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. 2019 Jul 3:12:2039-2052.
doi: 10.2147/JPR.S213912. eCollection 2019.

Rational treatment of chemotherapy-induced peripheral neuropathy with capsaicin 8% patch: from pain relief towards disease modification

Praveen Anand  1 , Enas Elsafa  1 , Rosario Privitera  1 , Kalnisha Naidoo  1 , Yiangos Yiangou  1 , Philippe Donatien  1 , Hani Gabra  2 , Harpreet Wasan  2 , Laura Kenny  2 , Amin Rahemtulla  3 , Peter Misra  1
Affiliations

Rational treatment of chemotherapy-induced peripheral neuropathy with capsaicin 8% patch: from pain relief towards disease modification

Praveen Anand et al. J Pain Res. .

Abstract

Purpose: Chemotherapy-induced peripheral neuropathy (CIPN) with associated chronic pain is a common and disabling condition. Current treatments for neuropathic pain in CIPN are largely ineffective, with unfavorable side-effects. The capsaicin 8% patch (capsaicin 179 mg patch) is approved for the treatment of neuropathic pain: a single topical cutaneous application can produce effective pain relief for up to 12 weeks. We assessed the therapeutic potential of capsaicin 8% patch in patients with painful CIPN, and its mechanism of action.

Patients and methods: 16 patients with chronic painful CIPN (mean duration 2.5 years), in remission for cancer and not receiving chemotherapy, were treated with 30 min application of capsaicin 8% patch to the feet. Symptoms were monitored using the 11-point numerical pain rating scale (NPRS), and questionnaires. Investigations were performed at baseline and three months after patch application, including skin biopsies with a range of markers, and quantitative sensory testing (QST).

Results: Patients reported significant reduction in spontaneous pain (mean NPRS: -1.27; 95% CI 0.2409 to 2.301; p=0.02), touch-evoked pain (-1.823; p=0.03) and cold-evoked pain (-1.456; p=0.03). Short-Form McGill questionnaire showed a reduction in neuropathic (p=0.0007), continuous (p=0.01) and overall pain (p=0.004); Patient Global Impression of Change showed improvement (p=0.001). Baseline skin biopsies showed loss of intra-epidermal nerve fibers (IENF), and also of sub-epidermal nerve fibers quantified by image analysis. Post-patch application skin biopsies showed a significant increase towards normalization of intra-epidermal and sub-epidermal nerve fibers (for IENF: structural marker PGP9.5, p=0.009; heat receptor TRPV1, p=0.027; regenerating nerve marker GAP43, p=0.04). Epidermal levels of Nerve Growth Factor (NGF), Neurotrophin-3 (NT-3), and Langerhans cells were also normalized. QST remained unchanged and there were no systemic side-effects, as in previous studies.

Conclusion: Capsaicin 8% patch provides significant pain relief in CIPN, and may lead to regeneration and restoration of sensory nerve fibers ie, disease modification.

Keywords: capsaicin; chemotherapy; neuropathic pain; skin biopsy.

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Conflict of interest statement

PA has received speaker fees for symposia and meetings organized by Astellas UK, but no remuneration for this investigator-led study. PA also reports grants from Astellas, during the conduct of the study. HG reports is jointly employed by Imperial College and Astra Zeneca and received personal fees from Sensorkinesis. HG is also the Chief Scientific Officer and patent holder for Papyrus Therapeutics, during the conduct of the study. The authors report no other conflicts of interest in this work.

Figures

Figure 1
Figure 1
Study flow diagram. Abbreviations: NCS, nerve conduction study, PGIC, patient global impression of change.
Figure 2
Figure 2
Immunohistochemistry in skin biopsies for PGP9.5, before and after capsaicin 8% patch treatment. Intra-epidermal nerve fibers (arrowed) and sub-epidermal nerve fibers from (A) control subjects, at the baseline visit (B, Q PRE) and, after capsaicin 8% patch treatment (C, Q POST), magnification x40. (D) Bar chart of intra-epidermal nerve fibers for PGP 9.5 counts, (E) bar chart of sub-epidermal (SENF) analysis (% area). Notes: *Significant; **very significant.
Figure 3
Figure 3
Immunohistochemistry in skin biopsies for TRPV1, before and after capsaicin 8% patch treatment. Intra-epidermal nerve fibers (arrowed) and sub-epidermal nerve fibers from (A) control subjects, at the baseline visit (B, Q PRE) and, after capsaicin 8% patch treatment (C, Q POST), magnification x40. (D) Bar chart of intra-epidermal nerve fibers for TRPV1 (IENF) counts; (E) bar chart of sub-epidermal (SENF) analysis (% area) for TRPV1. Notes: *Significant; **very significant.
Figure 4
Figure 4
Immunohistochemistry in skin biopsies for SNSR, before and after capsaicin 8% patch treatment. Intra-epidermal nerve fibers (arrowed) and sub-epidermal nerve fibers from (A) control subjects, at the baseline visit (B, Q PRE) and, after capsaicin 8% patch treatment (C, Q POST), magnification x40. (D) Bar chart of intra-epidermal nerve fibers for SNSR (IENF) counts; (E) bar chart of sub-epidermal (SENF) analysis (% area) for SNSR. Note: *Significant.
Figure 5
Figure 5
Immunohistochemistry in skin biopsies for GAP43, before and after capsaicin 8% patch treatment. Representative image of intra-epidermal nerve fibers (arrowed) and sub-epidermal nerve fibers from (A) control subjects, at the baseline visit (B, Q PRE) and, after capsaicin 8% patch treatment (C, Q POST), magnification x40. (D) Bar chart of intra-epidermal nerve fibers for GAP43 (IENF) counts; (E) bar charts of sub-epidermal (SENF) analysis (% area) for GAP43. Notes: *Significant; **very significant.
Figure 6
Figure 6
Immunohistochemistry in skin biopsies for NGF, before and after capsaicin 8% patch treatment. NGF immunostaining of basal epidermis in calf skin obtained from (A) control subjects, and CIPN patients before (B, Q PRE) and after capsaicin 8% patch treatment (C, Q POST), magnification x40. (D) Bar chart showing the basal cell NGF image analysis (% area). Notes: *Significant; **very significant.
Figure 7
Figure 7
Immunohistochemistry in skin biopsies for NT3, before and after capsaicin 8% patch treatment. NT3 immunostaining from (A) control subjects, and CIPN patients before (B, Q PRE) and after capsaicin 8% patch treatment (C, Q POST). (D) Bar chart showing NT3 suprabasal image analysis (% area). Notes: *Significant; **very significant.
Figure 8
Figure 8
Immunohistochemistry in skin biopsies for Langerhans cells (LCs), before and after capsaicin 8% patch treatment. LCs immunostaining in the epidermis of calf skin from (A) control subjects, and CIPN patients before (B, Q PRE) and after capsaicin 8% patch treatment (C, Q POST), magnification x40. (D) Bar chart showing LCs image analysis (% area). Note: **Very significant.
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