'Why Skin Matters': Panel Examines Current and Future Topical Treatments for Neuropathic Pain

PALM SPRINGS, CA—Increased understanding of the function of the epidermis can only lead to new assessments and more targeted topical treatments for acute and chronic pain, according to a panel presentation at the 2012 American Academy of Pain Medicine Annual Meeting.

Neuropathic pain affects 3% of the general population. In addition to resulting in a tripling of healthcare resource utilization and reduced productivity, neuropathic pain has a substantial impact on numerous domains of quality of life, said John F. Peppin, DO, The Pain Treatment Center of the Bluegrass, Lexington, KY, and panel chairperson.

There is a tremendous need for treatments for neuropathic pain, he added. Benefits of topical approaches, “which have been legion for millennia,” include reduced systemic exposure, reduced side effects, and reduced drug-drug interactions. Types of topical treatments include gel, patch, foams, powder, solid, sponge, tape, vapor, and paste.

Frank L. Rice, PhD, of Albany Medical College and Integrated Tissue Dynamics, LLC, Albany, NY, presented new insights regarding epidermal-based mechanisms of pain. The challenge: “the skin is the largest, most exposed, complex, integrated, multi-functional organ,” he said, with both functional and structural complexity.

The skin and its innervation are vulnerable to numerous debilitating painful and disfiguring afflictions—the symptoms of which are rash, sores, discoloration, pain, itch, and numbness—that lack effective therapeutics. These include >150 varieties of peripheral neuropathies and >1500 varieties of dermapathologies. However, “the skin and its innervation are especially susceptible to pharmacotoxicity and are a good model for assessing pharmacodynamics,” he pointed out, in that the epidermis functions like a neuronal system: one small event can cascade throughout the system.

For this reason, the skin is a “valuable tool in which to apply multi molecular approaches,” including elucidation of mechanisms of normal tactile sensation, distinguishing between different types of peripheral neuropathies and dermatopathies, identifying inclusion and exclusion criteria needed to match patients to the most effective and safe therapeutics more effectively, identifying and testing potential therapeutic strategies for the prevention and treatment of many chronic pain conditions, and assessing the safety of therapeutics in general.

Charles E. Argoff, MD, of Albany Medical Center, Albany, NY, provided an overview of currently available topical agents for neuropathic pain. First-line options include topical lidocaine; the secondary amine tricyclic antidepressants nortriptyline and desipramine; the serotonin–norepinephrine reuptake inhibitors milnacipran, duloxetine, and venlafaxine; and the calcium channel ligands gabapentin and pregabalin. Second-line options include tramadol.

He also outlined topical treatments for acute or chronic pain, including diclofenac (patch/gel/lotion), capsaicin, local anesthetics (lidocaine patch 5%/lidocaine-tetracaine), and over-the-counter preparations such as methylsalicylate 15%, 30% cream and ointment; menthol 2.5%, 5%, 105, and 16%; trolamine salicylate 10% cream and lotion; and camphor 11%/menthol 11%.

The diclofenac patch is approved for the treatment of acute musculoskeletal injury (sprains/strains); one patch is applied twice daily to intact skin only. Adverse effects include erythema, pruritus, dermatitis, and blisters. Diclofenac 1% gel is approved for the treatment of osteoarthritis of the knee/hand or other areas that can be reached by topical application, Dr. Argoff said. The gel is applied 4 times daily to the affected area. Adverse effects include local applicaqtion site skin complaints.

The capsaicin 8% patch, approved for the treatment of postherpetic neuralgia (PHN), is applied for 60 minutes every 3 months; up to 4 patches can be used per session. Adverse effects include application site erythema and pain.

The lidocaine 5% patch is also approved for PHN; up to 3 patches are applied 12 hours/day to intact skin. Local application site skin reactions are the most common side effects, he said, adding that systemic side effects have been reported such as nervousness, light-headedness, and confusion—but are uncommon.

The lidocaine 70mg/tetracaine 70mg patch, approved for local dermal analgesia for superficial venous access and dermatologic procedures, is applied to the skin for 20-30 minutes prior to the procedure. It contains a heating component to enhance local anesthetic delivery, he noted.

An overview of topical therapies for chronic pain syndromes was provided by Marco Pappagallo, MD, Director, New Medical Home for Chronic Pain, New York, NY. He noted that principles of topical therapies for pain include targeting regional pain by acting on skin and intradermal small nerve fibers and may reach deeper tissues and superficially running peripheral nerves. However, no clinically significant dose reaches the systemic circulation; therefore, no systemic side effects or drug-drug interactions are observed.

Classes of topical pharmacologic agents

  • Local anesthetics
  • Botulinum toxin
  • TRPV1 agonists (capsaicin)
  • Cyclooxygenase inhibitors (aspirin, diclofenac)
  • ATP-sensitive K+ channel openers
  • Opioids (morphine, loperamide, methadone + meperidine, methadone + morphine))
  • Alpha-2 agonists (clonidine patch for sympathetically maintained pain; clonidine 0.1% gel for PDN; ARC-4558 in development)
  • Tricyclic antidepressants (amitriptyline, amitriptyline + ketamine, doxepin, amitriptyline + ketamine + lidocaine)
  • NMDA receptor antagonists
  • Antioxidants (dimethylsulfoxide 50% [DMSO] for complex regional pain syndrome)
  • Endocannabinoids (palmitoylethanolamide [endogenous lipid; in development])

Burkhard Gustorff, MD, of Wilhelminenspital der Stadt Wien, Vienna, Austria, found that mechanical hyperalgesia responds to lidocaine and capsaicin patches; however, typical C-fiber mediated pain did not response to the lidocaine patch. Actual mechanism of response to capsaicin remains to be determined. He noted that thermal sensation may not serve as a predictor of response to capsaicin, whereas mechanical hyperalgesia may respond.

Mark S. Wallace, MD, of the University of California, San Diego, San Diego, CA, provided an overview of human experimental models of pain that can be used to test topical agents. These models are less expensive than conducting clinical trials, he said, especially since <10% of drugs that show promise in Phase I/II clinical trials are eventually marketed. In addition, they offer study population homogeneity, homogenous afferent activation, and translational research capabilities.

Key experimental medicine candidates include cold pressor, acute pain models, intradermal capsaicin, topical capsaicin, heat/capsaicin sensitization, UVB, brief thermal sensitization, and intramuscular capsaicin.