Capsaicin 8% Patch Treatment in Non-Freezing Cold Injury: Evidence for Pain Relief and Nerve Regeneration

Abstract

Introduction: Neuropathic pain associated with Non-freezing Cold Injury (NFCI) is a major burden to military service personnel. A key feature of NFCI is reduction of the intra-epidermal nerve fibre density in skin biopsies, in keeping with painful neuropathy. Current oral treatments are generally ineffective and have undesirable side effects. Capsaicin 8% patch (Qutenza) has been shown to be well-tolerated and effective for reducing neuropathic pain, for up to 3 months after a single 30-minute application. Methods: In this single-centre open label study, 16 military participants with NFCI (mean duration 49 months) received 30-minute Capsaicin 8% patch treatment to the feet and distal calf. Pain symptoms were assessed using a pain diary (with the 11-point Numerical Pain Rating Scale, NPRS) and questionnaires, the investigations included skin biopsies, performed before and three months after treatment. Results: Participants showed significant decrease in spontaneous pain (mean NPRS: -1.1, 95% CI: 0.37 to 1.90; p = 0.006), and cold-evoked pain (-1.2, 95% CI: 0.40 to 2.04; p = 0.006). The time-course of pain relief over 3 months was similar to other painful neuropathies. Patient Global Impression of Change showed improvement (p = 0.0001). Skin punch biopsies performed 3 months after the patch application showed significant increase of nerve fibres with structural marker PGP9.5 (intra-epidermal nerve fibres [IENFs], p < 0.0001; sub-epidermal nerve fibres [SENFs]; p =< 0.0001), and of regenerating nerve fibres with their selective marker GAP43 (p = 0.0001). The increase of IENFs correlated with reduction of spontaneous (p = 0.027) and cold-evoked pain (p = 0.019). Conclusions: Capsaicin 8% patch provides an exciting new prospect for treatment of NFCI, with regeneration and restoration of nerve fibres, for the first time, in addition to pain relief.

Keywords: capsaicin 8% patch; clinical trial; neuropathic pain; non-freezing cold injury; skin biopsy.

Figure 1

Time-course of pain relief in participants with NFCI treated with Capsaicin 8% patch. Time-course of pain scores for spontaneous pain (A, B) and cold evoked pain (C, D). Repeated measures ANOVA for baseline to week 12 period was statistically significant for spontaneous pain (F = 2.4; **p = 0.005); and cold evoked pain (F = 2.1; *p = 0.01); statistically significant difference was observed for the overall pain scores 3 months after the treatment (paired t test, B and D). 95% CI shown for spontaneous pain weekly (A, C), and p values, with Dunnett's Multiple Comparison Test (for a significance level of 0.05).

Figure 2

Immunohistochemistry results in skin biopsies for PGP9.5-positive nerve fibres. (A) Intra-epidermal PGP9.5 nerve fibres (IENFs/mm) at baseline (Q PRE), and significant increase at 3 months after treatment (Q POST) with Capsaicin 8% patch Qutenza (Q) (paired t-test). Statistically significant difference between control group and baseline (Q PRE), but not significant after treatment (Q POST) (Mann-Whitney test). (B) Sub-epidermal PGP9.5 nerve fibres (SENFs; % Area) at baseline (Q PRE) and 3 months after treatment (Q POST) with Capsaicin 8% patch Qutenza (Q). Statistically significant increase after Capsaicin 8% patch application (paired t-test). Statistically significant difference between control and treated group before (Q PRE) but not after (Q POST) Capsaicin 8% patch application (Mann-Whitney test).

Figure 3

Skin sections staining for PGP9.5 before and after application of Capsaicin 8% patch. (A) Control skin biopsy section, from a healthy human volunteer (intra-epidermal nerve fibre marked with arrowhead, and sub-epidermal nerve fibre with arrow). (B) Skin biopsy section from a participant with NFCI, pre-treatment (Q PRE); few intra-epidermal nerve fibres and sub-epidermal nerve fibres were observed before Capsaicin 8% patch Qutenza (Q) application. (C) Skin biopsy section from same participant as above with NFCI, post-treatment (Q POST); 3 months after Capsaicin 8% patch application, the abundance of both the IENFs and SENFs appeared restored. Magnification × 40.

Figure 4

Immunohistochemistry results in skin biopsies for GAP3 nerve fibres. (A) NFCI skin biopsy section before treatment with Capsaicin 8% patch (Q PRE): sub-epidermal nerve fibres (arrows) were present, at a density similar to control/normal skin. (B) NFCI skin biopsy section in the same participant as above, post-treatment (Q POST); skin biopsy collected 3 months after Capsaicin 8% patch Qutenza (Q) application: note the marked increase of GAP 43 positive SENFs in length and thickness. Original magnification ×20. (C) Sub-epidermal GAP43 nerve fibres (SENFs; % Area) at pre-treatment visit (Q PRE) and visit 3 months after treatment (Q POST) with Capsaicin 8% patch Qutenza (Q). Statistically significant increase of SENFs at 3 months after Capsaicin 8% patch application (paired t-test). Statistically non-significant difference between control group and treated group before treatment (Q PRE), but statistically significant difference between control group and treated group after Capsaicin 8% patch application (Q POST) (Mann-Whitney test).

Figure 5

Correlations between changes in intra-epidermal nerve fibre density and pain relief. Decrease in pain scores in spontaneous pain (A) and cold evoked pain (B) were correlated with changes in density of PGP 9.5 nerve fibres 3 months after the application of Capsaicin 8% patch, Spearman test; p values were respectively p = 0.027 and p = 0.019.