CASPAR: A retrospective cohort study of the high-concentration capsaicin topical system in patients with painful diabetic peripheral neuropathy of the feet
Journal article
Published on May 2, 2025

CASPAR: A retrospective cohort study of the high-concentration capsaicin topical system in patients with painful diabetic peripheral neuropathy of the feet

Contributors:

Überall M, Quandel T, Engelen S et al.

Name of journal:

BMJ Open Diabetes Research & Care

View Publication

DOI:

10.1136/bmjdrc-2024-004864

Topics:

DPN RWE CASPAR Cohort Observational Retrospective Peripheral neuropathic pain Capsaicin 8% topical system
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This page provides a summary of Überall M et al. BMJ Open Diab Res Care. 2025;13:e004864. 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 fur further details and disclosures.

The CASPAR study explored outcomes of the capsaicin 8% topical system (here referred to as high-concentration capsaicin topical system [HCCTS]) beyond its FDA-approved indications, including sleep, affective distress, quality of life, and concomitant pain medication use in patients with diabetic peripheral neuropathy (DPN) of the feet. HCCTS is not FDA-approved for these outcomes, and its safety and effectiveness for them have not been established. HCCTS is indicated in adults for neuropathic pain associated with postherpetic neuralgia (PHN) or diabetic peripheral neuropathy (DPN) of the feet. Consult the Important Safety Information and Full Prescribing Information for complete details on approved indications, safety, and risks.

Summary

Impact of ongoing treatments with high-concentration capsaicin topical system on patient-reported outcomes in patients with painful diabetic peripheral neuropathy of the feet (CASPAR study)1

Background

Diabetic peripheral neuropathy affects up to 50% of patients with diabetes, with symptomatic or painful pathology developing in 30–50% of patients.1 Pain associated with painful diabetic peripheral neuropathy can negatively impact the patient’s sleep, mood, and health-related quality of life (QOL).1

 

Capsaicin 8% topical system (here referred to as high-concentration capsaicin topical system [HCCTS]) is an approved topical treatment for painful diabetic peripheral neuropathy of the feet in the USA.1 This topical system uses a matrix technology that enables high concentrations of capsaicin to enter the epidermis, where it acts as a selective agonist for transient receptor potential vanilloid 1 (TRPV1) receptors that are expressed on cutaneous nociceptors.1 This triggers intracellular signaling pathways that lead to neurolysis of TRPV1-expressing nerve fibers.1,2 It has been shown that TRPV1-expressing nerve fibers begin to regenerate 1–3 months after treatment with high-concentration capsaicin topical system; however, due to the chronic nature of the underlying condition, lysed fibers may not fully recover normal function, and repeated treatments may be required to achieve clinical response.1

Aim

The CASPAR study was a retrospective, non-interventional, multi-cohort study that used real-world data from the German Pain e-Registry (GPeR).1 The manuscript published by Überall M et al. focused on a subpopulation of 365 patients with painful diabetic peripheral neuropathy of the feet who received 1–4 treatments with high-concentration capsaicin topical system and were followed up for 12 months.1 They aimed to evaluate the impact of high-concentration capsaicin topical system on pain, sleep, affective distress, QOL, and concomitant pain medication use in patients with painful diabetic peripheral neuropathy of the feet.1 Tolerability was also assessed.1

 

All 365 patients were evaluated for 12 months, regardless of their total number of HCCTS treatments (1 HCCTS: n=94, 2 HCCTS: n=88, 3 HCCTS: n=75, 4 HCCTS: n=108).

Study design and population. Image reproduced from Supplemental material 1 of Überall M et al. <i>BMJ Open Diabetes Res Care</i>. 2025;13:e004864.
Study design and population. Image reproduced from Supplemental material 1 of Überall M et al. BMJ Open Diabetes Res Care. 2025;13:e004864.

Statistical Analysis:

 

The statistical analysis used a real-world evidence case approach without imputing missing data, with no formal sample size calculations or prespecified comparisons.1 Results were stratified by the number of HCCTS treatments (one to four) over 12 months.1 Comparative analyses versus baseline or versus previous treatment employed descriptive and inferential statistics (t-tests, Wilcoxon’s signed-rank tests, χ² tests) with a two-sided 0.05 significance level, without multiplicity correction, and effect sizes calculated where applicable.1

Key findings

One application of the high-concentration capsaicin topical system was associated with observed reductions in mean 24-hour average pain intensity (API) by Month 3.1 Further reductions were seen with ongoing treatments over 12 months, while API increased in patients who discontinued high-concentration capsaicin treatment1

Patients assessed their API over the previous 24 hours with the visual analog scale.1

 

In the group receiving four HCCTS treatments (n=108), the mean 24-hour API significantly decreased from baseline to Month 121:

Pain reduction in patient with painful diabetic peripheral neuropathy of the feet
Pain reduction in patient with painful diabetic peripheral neuropathy of the feet
Significant improvement in sleep impairment was observed by Month 3 following one treatment with high-concentration capsaicin topical system and further improvements were seen with ongoing treatments.1 Patients who discontinued treatment lost benefits by Month 121

Impact of pain on sleep impairment was assessed using question 6 of the modified Pain Disability Index (mPDI)1.

From baseline to Month 12, the mPDI score decreased with four HCCTS treatments indicating improvement in sleep impairment (n=108)1:

A reduction in the proportion of patients reporting severe/extremely severe affective distress symptoms was seen with ongoing applications of high-concentration capsaicin topical system over 12 months. In contrast, the proportion of patients experiencing severe/extremely severe affective distress symptoms increased over time in those who discontinued treatment after one or two applications1

Patients self-reported depression, anxiety, and stress over the previous week using the 21-item Depression, Anxiety and Stress Symptom Scale (DASS-21).1

A high proportion of patients had severe/extremely severe symptoms of depression (33.2%), anxiety (39.5%), and stress (47.4%) at baseline (N=365).1

From baseline to Month 12, the greatest reductions in the proportion of patients reporting severe/extremely severe symptoms were seen for patients who received four HCCTS treatments (n=108)1:

Improvements in health-related QOL were observed with ongoing high-concentration capsaicin topical system treatments over 12 months but benefits were lost following treatment discontinuation1

Patients reported on their health-related QOL using the physical and mental component scores (PCS and MCS) from the Veterans RAND 12-item Health Survey (VR-12).1

Following four HCCTS treatments (n=108), significant improvements were seen from baseline to Month 12 in PCS and MCS, which progressed towards or surpassed the threshold score of 50 for normal functioning1:

An increase in the proportion of patients not taking any concomitant pain medications was observed with ongoing high-concentration capsaicin topical system treatments, with approximately one-third of patients who received at least three treatments being able to discontinue all concomitant pain medications by Month 121

At baseline, all patients (N=365) were taking concomitant pain medications, including opioids, antiepileptics, and antidepressants.1

Those receiving four HCCTS treatments saw a significant reduction in mean concomitant pain medications over 12 months (n=108)1:

The tolerability of the high-concentration capsaicin topical system was consistent with the known safety profile.1 Adverse drug reactions (ADRs) were transient, local application-site reactions, which all improved or fully resolved over time1

The proportion of patients with ≥1 ADR after each HCCTS treatment was1:

The mean number of ADRs per patient per treatment decreased with ongoing treatments, from 2.0 after the first treatment to 0.9 after the fourth treatment.1

A higher rate of discontinuation due to perceived lack of effectiveness was observed after a single treatment (6.6%) compared to four treatments (1.9%).1 Discontinuations due to ADRs were higher after four (20.4%) versus one (4.9%) treatment(s), which was unexpected, considering the decreased proportion of patients reporting ≥1 ADR and that no patients reported moderate or severe ADRs after the third or fourth HCCTS treatment.1 To learn more about treatment discontinuation rates see Table 1 in Überall et al.1

Conclusions

This real-world clinical study of ongoing treatments with 1–4 applications of high-concentration capsaicin topical system in patients with painful diabetic peripheral neuropathy of the feet demonstrated significant improvements vs baseline in pain intensity, sleep, mood, and QOL over 12 months.1 Importantly, improvements across all parameters were noted after the first treatment and increased further with ongoing treatments, while those who discontinued treatment lost benefits over time.1 Patients who received ongoing treatment also experienced substantial reduction in concomitant medication use, including opioids, antiepileptics and antidepressants, showing the potential to lessen patients’ pharmacological burden.1 The tolerability of the high-concentration capsaicin topical system was consistent with the known safety profile.1

Limitations

CASPAR is a real-world study, limited by its retrospective, non-randomized observational design.1 The non-interventional nature may have introduced selection bias among patients who were selected or voluntarily participated in the registry.1 The lack of a placebo potentially limits the interpretation.1 Causality cannot be established from the results of this study, and reverse causality (patients who received the most benefit being those who persisted) cannot be ruled out.1 In addition, this registry did not collect data on confounding factors such as glycemic control, alcohol or tobacco use, or nutritional status, which limits interpretation of the results.1

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Footnotes

ADR, adverse drug reaction; API, average pain intensity; DASS-21, Depression, Anxiety and Stress Symptom Scale; FDA, US Food and Drug Administration; GPeR, German Pain e-Registry; HCCTS, high-concentration capsaicin topical system; MCS, mental component score; mPDI, Modified Pain Disability Index; PCS, physical component scale; PDPN, painful diabetic peripheral neuropathy; QOL, quality of life; TRPV1, transient receptor potential vanilloid 1; USA, United States of America; VR-12, Veterans RAND 12-item Health Survey.

QZA-03-25-0012 | June 2025