Background & Aims

Topical 8% capsaicin applied for 1 hour causes an intra-epidermal nerve fiber reduction 3 and a progressive de-functionalization of nociceptors 1. Here, our main objective was to investigate the pattern of de-functionalization and temporal recovery for specific nociceptor sub-types over a time-period of 7 weeks after 4 days of 8% capsaicin-patch application. Excitation profiles specific for different C-nociceptor classes was explored: electrical single 1 Hz sinusoidal pulses of 500ms duration causes a burst of action potentials in “polymodal” nociceptors 4, and continuous 4 Hz sinusoidal stimuli additionally activate “silent” nociceptors 2. The 4 Hz stimulation profile was also delivered adjacent to the capsaicin treated skin to assess functional contribution of C-nociceptors within the secondary hyperalgesia zone.

Methods

An 8% capsaicin (Qutenza®) patch of 1.5 x 1.5 cm was applied onto one and a vehicle patch on the contra-lateral forearm (n=14 subjects). Both patches were renewed every 24 hours over four consecutive days. Sensory tests to electrical (rectangular and sinusoidal pulses), thermal (thresholds and continuous heat) and mechanical (pinprick) stimuli were performed on each of the 4 days and thereafter weekly over 49 days. The axon reflex flare evoked by 4 Hz sinusoidal stimulation inside the patch-treated area was recorded by Laser Doppler Imaging (LDI). Also, skin blood flow intensity (flux) and pain (numeric rating scale, NRS 0-10) was recorded upon 1 min 4 Hz sinusoidal stimulation (0.4mA) delivered 1 cm distal to the capsaicin-patch treated skin site.

Results

Capsaicin abolished heat pain (48°C, 5 s) whereas pain to electrical sinusoidal stimulation was reduced but never abolished during the 4 treatment days. Pain recovery to “polymodal” nociceptor stimulation upon electrical 1 Hz half-period sinusoidal pulses took longer to return to placebo condition than pain ratings to electrical 4 Hz 2.5 s sinusoidal stimulation additionally activating “silent” nociceptors (28 vs. 7 days). Axon reflex flare was virtually absent during capsaicin and only recovered to about 50% even after 49 days. Also, skin blood flow intensity to 4 Hz stimulation delivered 1 cm distal to the capsaicin treated site did not increase across the borders of the patch. Intensity of pain sensation to the electrical stimulation delivered adjacent to the capsaicin patch was enhanced throughout 7 weeks and when compared to pain recorded from the placebo site. It did not correlate however with the skin flux recorded from the stimulation site outside the patch.

Conclusions

Capsaicin completely suppresses heat transduction whereas small diameter axons sensitive to sinusoidal electrical stimulation can still be activated. Axonal branches that facilitate discharge to the depolarizing 1 Hz stimulus recover slower after capsaicin than 4 Hz sensitive nociceptors. The difference in recovery suggests differential time-courses of functional restoration for C-nociceptor sub-types after capsaicin. Long lasting increased electrical pain adjacent to the capsaicin patch might indicate that untreated branches of nociceptors with receptive fields inside and outside the patch received additional sodium channels that no longer could be trafficked to the “capsaicin-axotomized” branches. The complete sensory recovery within 7 weeks is shorter than neuropathic pain relief in patients lasting months even after 1-hour 8% capsaicin. Capsaicin-evoked analgesia in patients with spontaneous neuropathic pain apparently differs to capsaicin-induced hypoalgesia in healthy volunteers.

References

[1] Anand P, Bley K. Topical capsaicin for pain management: therapeutic potential and mechanisms of action of the new high-concentration capsaicin 8% patch. BrJAnaesth 2011;107(4):490-502.
[2] Jonas R, Namer B, Stockinger L, Chisholm K, Schnakenberg M, Landmann G, Kucharczyk M, Konrad C, Schmidt R, Carr R, McMahon S, Schmelz M, Rukwied R. Tuning in C-nociceptors to reveal mechanisms in chronic neuropathic pain. Ann Neurol 2018;83(5):945-957.
[3] Kennedy WR, Vanhove GF, Lu SP, Tobias J, Bley KR, Walk D, Wendelschafer-Crabb G, Simone DA, Selim MM. A randomized, controlled, open-label study of the long-term effects of NGX-4010, a high-concentration capsaicin patch, on epidermal nerve fiber density and sensory function in healthy volunteers. JPain 2010;11(6):579-587.
[4] Rukwied R, Thomas C, Obreja O, Werland F, Kleggetveit IP, Jorum E, Carr RW, Namer B, Schmelz M. Slow depolarizing stimuli differentially activate mechanosensitive and silent C-nociceptors in human and pig skin. Pain 2020;161(9):2119-2128.

Presenting Author

Roman Rukwied

Poster Authors

Roman Rukwied

Ph.D.

Dept. Exp. Pain Research, MCTN, Med. Faculty Mannheim, Heidelberg University, Mannheim, Germany

Lead Author

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Divya Gutti

Experimental Pain Research, Medical Faculty Mannheim, Heidelberg University, Germany

Lead Author

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Richard Carr

Dept. Exp. Pain Research, MCTN, Med. Faculty Mannheim, Heidelberg University, Mannheim, Germany

Lead Author

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Martin Schmelz

Heidelberg University, Dept. Exp. Pain Research, MCTN Mannheim

Lead Author

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