Iontophoresis Analgesic Medications

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Continuing Education Activity

Analgesic iontophoresis is the administration of analgesic medications via iontophoresis used in the management and treatment of pain. The technique may employ multiple classes of drugs. This activity outlines the indications, action, and contraindications for iontophoresis as a valuable agent in the management of painful conditions. This activity will highlight the mechanism of action, adverse event profile, and other key factors (e.g., off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant interactions) pertinent for members of the healthcare team and patients in the management of patients with acute or chronic pain and related conditions.


  • Identify the mechanism of action and administration of iontophoretic analgesia.
  • Describe the adverse effects and contraindications of iontophoretic analgesia.
  • Outline appropriate monitoring and toxicity of iontophoretic analgesia.
  • Review interprofessional team strategies for improving care coordination and communication to advance iontophoretic analgesia and improve outcomes.


Iontophoresis is a method of transdermal drug delivery wherein a clinician uses an electric current to promote localized, superficial permeation of a therapeutic agent through the skin. Among the earliest applications of electrical current for medical therapy was by Pivati in 1740 to treat arthritis.[1] More notable advances were made during the 1800s by pioneering scientists such as Benjamin Ward Richardson, William James Morton, and Frtiz Frankenhäuser - the latter of whom coined the phrase “iontophoresis” in favor of “cataphoresis” which had been used more commonly prior to the 20th century.[2] More recently, iontophoresis has been referred to as “electrically-assisted transdermal drug delivery” in some clinical contexts as well.

Nomenclature notwithstanding, the indications for iontophoresis are numerous and may involve local, regional, or systemic delivery. Localized delivery of therapeutic agents includes local anesthetics (e.g., lidocaine) and fentanyl for analgesia, retinoids, and corticosteroids to treat scarring from acne, and antiperspirants for palmar and plantar hyperhidrosis.[2][3][4][5] Regional applications of iontophoresis include the delivery of anti-inflammatory agents into subcutaneous tissue and joint spaces to relieve tendonitis, arthritis, or transient muscle soreness. Lastly and more rarely, systemic delivery of drugs via transdermal iontophoresis include fentanyl for analgesia, antimigraine agents (e.g., triptan drugs) for headache, nicotine for smoking cessation, reversible cholinesterase inhibitors such as rivastigmine for Alzheimer disease, and even proteins or peptides such as insulin.[6][7][8][9][10][11][12][13]

This activity will explore the indications, mechanisms, and benefits/risks of iontophoresis in the context of analgesic medication delivery and pain relief both locally and systemically.

Mechanism of Action

Transdermal iontophoresis of analgesics involves the use of an electromotive gradient (i.e., voltage) across a positively-charged anode and negatively-charged cathode to induce percutaneous infiltration of a therapeutic agent via active transport for local, regional, or systemic delivery (Figure 1). The primary interface medications must travel through is the stratum corneum (SC) of the skin, approximately 10 to 100 micrometers in thickness.[2] Three primary pathways exist for absorption through the SC: paracellular (between keratinocytes), transcellular (through keratinocytes), and appendageal (through hair follicles, sudoriferous glands, sebaceous glands, etc.) with the latter believed to have the lowest electromotive resistance.[2][14] The quantification of percutaneous permeation is generally as a chemical flux (flow rate of the molecular or ionic agents over a given surface area). Employing electron-repulsion as a driving force, iontophoresis entails placing positively-ionized (cationic) or neutral medications below the positively-charged electrode (anode). In contrast, negatively-ionized drugs become oriented below the negatively-charged electrode (cathode) (Figure 1). Due to electrostatic repulsion, agents are driven away from their like-charged electrode(s) and through the integumentary interface. Numerous factors affecting medication flux and end-delivery have been elucidated and include the following [2]:

  • Electrochemical properties of the analgesic solution (e.g., charge, concentration, molecular size, delivery mechanism, buffer type, and viscosity of analgesic and non-analgesic constituents)
  • Iontophoretic equipment parameters (current amplitude, type, frequency, and duration)
  • Patient physiology (skin moisture, local blood flow, temperature)


Multiple formulations for analgesic agent delivery via iontophoresis exist currently with approval from the Food and Drug Administration. These include various formulations including patient-activated fentanyl 40 mcg solution, lidocaine hydrochloride (HCl) 2% with epinephrine 1 to 100000 solution, lidocaine HCl with epinephrine topical iontophoretic patch (10%/0.1%), and lidocaine HCl 4% solution.

Adverse Effects

Transdermal iontophoresis is generally considered one of the safest delivery modalities; however, researchers have noted adverse effects in the literature. Due to its penetration of cutaneous media, among the most reported side effects of the procedure include local paresthesia, itching, irritation, erythema, edema, and galvanic urticaria.[15][16][17] More rarely, however, patients may experience a burning sensation and even superficial skin burns, most often due to improper electrode placement or medication formulation. Factors such as higher current, longer durations of administration, electrode placement over skin defects, use of inadequate or relatively alkaline phase buffers, and use of bare metal or carbon electrodes all increase the risk of skin damage and burns.[18] Patients and healthcare providers may mitigate the likelihood of cutaneous injuries by avoiding non-uniform electrode compression at the cutaneous surface with an adhesive seal, placing adequately wetted sponges between the electrode and skin, cleaning the application site with alcohol, and avoiding areas of skin lesions or defects with a current, and maintaining an ion flux of below 0.5 mA/cm^2.[15][19][20]


Contraindications to iontophoresis include those related to direct electrical stimulation and from the therapeutic agent involved. Patients with a history of hypersensitivity or adverse reactions associated with the delivered drug in question should avoid iontophoresis of the offending agent. Patients with prior medical histories of cardiac arrhythmias or hypercoagulability should not receive the procedure near cardiac pacemakers and superficial blood vessels. Clinicians should avoid the procedure in the vicinity of embedded wires, stapes, orthopedic implants, and areas of skin with lesions and impaired sensation.[21] There has been no investigation of iontophoresis during pregnancy and, therefore, it either should not be used or used with extreme caution during pregnancy.


Depending on the analgesic agent delivered, the scope and intensity of patient monitoring may vary. As mentioned before, among the most used agents for analgesia in the context of iontophoresis include local anesthetics and fentanyl. For both agents, signs of adverse skin reactions and systemic symptoms indicative of hypersensitivity or toxicity require close monitoring, and the treating clinician should undertake steps to mitigate and reverse symptoms promptly.[22][23][24] Additional monitoring modalities may include:

  1. Electrocardiography (EKG)
  2. Pulse oximetry
  3. Blood pressure


In addition to localized, cutaneous adverse effects, patients may experience adverse or even toxicity symptoms stemming from offending therapeutic agents as well. In the context of iontophoretic analgesia, the most used medicines are local anesthetics and fentanyl. With the use of local anesthetics (chiefly lidocaine and lidocaine/epinephrine), acute concerns arise for local adverse reactions and local anesthetic systemic toxicity (LAST). Cardiopulmonary symptoms include heart block, cardiac arrhythmia, respiratory insufficiency and arrest, and cardiac arrest. The central nervous system may similarly experience depression with symptoms such as tinnitus, ataxia, akathisia, seizures, altered levels of consciousness, and coma.[22][25] Management of LAST includes [22][26][27]:

  1. Airway management with ventilation, oxygenation
  2. Cardiovascular support with epinephrine and antiarrhythmic agents
  3. Prophylaxis and suppression of seizures with benzodiazepines and succinylcholine
  4. Local anesthetic reduction from intravascular space with lipid-emulsion and bypass

With the use of fentanyl, patients may experience cardiopulmonary and CNS depressive symptoms as described before with LAST, however, due to its narrow therapeutic window and often systemic delivery, toxicity symptoms of more acute concern.[28] Although there are no reports of cases of an iontophoretic fentanyl overdose, any compromise to the delivery mechanism may result in the administration of supratherapeutic doses without patient awareness.[15] In cases of a fentanyl overdose, medically appropriate interventions are similar to those of other opioid overdoses, including [28]:

  1. Primary survey with airway, breathing, and circulatory support
  2. Administration of intravenous (IV), intramuscular (IM), subcutaneous (SQ), or intranasal (NAS) administration of naloxone
  3. If indicated, some special circumstances may require complementing the above regimen with activated charcoal, bowel irrigation, and buprenorphine.

Enhancing Healthcare Team Outcomes

Analgesic iontophoresis has numerous applications and offers benefits, including its relative non-invasiveness and bypass of the first-pass metabolism. However, its use in pain relief has been precluded by the more cost-effective nature of injection and transdermal skin patches in addition to safety concerns of unintended overdose.[15] Nonetheless, newer advances may make technology more promising for analgesia in the future. Practitioners prescribing or administering iontophoretic therapies in addition to patients should be acutely aware of indications, realistic therapy goals, and the benefits and risks that accompany the intervention, and consult with a pharmacist to ensure appropriate dosing and the absence of drug interactions. Patients and practitioners should moreover be adequately informed of all clinically germane aspects of the procedure to ensure the correct use and proper administration. Lastly, all of the interprofessional team involved (e.g., physicians, nurses, therapists, pharmacists, patients) should be aware of adverse symptoms and potential signs of toxicity and hypersensitivity and adequately monitor for these signs, as discussed before, to mitigate any adverse outcomes promptly. Pharmacists review medications for indications, dosage, and interactions. Nurses monitor patients, provide education, and report responses and issues to the team. [Level 5]

Article Details

Article Author

Nafiz K. Sheikh

Article Editor:

Anterpreet Dua


8/1/2022 8:03:45 PM



Anliker MD,Kreyden OP, Tap water iontophoresis. Current problems in dermatology. 2002;     [PubMed PMID: 12471698]


Rawat S,Vengurlekar S,Rakesh B,Jain S,Srikarti G, Transdermal delivery by iontophoresis. Indian journal of pharmaceutical sciences. 2008 Jan;     [PubMed PMID: 20390073]


Maloney JM, Local anesthesia obtained via iontophoresis as an aid to shave biopsy. Archives of dermatology. 1992 Mar;     [PubMed PMID: 1550364]


Schmidt JB,Binder M,Macheiner W,Bieglmayer C, New treatment of atrophic acne scars by iontophoresis with estriol and tretinoin. International journal of dermatology. 1995 Jan;     [PubMed PMID: 7896490]


Sloan JB,Soltani K, Iontophoresis in dermatology. A review. Journal of the American Academy of Dermatology. 1986 Oct;     [PubMed PMID: 3534013]


Siegel SJ,O'Neill C,Dubé LM,Kaldeway P,Morris R,Jackson D,Sebree T, A unique iontophoretic patch for optimal transdermal delivery of sumatriptan. Pharmaceutical research. 2007 Oct;     [PubMed PMID: 17577644]


Pierce M,Marbury T,O'Neill C,Siegel S,Du W,Sebree T, Zelrix: a novel transdermal formulation of sumatriptan. Headache. 2009 Jun;     [PubMed PMID: 19438727]


Chelly JE,Grass J,Houseman TW,Minkowitz H,Pue A, The safety and efficacy of a fentanyl patient-controlled transdermal system for acute postoperative analgesia: a multicenter, placebo-controlled trial. Anesthesia and analgesia. 2004 Feb;     [PubMed PMID: 14742382]


Escobar-Chávez JJ,Merino V,López-Cervantes M,Rodríguez-Cruz IM,Quintanar-Guerrero D,Ganem-Quintanar A, The use of iontophoresis in the administration of nicotine and new non-nicotine drugs through the skin for smoking cessation. Current drug discovery technologies. 2009 Sep;     [PubMed PMID: 19496753]


Jaskari T,Vuorio M,Kontturi K,Urtti A,Manzanares JA,Hirvonen J, Controlled transdermal iontophoresis by ion-exchange fiber. Journal of controlled release : official journal of the Controlled Release Society. 2000 Jul 3;     [PubMed PMID: 10825552]


Chien YW,Siddiqui O,Shi WM,Lelawongs P,Liu JC, Direct current iontophoretic transdermal delivery of peptide and protein drugs. Journal of pharmaceutical sciences. 1989 May;     [PubMed PMID: 2664126]


Rastogi SK,Singh J, Transepidermal transport enhancement of insulin by lipid extraction and iontophoresis. Pharmaceutical research. 2002 Apr;     [PubMed PMID: 12033375]


Chen H,Zhu H,Zheng J,Mou D,Wan J,Zhang J,Shi T,Zhao Y,Xu H,Yang X, Iontophoresis-driven penetration of nanovesicles through microneedle-induced skin microchannels for enhancing transdermal delivery of insulin. Journal of controlled release : official journal of the Controlled Release Society. 2009 Oct 1;     [PubMed PMID: 19481577]


Riviere JE,Heit MC, Electrically-assisted transdermal drug delivery. Pharmaceutical research. 1997 Jun;     [PubMed PMID: 9210183]


Roustit M,Blaise S,Cracowski JL, Trials and tribulations of skin iontophoresis in therapeutics. British journal of clinical pharmacology. 2014 Jan;     [PubMed PMID: 23590287]


Li GL,Van Steeg TJ,Putter H,Van Der Spek J,Pavel S,Danhof M,Bouwstra JA, Cutaneous side-effects of transdermal iontophoresis with and without surfactant pretreatment: a single-blinded, randomized controlled trial. The British journal of dermatology. 2005 Aug;     [PubMed PMID: 16086757]


Meffert JJ, Galvanic urticaria. Cutis. 1999 Jun;     [PubMed PMID: 10388952]


Lesions and shocks during iontophoresis. Health devices. 1997 Mar;     [PubMed PMID: 9067727]


Warden GD, Electrical safety in iontophoresis. Rehab management. 2007 Mar;     [PubMed PMID: 17366933]


Dixit N,Bali V,Baboota S,Ahuja A,Ali J, Iontophoresis - an approach for controlled drug delivery: a review. Current drug delivery. 2007 Jan;     [PubMed PMID: 17269912]


Hölzle E, [Tap water iontophoresis]. Der Hautarzt; Zeitschrift fur Dermatologie, Venerologie, und verwandte Gebiete. 2012 Jun;     [PubMed PMID: 22660258]


Mahajan A,Derian A, Local Anesthetic Toxicity 2019 Jan;     [PubMed PMID: 29763139]


Schiller EY,Mechanic OJ, Opioid Overdose 2019 Jan;     [PubMed PMID: 29262202]


Wolfe RC,Spillars A, Local Anesthetic Systemic Toxicity: Reviewing Updates From the American Society of Regional Anesthesia and Pain Medicine Practice Advisory. Journal of perianesthesia nursing : official journal of the American Society of PeriAnesthesia Nurses. 2018 Dec;     [PubMed PMID: 30449428]


Becker DE,Reed KL, Essentials of local anesthetic pharmacology. Anesthesia progress. 2006 Fall;     [PubMed PMID: 17175824]


Weinberg GL, Treatment of local anesthetic systemic toxicity (LAST). Regional anesthesia and pain medicine. 2010 Mar-Apr;     [PubMed PMID: 20216036]


Picard J,Meek T, Lipid emulsion to treat overdose of local anaesthetic: the gift of the glob. Anaesthesia. 2006 Feb;     [PubMed PMID: 16430560]


Ramos-Matos CF,Lopez-Ojeda W, Fentanyl 2019 Jan;     [PubMed PMID: 29083586]