Publication extender

Diabetic peripheral neuropathy: Pathophysiology and new insights into the mechanism of action of high-concentration topical capsaicin

Averitas Pharma

DOI: 10.26303/777h-gn16

This page is intended for US healthcare professionals only and provides a summary of Armstrong DC, et al. Journal of Experimental Pharmacology. 2025;17:651–665. It is a simplified representation created by Averitas Pharma, and should not be considered a replacement for the full article or its abstract. This publication was developed with support from Averitas Pharma. Please refer to the original publication for further details and disclosures. Disclaimer: Capsaicin 8% topical system is approved by the FDA for the treatment of neuropathic pain associated with diabetic peripheral neuropathy of the feet. This publication includes mechanistic observations and clinical findings that extend beyond the FDA-approved labeling. The safety and efficacy of capsaicin 8% topical system for uses not described in the approved labeling have not been established. Read the original publication. Read the Indication and Select Important Safety Information.

What is it about?

Diabetic peripheral neuropathy (DPN) occurs when ongoing metabolic imbalances from diabetes damage sensory nerves and supporting blood vessels. This reduces nerve fiber density in the skin, and the remaining fibers become more sensitive due to structural and functional changes. Together with changes in local blood flow, these effects may result in patients experiencing pain, loss of normal sensation, and slower wound healing, particularly in the feet.

The capsaicin 8% topical system (referred to here as a high-concentration capsaicin topical system, or HCCTS) contains capsaicin, targets transient receptor potential vanilloid subtype 1 (TRPV1), a receptor found on certain pain-sensing nerve fibers.

Activation of TRPV1 causes an influx of calcium ions into nerve cells, triggering processes that result in the trimming of nerve fibers, or neurolysis. Trimming of nerve fibers may result in temporarily suspended pain signaling.

Over time, nerve fibers may regrow with increased density, reduced hyperexcitability, and improved blood flow responses in the skin. However, the ongoing metabolic and microvascular changes associated with diabetes can continue to cause nerve fiber dysfunction resulting in pain. HCCTS treatment may support cycles of neurolysis and nerve regrowth.

Limitations:

Further research is needed to better understand nerve damage in type 1 and type 2 diabetes and to determine when capsaicin-based therapy may be most effective, potentially at earlier disease stages. Additional studies should further characterize biologic and clinical effects of repeated treatment beyond pain relief, including potential effects on nerve damage progression and functional outcomes.

Why is it important?

In DPN, progressive loss and dysfunction of small nerve fibers occurs over time and can lead to both increased pain signaling and loss of normal sensation. Oral systemic therapies commonly used in clinical practice may be associated with challenges related to efficacy, tolerability, and adherence. There remains a need for non-systemic treatments that are effective, well-tolerated, and more conducive to consistent use.

The HCCTS acts locally on pain-sensing nerve fibers in the skin. Following treatment, published data describe an initial reduction in nerve fiber endings followed by regrowth over time, along with changes in blood flow that may support nerve regeneration. Clinical study findings suggest repeated treatment may be associated with reductions in pain and changes in sensory function over time. Changes in concomitant medication use and quality of life have also been reported across clinical, post-hoc, and exploratory analyses.

Key takeaways:

  • HCCTS is described as providing localized pain relief by inducing temporary neurolysis of TRPV1-expressing sensory nerve fibers followed by nerve regrowth which has been evaluated in post-hoc and clinical analyses, with changes in sensory function in some patients across clinical and post hoc analyses
  • Repeated HCCTS treatment has been associated with sustained pain relief over time, with additional observations from exploratory analyses evaluating quality of life

--- Abbreviations and references: DPN, diabetic peripheral neuropathy; HCCTS, high-concentration capsaicin topical system; TRPV1, transient receptor potential vanilloid.

Armstrong DC, et al. Journal of Experimental Pharmacology. 2025;17:651–665. Averitas Pharma provided financial and medical editorial support for the development of Armstrong DC et al. J Exp Pharmacol. 2025.

QZA-02-26-0027 | June 2026

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Who is involved?

Indication and Select Important Safety Information

Information updated in April 2026.

INDICATION

In the USA, capsaicin 8% topical system is indicated for the treatment of neuropathic pain associated with postherpetic neuralgia (PHN) and neuropathic pain associated with diabetic peripheral neuropathy (DPN) of the feet.

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