Reversing painful and non-painful diabetic neuropathy with the capsaicin 8% patch: Clinical evidence for pain relief and restoration of function via nerve fiber regeneration
Journal article
Published on October 26, 2022

Reversing painful and non-painful diabetic neuropathy with the capsaicin 8% patch: Clinical evidence for pain relief and restoration of function via nerve fiber regeneration

Contributors:

Anand P, Privitera R, Donatien P et al.

Name of journal:

Frontiers in Neurology

View publication

DOI:

10.3389/fneur.2022.998904

Topics:

DPN Phase 4 Peripheral neuropathic pain Randomized controlled trial Capsaicin 8% topical system
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This page provides a summary of Anand P et al. Front Neurol. 2022;13:998904. It is a simplified representation of the key points that was created by Averitas Pharma, and should not be considered a replacement for the full article or its abstract. Please refer to the original publication for further details and disclosures.

Summary

Investigating the potential of capsaicin 8% topical system to promote epidermal nerve fiber regeneration in patients with diabetic peripheral neuropathy1

Background

Diabetic peripheral neuropathy results from dysfunction of peripheral nerve fibers in people with diabetes and can involve neuropathic pain, a condition known as painful diabetic peripheral neuropathy (PDPN).1 Dysfunction or loss of sensory fibers in patients with diabetic peripheral neuropathy are associated with loss of protective sensation, axon-reflex vasodilation, and trophic changes.1 These can contribute to the development and non-healing of foot ulcers, leading to an increased risk of amputations.1

Capsaicin 8% topical system (previously known as capsaicin 8% patch) is an FDA-approved topical treatment for PDPN of the feet.1 It is a transient receptor potential vanilloid 1 (TRPV1) channel agonist that acts by inducing a mechanism of temporary neurolysis (or defunctionalization) in sensory nerve terminals in the outermost layers of the skin.1,2

Peripheral nerve fiber dysfunction and pain of the feet in painful diabetic peripheral neuropathy<sup>1</sup>
Peripheral nerve fiber dysfunction and pain of the feet in painful diabetic peripheral neuropathy1

Aim

The primary objective of this phase 4, interventional, randomized controlled trial was to investigate the mechanisms underlying pain relief in patients with PDPN of the feet following a 30-min application of the capsaicin 8% topical system plus standard of care (SOC) versus SOC alone for up to 3 months.1 Patients with non-painful diabetic peripheral neuropathy (NPDPN) were also included to further explore potential changes in epidermal nerve fiber density following treatment with capsaicin 8% topical system.1

Pain symptoms were assessed using the numerical pain rating scale (NPRS) and the Short-Form McGill Pain Questionnaire-2 (SF-MPQ-2).1 The structural nerve marker protein gene product 9.5 (PGP9.5) was used to quantify intraepidermal (IENF) and subepidermal (SENF) nerve fiber density from calf skin biopsy sections (15 and 50 µm).1 Quantification of SENFs was also done with the nerve fiber regeneration marker growth-associated protein 43 (GAP43).1

Capsaicin 8% topical system acts locally on nociceptive nerve fibers in the outermost layers of the skin<sup>1</sup>
Capsaicin 8% topical system acts locally on nociceptive nerve fibers in the outermost layers of the skin1

Key findings

The capsaicin 8% topical system significantly increased density of IENF and SENF nerve fibers both in patients with painful and non-painful diabetic peripheral neuropathy, indicating nerve fiber regeneration1

When comparing IENF and SENF densities between baseline and 3 months after treatment in the study groups who received standard of care (SOC) and the 30-min treatment with capsaicin 8% topical system (Q), significant increases in nerve fiber density were seen1:

Skin biopsies collected at 3-month intervals from a patient in the PDPN Q+SOC group showed that 9 months post-treatment GAP43 SENF density returned to pre-treatment levels, indicating temporary regeneration of nerve fibers after a single application of capsaicin 8% topical system.1

 

To learn more about repeated treatment with capsaicin 8% topical system, check out the results from the PACE and CASPAR studies.

Pain relief and nerve fiber regeneration following treatment with capsaicin 8% topical system<sup>1</sup>
Pain relief and nerve fiber regeneration following treatment with capsaicin 8% topical system1
Significant pain reductions were seen for patients with painful diabetic peripheral neuropathy treated with the capsaicin 8% 
topical system1

Three months after treatment, patients in the PDPN Q+SOC group (n=25) had significant pain reductions as assessed through both the NPRS and the SF‑MPQ‑2:

Patients with painful diabetic peripheral neuropathy who received SOC alone (PDPN SOC; n=12) did not have significant pain relief.1

Warm perception threshold significantly improved for the PDPN Q+SOC group (p=0.02).1

Increases in nerve fiber density in the PDPN Q+SOC group correlated with pain relief, while increases in nerve fiber density in a NPDPN Q+SOC subset correlated with axon-reflex vasodilation1

The increases in PGP9.5 IENF, PGP9.5 SENF and GAP43 SENF densities correlated with pain relief for the PDPN Q+SOC group (p=0.0008, p=0.0001 and p=0.004, respectively), while patients who did not experience pain relief did not show any increase in PGP9.5 IENF, PGP9.5 SENF, or GAP43 SENF density.1

Seven patients in the NPDPN Q+SOC group had a positive correlation between their PGP9.5 IENF increase and axon-reflex vasodilation (p=0.03).1

Conclusions

The authors suggested that the capsaicin 8% topical system appears to reverse the natural decline of nerve fiber density both in patients with painful and non-painful diabetic peripheral neuropathy.1 Additionally, it can provide pain relief and improve warm sensory perception and axon-reflex vasodilation.1

Considering the clinical importance of nerve fiber regeneration and improvement in function in patients with diabetic peripheral neuropathy, they also suggested that capsaicin 8% topical system might offer preventative treatment for foot ulcers and amputations in such patients.1

Limitations

Future studies should systematically assess factors influencing the effects of capsaicin 8% topical system on nerve regeneration, ensuring a sufficiently large sample size and appropriate participant stratification.1 Identifying and validating non-invasive biomarkers to predict treatment response would also be valuable.1 Additionally, future research should include studies of the cellular and molecular environment for nerve regeneration, as well as treatments that may synergize with capsaicin 8% topical system to enhance nerve regeneration, such as neurotrophic factors.1

Footnotes

FDA, United States Food and Drug Administration; GAP43, growth-associated protein 43; IENF, intraepidermal nerve fiber; NPDPN, non-painful diabetic peripheral neuropathy; NPRS, numerical pain rating scale; PDPN, painful diabetic peripheral neuropathy; PGP9.5, protein gene product 9.5; Q, capsaicin 8% topical system; SENF, subepidermal nerve fiber; 
SF-MPQ-2, Short-Form McGill Pain Questionnaire-2; SOC, standard of care; TRPV1, transient receptor potential vanilloid 1; USA, United States of America.

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