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Review
. 2025 Sep 9:17:651-665.
doi: 10.2147/JEP.S526968. eCollection 2025.

Diabetic Peripheral Neuropathy: Pathophysiology and New Insights into the Mechanism of Action of High-Concentration Topical Capsaicin

David G Armstrong  1 , Keith Bley  2 , David M Simpson  3 , Peter Staats  4 , Samuel Allen  5 , Audrey Carnevale  5 , Lizandra Marcondes  5
Affiliations
Review

Diabetic Peripheral Neuropathy: Pathophysiology and New Insights into the Mechanism of Action of High-Concentration Topical Capsaicin

David G Armstrong et al. J Exp Pharmacol. .

Abstract

Diabetic peripheral neuropathy (DPN) is a chronic, progressive complication of diabetes. Pain in DPN can be severe and detrimental to the patient's quality of life. In this review, we provide an update on the mechanism of action (MOA) of high-concentration capsaicin topical system (HCCTS) for treatment of painful DPN, with an emphasis on neuroregeneration. In diabetes, hyperglycemia and other metabolic imbalances lead to oxidative stress and inflammation, which result in degeneration of the axons of afferent neurons (particularly C and Aδ fibers) within the peripheral nervous system. Dysfunction of the microvasculature supporting the nerves further exacerbates neural damage. As a result, epidermal nerve fiber density (ENFD) diminishes, and physical and chemical changes to the remaining afferent fibers render them hypersensitive to painful stimuli and hyposensitive to normal stimuli. As the longest axons are usually damaged first, DPN normally begins in the feet, then legs, and finally the hands. HCCTS incorporates a matrix technology that forcibly diffuses a high concentration of capsaicin (a TRPV1 agonist) to the dermis and epidermis, targeting TRPV1 receptors that are upregulated in DPN and play a key role in pain generation. HCCTS activates TRPV1 receptors expressed on the neuron cell membrane and endoplasmic reticulum, leading to cytoplasmic calcium ion overload, and then a cascade of cellular events resulting in reversible neurolysis of these afferent terminals. After 1-3 months, the terminals regenerate with a "healthier" phenotype, increasing ENFD, resulting in vasodilation, which may lead to a microenvironment conducive to improved neuroregeneration. This MOA is supported by clinical evidence demonstrating that repeated HCCTS treatment provides cumulative benefits in pain and improvements in sensory function of the feet compared with baseline. If effects on sensory function are confirmed in large-scale clinical studies, HCCTS could help slow the progression of DPN to more severe forms of diabetic foot syndrome.

Keywords: DPN; TRPV1; capsaicin; degeneration; hyperalgesia; neurolysis.

Plain language summary

Diabetic peripheral neuropathy, or DPN, is a long-term complication of diabetes that gets worse over time if left untreated. People with DPN may experience severe pain and poor physical and mental health. DPN occurs when elevated blood sugar levels progressively damage sensory nerve fibers in the skin and their supporting blood vessels. As a result, the number of nerve fibers in the skin decreases, and the remaining nerve fibers undergo changes that heighten their sensitivity. These changes can also lead to loss of normal feeling in the skin and slow wound healing, especially in the feet. High-concentration capsaicin topical system (HCCTS) is a treatment that is placed directly onto the skin, and approved in many countries to manage peripheral neuropathic pain; in the United States, it is approved for treatment of pain associated with DPN in the feet. HCCTS is applied by a healthcare professional to the feet for 30 minutes, and this medicine works by targeting and silencing pain receptors on nerve fibers, which leads to pain relief. After 1–3 months, nerve fibers grow back and are “healthier” than before, responding more normally to stimuli. Improved nerve functioning increases blood flow, which may help improve regeneration of healthier nerves. Repeated treatment of DPN with HCCTS is needed because diabetes is a long-term condition in which the nerves are constantly under attack from high blood sugar levels. Studies in patients with DPN have shown that HCCTS can provide long-lasting pain relief and improve quality of life.

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Conflict of interest statement

SA, AC, and LM were employees of Averitas Pharma at the time of writing this review. DS reports personal fees from Averitas and Grunenthal, outside the submitted work. PS reports royalties for patent on high-dose capsaicin; grants from Nalu, and Saluda, outside the submitted work. The authors report no other conflicts of interest in this work.

Figures

None
Graphical abstract
Figure 1
Figure 1
Mechanisms of neuronal damage caused by hyperglycemia and dyslipidemia in type 1 and type 2 diabetes. Asterisks indicate mechanisms in type 2 diabetes only. Adapted from Feldman EL, Callaghan BC, Pop-Busui R, et al. Diabetic neuropathy. Nat Rev Dis Primers. 2019;5(1):41. With permission from SNCSC.
Figure 2
Figure 2
Proposed model for the effect of the HCCTS on nerve fiber anatomy and function via localized neurolysis and regeneration of TRPV1-positive nerve fibers. Nerve fiber density is reduced in the epidermis of patients with DPN, and the remaining fibers may exhibit an altered pain response. Following treatment with the HCCTS, the localized neurolysis of epidermal nerve fiber endings is followed by regeneration with potential restoration of a more normal phenotype and response to external stimuli. Based on findings from Kennedy et al, 2010 and Anand & Bley, 2022.
Figure 3
Figure 3
Structure of the HCCTS matrix technology and capsaicin delivery system. Therapeutic patch for transdermal delivery of capsaicin. Patent: US-8821920-B2. 2014. https://pubchem.ncbi.nlm.nih.gov/patent/US-8821920-B2.
Figure 4
Figure 4
Molecular changes occurring following activation of TRPV1 by high-dose capsaicin. Adapted from Anand P, Bley K. Topical capsaicin for pain management: therapeutic potential and mechanisms of action of the new high-concentration capsaicin 8% patch. Br J Anaesth. 2011;107(4):490–502. Creative Commons.
Figure 5
Figure 5
Continued.
Figure 5
Figure 5
Data demonstrating benefit of continued HCCTS treatment on the feet in patients with DPN. (A) Data from PACE: Mean 24-hour pain intensity over 12 months following seven applications of HCCTS with ≥8-week intervals. SOC was optimized for each patient at the discretion of each investigator and was assessed at clinic visits and on days 1 to 5 post treatment by completion of a rescue pain medication diary. Adapted from Vinik AI, Perrot S, Vinik EJ, et al. Repeat treatment with capsaicin 8% patch (179mg capsaicin cutaneous patch): effects on pain, quality of life, and patient satisfaction in painful diabetic peripheral neuropathy: an open-label, randomized controlled clinical trial. J CurrMed Res Opinion. 2019;2(12):388–401. Creative Commons. (B) Post-hoc analysis of PACE: Sensory perception in patients with abnormally low sensation at baseline (measured via the Brief Sensory Pain Examination), using five sensory modalities. Data indicate patients who experienced a shift from “below normal” to “normal” after up to six 30-minute applications of HCCTS at the months indicated. (C) Data from CASPAR, a retrospective observational study: Average 24-hour pain intensity (measured via a VAS; 0 = no pain; 100 = worst possible pain) among patients who received four HCCTS treatments (n=108). Adapted with permission from Katz N, Allen S, Carnevale A, Gordon K. Impact of treatment with high-concentration capsaicin (8%) (QTZ) topical system on sensory testing in patients living with painful diabetic peripheral neuropathy of the feet: a post-hoc analysis of the PACE trial. In: American Podiatric Medical Association (AMPA) Annual Scientific Meeting. Washington DC; 2024.
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