe, with a combined enrollment of 2,100 patients. The three studies used similar protocols, with bolus doses of IV fentanyl or morphine allowed during the first three hours postoperatively, and patients randomized to self-activated dosing with the iontophoretic fentanyl patch (40 micrograms over 10 minutes) or IV morphine (up to 10 mg per hour) for 24 hours. Due to the different delivery methods (skin patch vs. IV line), these studies were open-label. The primary efficacy measure, patient global assessment of pain control, and the secondary measure of pain-intensity scores, were similar for the two groups (e.g., "excellent" or "good" ratings of 83 percent vs. 82 percent, respectively, and pain ratings of 3.0 vs. 3.0, respectively).⁵ Common adverse events during treatment were similar in the two groups; no cases of respiratory depression were reported with transdermal iontophoresis.^5,6,7 Mild to moderate skin irritation was common with the fentanyl patch systems. In one study, over 50 percent of patients in the iontophoresis group were found to have erythema 24 hours after system removal.⁶ Results from these five studies, which show greater pain relief than placebo and similar pain relief to morphine in the acute postoperative period, support the clinical efficacy of the patient-controlled iontophoretic fentanyl system.

Iontophoretic administration of ketamine was not more effective than placebo in 33 patients with intractable central pain.⁸ Other randomized double-blind controlled studies examined iontophoretic application of acetic acid or dexamethasone for a variety of soft tissue pain syndromes. A study of iontophoretic dexamethasone (up to six treatments within 15 days) in 199 patients with acute lateral epicondylitis found a significant 23-mm improvement on the 100-mm patient VAS ratings, compared with 14 mm for placebo at two days after completing treatment and 24 mm compared with 19 mm at one month.⁹ No difference was observed in the percentage of patients from each group who rated their global improvement as moderate or better (48 percent dexamethasone vs. 41 percent saline). Another small study (n = 25) compared iontophoresis of dexamethasone with saline in patients with acute Achilles tendon pain.¹⁰ No differences were observed for a toe-raise test or range of motion test. The authors reported that some pain measures were decreased with iontophoretic dexamethasone at some time points. However, only 1 of 4 dichotomous (yes/no) pain measures showed consistent improvement over the four assessments (two weeks to six months), and no adjustment was made for missing data or for the multiple comparisons. A third study with only 31 patients found that iontophoretic dexamethasone was not effective for plantar fasciitis.¹¹ The same study reported that iontophoresis of acetic acid was better than dexamethasone for plantar fasciitis. However, since only 1 of the 14 outcome measures was shown to be better than placebo, the clinical relevance of this finding is unclear. Another study (36 patients) found that acetic acid iontophoresis added no clinical benefit to physiotherapy for the treatment of calcifying tendonitis of the shoulder.¹² Overall, the results from these studies do not provide support for the iontophoretic application of acetic acid or dexamethasone for pain, tendonitis or fasciitis.

Amirjani et al.¹³ conducted a study in Canada (n = 17) comparing six sessions of iontophoresis with 0.4 percent dexamethasone sodium phosphate with distilled water to determine the effectiveness of corticosteroid iontophoresis in relieving carpal tunnel syndrome manifestations in mild to moderate cases. The results showed iontophoretic delivery of dexamethasone to be well tolerated; however, it was not shown to be an effective treatment. Given the small size of the study and variability of drug delivery to the targeted tissue, these data are inconclusive.

Gurney et al.¹⁴ conducted a study (n = 29) to compare the concentrations of dexamethasone in tendon tissues of humans using iontophoresis versus sham. The authors concluded that "Iontophoresis facilitates the transmission of dexamethasone to connective tissues in humans." However, given the small size of this study, author-reported issues with electrode placement, lack of clinical outcomes and conflicting results with other clinical trials that examined the effectiveness of iontophoresis on inflammatory conditions, there is lack of evidence demonstrating the clinical efficacy of iontophoretic delivery of dexamethasone for the treatment of inflammatory conditions.

A review article by Turner et al.¹⁵ discussed the use of laser Doppler flowmetry/imaging to measure cutaneous perfusion accompanied by iontophoresis of acetylcholine and sodium nitroprusside for determining patients at risk of development and progression of cardiovascular disease. The authors concluded that "It is clear from previous studies that this technique provides an easy, validated and reproducible method for investigators to assess and monitor endothelial function in patients with a variety of pathologic conditions, but it may also be used to examine disease progression over time and responsiveness to treatment, thereby facilitating clinical trials. However, a standardization of protocols would help reduce the apparent controversy seen in the literature." These data are inconclusive to draw conclusions regarding the clinical use of iontophoresis to monitor endothelial function.

A review article by Rao et al.¹⁶ discussed the transdermal drug delivery technologies with a focus on phonophoresis used alone as a sole transdermal technique or in combination with other transdermal delivery techniques. The authors stated that "Sonophoresis (phonophoresis) has been shown to increase skin permeability to various low and high molecular weight drugs, including insulin and heparin. However, its therapeutic value is still being evaluated."

Phase III clinical trials are underway for an iontophoretic sumatriptan patch (Zelrix™, NuPathe, Inc.).¹⁷

As of October 2009, this transdermal formulation for migraines has not been approved by the U.S. Food and Drug Administration (FDA).

Summary
The available evidence for the use of iontophoresis to administer local anesthesia prior to a venipuncture or dermatologic procedure, and fentanyl for the short-term (i.e., less than 24 hours) management of acute postoperative pain in adult patients is sufficient to show improvement in net health outcome. Therefore, the policy statements for their use as medically necessary remain unchanged.

Given the lack of evidence to show improvement in net health outcome, the policy has been modified with the addition of a policy statement on the use of phonophoresis as a transdermal delivery technique, alone or in combination with iontophoresis, which is INVESTIGATIONAL.

BlueCard is a registered mark of this health plan. IONSYS is not a trademark of this health plan. SonoPrep is not a registered mark of this health plan.

References:

1. 2003 TEC Assessments: Tab 3.
2. 2000 TEC Assessments: Tab 20.
3. Chelly JE, Grass J, Houseman TW et al. The safety and efficacy of a fentanyl patient-controlled transdermal system for acute postoperative analgesia: a multicenter, placebo-controlled trial. Anesth Analg 2004; 98(2):427-33.
4. Viscusi ER, Reynolds L, Tait S et al. An iontophoretic fentanyl patient-activated analgesic delivery system for postoperative pain: a double-blind, placebo-controlled trial. Anesth Analg 2006; 102(1):188-94.
5. Hartrick CT, Bourne MH, Gargiulo K et al. Fentanyl iontophoretic transdermal system for acute-pain management after orthopedic surgery: a comparative study with morphine intravenous patient-controlled analgesia. Reg Anesth Pain Med 2006; 31(6):546-54.
6. Viscusi ER, Reynolds L, Chung F et al. Patient-controlled transdermal fentanyl hydrochloride vs intravenous morphine pump for postoperative pain: a randomized controlled trial. JAMA 2004; 291(11):1333-41.
7. Grond S, Hall J, Spacek A et al. Iontophoretic transdermal system using fentanyl compared with patient-controlled intravenous analgesia using morphine for postoperative pain management. Br J Anaesth 2007; 98(6):806-15.
8. Vranken JH, Dijkgraaf MG, Kruis MR et al. Iontophoretic administration of S(+)-ketamine in patients with intractable central pain: a placebo-controlled trial. Pain 2005; 118(1-2):224-31.
9. Nirschl RP, Rodin DM, Ochiai DH et al. for the DEX-AHE-01-99 Study Group. Iontophoretic administration of dexamethasone sodium phosphate for acute epicondylitis. A randomized, double-blinded, placebo-controlled study. Am J Sports Med 2003; 31(2):189-95.
10. Neeter C, Thomee R, Silbernagel KG et al. Iontophoresis with or without dexamethazone in the treatment of acute Achilles tendon pain. Scand J Med Sci Sports 2003; 13(6):376-82.
11. Osborne HR, Allison GT. Treatment of plantar fasciitis by LowDye taping and iontophoresis: short term results of a double blinded, randomised, placebo controlled clinical trial of dexamethasone and acetic acid. Br J Sports Med 2006; 40(6):545-9.
12. Leduc BE, Caya J, Tremblay S et al. Treatment of calcifying tendinitis of the shoulder by acetic acid iontophoresis: a double-blind randomized controlled trial. Arch Phys Med Rehabil 2003; 84(10):1523-7.
13. Amirjani N, Ashworth NL, Watt MJ et al. Corticosteroid iontophoresis to treat carpal tunnel syndrome: a double-blind randomized controlled trial. Muscle Nerve 2009; 39(5):627-33.
14. Gurney AB, Wascher DC. Absorption of dexamethasone sodium phosphate in human connective tissue using iontophoresis. Am J Sports Med 2008; 36(4):753-9.
15. Turner J, Belch JJ, Khan F. Current concepts in assessment of microvascular endothelial function using laser Doppler imaging and iontophoresis. Trends Cardiovasc Med 2008; 18(4):109-16.
16. Rao R, Nanda S. Sonophoresis: recent advancements and future trends. J Pharm Pharmacol 2009; 61(6):689-705.
17. Zelrix™ - Transdermal Treatment for Acute Migraine, NuPathe^®, Inc. (not FDA approved). 

Coding Section 

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive. 

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies and accredited national guidelines.

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