Impact of Treatment with High Concentration Capsaicin (8%) Topical System on Sensory Testing in Patients Living with Painful Diabetic Peripheral Neuropathy of the feet: a Post-Hoc Analysis of the PACE Trial

Impact of Treatment with High Concentration Capsaicin (8%) Topical System on Sensory Testing in Patients Living with Painful Diabetic Peripheral Neuropathy of the feet: a Post-Hoc Analysis of the PACE Trial

Background:

The most prevalent complication of diabetes is neuropathy, occurring in 50% of patients, which typically manifests as a loss of distal sensory function in the lower extremities¹. The likelihood of diabetic peripheral neuropathy (DPN) increases with the duration of diabetes and at least one out of five patients experience pain^1-3. The vascular supply to peripheral nerves in patients with DPN is often inadequate, leading to compromised blood flow resulting in distal axons that are innately too weak to support themselves for the long transport of nutrients, neurotrophic factors, as well as other signals⁴. These consequences of DPN can result in physical and chemical alterations of epidermal nerve fibers and change sensation in the extremities^1,5. As patients combat both the loss of mechanical sensory information and increasing perception of pain, quality of life (QOL) can be directly impacted¹.

Purpose/Objectives:

PACE was an open label, Phase III, randomized, 3-arm, multinational safety, and tolerability study in patients with painful DPN (PDPN) over 52 weeks. The study was designed to assess the effect of repeat applications of QUTENZA (capsaicin) 8% topical system (QTZ) with standard of care (SOC) vs. SOC alone^6,7. Among the primary and secondary endpoints there was a positive change from baseline in both the Norfolk quality of life diabetic neuropathy (QOL-DN) total score and the Utah Early Neuropathy Scale (UENS) suggesting improvements in QOL, with no deterioration in nerve fiber function^6,7. These improvements suggested the need for further analysis of another secondary measure, the Brief Sensory Pain Examination. This post-hoc analysis was conducted to determine the effect of QTZ + SOC on sensory function after multiple applications.

Method:

The Brief Sensory Pain Examination assessed reduced or increased stimulus perception by rating evoked sensations from the most painful area compared to an asymptomatic control site. It involved the assessment of 5 modalities: vibration, heat, cold, sharp sensations, and the assessment of deep tendon reflexes. Treatment area was identified based on the presence of spontaneous and evoked pain (includes mechanical dynamic allodynia [e.g., pain in response to brush stroke], cold or warm thermal allodynia [e.g., pain in response to touch with a cold or warm object], and/or hyperalgesia [e.g., exaggerated pain in response to pinprick] as determined by a sensory examination from the Investigator. The post-hoc analysis included two subgroups of patients. The first subgroup was comprised of patients with a reported score of zero (no sensation) at baseline in each of the five modalities. The second subgroup was comprised of patients with abnormally low sensation reported at baseline in each of the five modalities. The percentage of sensory tests in these two groups that shifted to either some positive, or normal sensation, respectively were collected in patients treated with QTZ for 30min + SOC.

Results:

The proportion of patients treated with QTZ for 30 min + SOC in each subgroup reporting increased sensory perception increased over multiple applications. In subgroup one (score of zero at baseline), the percentage of sensory tests increased over multiple applications in all five sensory modalities. In subgroup two (abnormally low sensation at baseline), the shift to normal sensation, was also increased by the 6^th application in all five sensory modalities.

Conclusions: Improvements in sensory perception were observed with multiple treatments of QTZ in patients with PDPN. Treatment with high concentration capsaicin ensures sufficient selective binding to transient receptor potential vanilloid 1 (TRPV1)-expressing nociceptive fibers, resulting in a reversible chemical ablation leading to significant pain relief in patients with PDPN8-11. A secondary effect of capsaicin is the release of calcitonin gene-related peptide (CGRP) in the skin, which is likely the main initiator of neurogenic inflammation, characterized by increased blood flow resulting in edema and erythema12,13. The results of this post-hoc analysis suggests that local vasodilation may result in better neuronal function, and therefore, improved sensory perception for patients with PDPN. More research is warranted to expand on these findings to better understand the benefits of QTZ for PDPN patients.

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