Functional and histological improvements of small nerve neuropathy after high-concentration capsaicin patch application: A case study

Abstract

Introduction:
Small fiber neuropathy has been found to occur in a large variety of pathological onditions, and the gold standard for diagnosis of small fiber neuropathy is skin biopsy. Sudorimetry is now considered an accurate technique to evaluate small fiber function with a good sensitivity and specificity for the diagnosis of small fiber neuropathy. Capsaicin high-concentration patch is approved for the treatment of peripheral neuropathic pain in adults either alone or in combination with other medicinal products for pain.

Methods:
We describe the case of a 50-year-old woman diagnosed with small fiber neuropathy. After 2 previous treatment failures, she was proposed a treatment with high-dose capsaicin patches on the sole of her foot. The patient experienced an important diminution of her neuropathic pain. There was a 50% decrease in the pain numeric scale. Electrochemical skin conductance and skin biopsy were repeated 3 months after patch application.

Results:
At 3 months, the patient then experienced an important diminution of her neuropathic pain, electrochemical skin conductance had normalized both in the hands and feet and intraepidermal nerve fiber density at distal leg increased almost reaching normal range.

Conclusion:
This case report shows the correlation between clinical improvement, electrochemical skin conductance normalization, and intraepidermal nerve fiber density improvement after a high-dose capsaicin patch in a patient with small fiber neuropathy.

Full text

Neuropathic
Case Report
Functional and histological improvements of small
nerve neuropathy after high-concentration
capsaicin patch application: A case study
Anne-Priscille Trouvin
a,b,
*, Serge Perrot
a,b
Abstract
Introduction: Small fiber neuropathy has been found to occur in a large variety of pathological onditions, and the gold standard for
diagnosis of small fiber neuropathy is skin biopsy. Sudorimetry is now considered an accurate technique to evaluate small fiber
function with a good sensitivity and specificity for the diagnosis of small fiber neuropathy. Capsaicin high-concentration patch is
approved for the treatment of peripheral neuropathic pain in adults either alone or in combination with other medicinal products for
pain.
Methods: We describe the case of a 50-year-old woman diagnosed with small fiber neuropathy. After 2 previous treatment failures,
she was proposed a treatment with high-dose capsaicin patches on the sole of her foot. The patient experienced an important
diminution of her neuropathic pain. There was a 50% decrease in the pain numeric scale. Electrochemical skin conductance and
skin biopsy were repeated 3 months after patch application.
Results: At 3 months, the patient then experienced an important diminution of her neuropathic pain, electrochemical skin
conductance had normalized both in the hands and feet and intraepidermal nerve fiber density at distal leg increased almost
reaching normal range.
Conclusion: This case report shows the correlation between clinical improvement, electrochemical skin conductance
normalization, and intraepidermal nerve fiber density improvement after a high-dose capsaicin patch in a patient with small fiber
neuropathy.
Keywords: Capsaicin, Sudorimetry, Small fiber neuropathy, Intraepidermal nerve fiber density
1. Introduction
Small fiber neuropathy has been found to occur in a large variety
of pathological conditions (eg, diabetes mellitus, infectious
diseases, toxic causes, and dysimmune disease). The gold
standard for diagnosis of small fiber neuropathy is skin biopsy.
5
Skin biopsy is followed by indirect immunofluorescence or
immunohistochemical analysis to assess the density of small
nerve fibers in the epidermis of the skin.
5
In the European
guidelines, an epidermal nerve fiber density lower than 7.6/mm at
the leg has a diagnostic value of 88% to 90% with 90% to 95%
specificity and 70% to 83% sensitivity for small fiber neuropa-
thy.
10
A more recent study published new intraepidermal nerve
fiber (IEFN) density normative values for clinical use for each year
of age and patients’ sex.
6
Sudorimetry is a quick noninvasive technique that measures
sudomotor function based on reverse iontophoresis and chro-
noamperometry. By measuring electrochemical skin conduc-
tance, sudorimetry serves as a biomarker for sweat gland
function, which is related to sweat gland innervation by
sympathetic unmyelinated nerve fibers of small diameter.
Sudorimetry is now considered an accurate technique to evaluate
small fiber function.
15
To date, sudorimetry displays, in many
studies, a good sensitivity and specificity for the diagnosis of small
fiber neuropathy.
3,11
The link between impaired electrochemical skin conductance
and low IEFN density has been highlighted in 2 studies.
13,14
Novak showed a significant correlation between impaired
electrochemical skin conductance and abnormally low epidermal
nerve fiber density and abnormally low sweat gland nerve fiber
density.
13
These results support the previous results of Smith
Sponsorships or competing interests that may be relevant to content are disclosed
at the end of this article.
a
Hˆopital Cochin, Centre d’Etude et Traitement de la Douleur, France,
b
Universit ´e
Paris Descartes, Facult ´edeM´edecine, Paris, France
*Corresponding author. Address: Centre d’Evaluation et Traitement de la Douleur,
Hˆopitaux Universitaire Paris Centre, Cochin, 27, Rue du Faubourg Saint Jacques,
75014 Paris, France. Tel.: 133 1 58 41 26 24; fax: 133 1 58 41 15 55. E-mail
address: annepriscille.trouvin@aphp.fr (A.-P. Trouvin).
Copyright ©2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf
of The International Association for the Study of Pain. This is an open-access article
distributed under the terms of the Creative Commons Attribution-Non Commercial-
No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and
share the work provided it is properly cited. The work cannot be changed in any way
or used commercially without permission from the journal.
PR9 4 (2019) e761
http://dx.doi.org/10.1097/PR9.0000000000000761
4 (2019) e761 www.painreportsonline.com 1

et al.,
14
which showed that electrochemical skin conductance
has the same diagnostic efficiency with similar area under curve.
Capsaicin is derived from chili peppers and is a natural ligand of
the transient receptor potential vanilloid 1 channel. In 2009,
a high-concentration transdermal capsaicin 8% patch (Qutenza;
Acorda Therapeutics, Inc, Ardsley, NY; Astellas Pharma Europe
Ltd, Chertsey, Surrey, United Kingdom) was approved. To date,
in Europe, the capsaicin high-concentration patch is approved for
the treatment of peripheral neuropathic pain in adults either alone
or in combination with other medicinal products for pain.
The high-concentration capsaicin patch is proven to be
effective in neuropathic pain. The effect of the patch remains for
a mean 5 months before return of the symptoms.
12
Trials were
originally designed for postherpetic neuralgia and HIV-associated
neuropathy. Recent data suggest it is also effective in peripheral
diabetic neuropathy.
16
The Cochrane review in 2017 concluded
that high-concentration topical capsaicin used in neuropathic
pain in postherpetic neuralgia, HIV neuropathy, and painful
diabetic neuropathy was shown to produce moderate or
substantial levels of pain relief compared with control treatment
using a much lower concentration of capsaicin. Yet, the quality of
evidence was moderate to very low.
7
Thus, the 2015 NeuPSIG
gave only a weak recommendation for high-concentration
capsaicin for use and proposal as second-line treatment.
8
We report here a first case of both electrochemical skin
conductance and IEFN density improvement after high-
concentration capsaicin patches for an idiopathic small nerve
neuropathy.
2. Methods
2.1. Case Report
We report the clinical case of a 50-year-old woman who was seen
as an outpatient for bilateral pain of the soles of her feet.
Moreover, she presented with dysautonomic symptoms such as
tachycardia, nausea, and constipation. Neuropathic pain was
suspected; the DN4 questionnaire yielded a positive score of
5/10. The clinical neurological examination confirmed this
suspicion of neuropathic pain. A small fiber neuropathy was
suspected. Sudorimetry with Sudoscan (Impeto Medical, Paris,
France). Sudoscan provides a quantitative measure of chloride
conductance (measured in microsiemens). The sudorimetry for
this patient revealed an impaired electrochemical skin conduc-
tance (Fig. 1) in both hands and feet. A skin biopsy was
performed at distal leg with 3-mm punch biopsy, and it was
processed in a standard fashion as recommended.
10
IENF
density was assessed with bright-field immunohistochemistry. In
this patient, a reduced IEFN density was shown at distal leg 3.03
IENF/mm (lower fifth percentile normal IENF density for the age
and gender, as defined by Collongues et al.
6
, is 4.9 IENF/mm).
Extensive explorations were made to find the origin, although
none was found, and she was diagnosed with idiopathic small
fiber neuropathy. Laboratory test showed normal blood count,
normal renal function, normal hepatic function, normal fasting
glucose and glucose tolerance test, normal vitamin B6 and B12
level, no antinuclear antibodies, no anti-ENA, and no anti-DNA.
Serological tests were negative for HVB, HVC, and HIV. Electro-
neuromyogram of the legs was normal.
As treatment, she responded insufficiently to gabapentin up to
1800 mg/d and did not tolerate further increase in dosage. She
did not tolerate amitriptyline nor clomipramine. Lidocaine patches
were poorly efficient; the decrease in pain numeric scale was only
10%. Hence, she was prescribed high-concentration capsaicin
patches on the sole. Patches were applied, simultaneously,
during half an hour on both entire soles. Immediate tolerance was
good with moderate burning sensations during the patches
application; this was relieved by icing the soles. She received only
one application on both soles and was revaluated 3 months
afterwards.
3. Results
At 3 months after capsaicin application, the patient then
experienced an important diminution of her neuropathic pain.
Decrease in the pain numeric scale was 50% with a pain rating of
Figure 1. Electrochemical skin conductance by sudorimetry of the patient at diagnosis of her small fiber neurop athy. ms, microsiemens; ESC, electrochemical skin
conductance.
2A.-P. Trouvin, S. Perrot·4 (2019) e761 PAIN Reports
®

3/10. Also, 3 months after capsaicin application, sudorimetry
showed a normalization of the electrochemical skin conductance
at the feet and a normalization of skin conductance at the hands
(Fig. 2).
Given this normalization of sudorimetry, the patient agreed to
a new skin biopsy (3 months after the capsaicin patch). The
biopsy showed an increase in IEFN density at distal leg, almost
reaching normal range: 4.17 IENF/mm.
4. Discussion
To the best of our knowledge, this is the first report of both
functional and histological improvement after active high-
concentration capsaicin patch treatment for neuropathic pain.
This case leads to 2 discussions, first, the histological and
functional improvements and, second, the potential interest of
sudorimetry as a marker of treatment efficacy.
The potential action of capsaicin on small nerve fibers is shown
in many immune-histochemical studies. They provide evidence
that capsaicin can produce highly localized diminution of
nociceptive nerve fiber terminals in the epidermis and dermis.
1,9
However, after capsaicin application, there is a regrowth and
intraepidermal nerve density returns to baseline level. In Gibbons
et al.
9
, comparing the effects of topical capsaicin on cutaneous
autonomic nerves, baseline intraepidermal nerve density returned
to baseline level by day 100. The same pattern of decrease and
return to baseline was seen in sudomotor function measured by
quantitative sudomotor axon reflex testing and in sweat gland
nerve fiber density.
9
Here, after 90 days, the patient’s intra-
epidermal nerve density has neither decreased nor is back to
baseline level but has increased, almost reaching normal density.
Moreover, this unexpected regrowth with a higher density than
baseline level seems to have been of more functional small fiber
since it is correlated with sudorimetry normalization for this
patient.
Sudorimetry is now being assessed as a tool to measure
progression and regression of disease. In this case, sudorimetry
improvement is correlated with histological improvement and
clinical efficacy. In one study, it was demonstrated that
electrochemical skin conductance improved with intensified
insulin treatment in patients with diabetes.
2
Yet, larger studies
are still needed in diabetes with strict glycemic control but also in
other etiologies with other neuropathic treatment. In another
recent study, electrochemical skin conductance improved at 12
weeks and continued to improve at 24 weeks after bariatric
surgery in obese patients with type 2 diabetes.
4
To date, no study has shown improved electrochemical skin
conductance after a high-concentration capsaicin patch, and we
report here the first case with improvement of pain intensity,
electrochemical skin conductance, and IEFN density (although
IENF density of the patient remained under healthy control).
Larger cohorts are needed to demonstrate the good correla-
tion between sudorimetry variation and clinical improvement to
use sudorimetry as a monitoring tool for treatment efficacy.
Disclosures
A.-P. Trouvin lecture fees from Astellas; S. Perrot reports personal
fees from Astellas and Grunenthal, for advisory boards, outside
the submitted work.
Acknowledgments
The authors thank the patient for agreeing to this publication.
Article history:
Received 14 February 2019
Received in revised form 4 May 2019
Accepted 8 May 2019
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