Using PREP, we show that N1 latencies, ie, the duration until a potential can be recorded from Cz after peripheral stimulation, correlate with CDT. Thus, impaired cold detection through A-delta fibers is associated with prolonged PREP N1 latencies. This finding adds to the evidence that PREPs are based on A-delta conduction,9,11,15 provided methodological caveats such as thresholds for stimulation intensities are observed and measures assuring data reproducibility are taken.
Besides the fact that pretreatment A-delta fiber impairment was present only in the patient group, the different PREP stimulation sites may have had an impact on our results. The younger median age of our control group may have been another influential factor changing A-delta fiber excitability. Here, also the long duration of the refractory phases after TRPV1 channel activation by capsaicin may be of importance.28 During this period of “desensitization,” TRPV1 carrying nociceptors cannot be excited by a wide range of stimuli, potentially including electrical current30 because the calcium-dependent conformational changes in the TRPV1 protein close the channel pore.16 It is possible that these mechanisms are altered in patients with neuropathic pain. Furthermore, it has to be taken into account that TRPV1 channels are mostly located on C-fibers, thus our results may not reflect the entire spectrum.
It is an intriguing observation that 1 male and 2 female healthy controls did not develop any pain or hypersensitivity on capsaicin 8% patch application at all and also did not show a reduction, but rather a sustained increase in PPA after treatment. These cases may help to better understand the physiological basis of Qutenza responsiveness and A-delta properties. We speculate on physiologically diverse capsaicin susceptibility of TRPV1 receptors. If the receptors can be activated by capsaicin, this leads to pain. Additional electrical stimulation of these already maximally activated nociceptors then can only elicit lower PPA than stimulation of naive nociceptors. By contrast, if the individual TRPV1 receptors are not susceptible to capsaicin, then no pain occurs, and the nociceptors can still be stimulated by electrical current, resulting in normal PPA. Contrary to this speculation, the patient in the nonresponder group with recordable PREP also reported no capsaicin-induced pain but showed PPA reduction within 2 hours after treatment. This, in turn, may be due to the pathologically altered TRPV1 channels in diseased nociceptors. Another possibility are genetic alterations changing TRPV1 activation properties and somatosensorics also in healthy controls.1,6
There are further open questions that need to be considered when interpreting our data. Although it was shown that capsaicin reaches the dermal layers of the skin within 30 minutes of application,36 we did not measure the cutaneous penetration depth of capsaicin in our subjects. Thus, dermal concentrations may have been different between the study participants. Capsaicin may exert its effects depending on the underlying diagnosis10 and our patient cohort consisted of different diagnoses. Effects may change in homogenous large diagnostic groups. The question, why some patients develop capsaicin-induced pain and others do not is still open. Here, the receptor repertoire on the intraepidermal nerve fibers is a crucial factor that is, however, not easy to assess. It is plausible that pain syndromes based on the overexpression or overexcitation of ion channels other than TRPV1 may not respond to capsaicin treatment. Also, the effects of the surrounding keratinocytes and fibroblasts that both express TRPV1 channels have not been taken into account in the studies conducted so far.
One limitation of our study is the low number of subjects investigated, which has also hampered our analysis for predictive markers. However, in this small study group, we applied many tests allowing insights into small nerve fibers from functional, electrical, and histological perspectives. Another limitation is that patients were stimulated at different anatomical sites, depending on their painful area, whereas electrical stimulation was standardized to the hand and sole in controls. This restricts cross-comparability of our results, but is of minor relevance when regarding PREP parameter changes before and after treatment, which was the main goal of our study. Also, we cannot exclude that some of the patients might have had neuropathy of A-delta fibers, which may have affected the PREP stimulation threshold.
Pain-related evoked potential amplitude reduction was most prominent at 2 hours after Qutenza which theoretically may have been due to pain caused by capsaicin; however, only a subgroup of subjects developed Qutenza-induced pain. We can only speculate at this point, but assume a relevant influence of the individual genetic background determining ion channel activity and excitability as has been shown for capsaicin-induced changes in thermal perception thresholds of healthy controls carrying different allele variants of a TRPV1 polymorphism.6 Although we cannot completely exclude the influence of attention, we tried to control this confounding factor by asking the patient to lightly close their eyes during the recordings, count the stimulations applied, and rate the painfulness of the pin-prick sensation; this should lead to comparable attention levels in all subjects. To avoid habituation, PREP stimulations were applied with a random and various interstimulus interval of 15 to 17 seconds.
Pain-related evoked potential proves to be a reliable A-delta test that shows capsaicin-induced reduction in PPA in healthy controls and patients with neuropathic pain. To predict a capsaicin response, a set of A-delta properties may be more promising than the search for single predictors, which we also could not detect here. Our data parallel a previous study using laser-evoked potentials (LEPs) to stimulate A-delta nerve fibers and assessing the effect of tramadol on LEP parameters.32 Interestingly, tramadol also led to a reduction in LEP amplitudes in healthy controls, which was partially reversed by naloxone. Thus, assessment of PREPs may become a valuable tool to decipher the underlying mechanisms of topically applicable drugs.
A. Papagianni and G. Siedler: report no conflicts of interest. C. Sommer: received honoraria, travel grants, and research grants from Astellas, Baxalta, Genzyme, Air Liquide, CSL-Bering, Pfizer, UCB, LFB, Grifols, and Kedrion. N. Üçeyler: received honoraria, travel grants, and research grants from Sanofi Genzyme, Shire, Daiichi Sankyo, and Baxalta.
The study was supported by intramural funds of the Department of Neurology, University of Würzburg, Germany.
Expert technical help by Judith Sauer and Daniela Urlaub is gratefully acknowledged. We also thank Dr. Daniel Zeller for providing hard- and software equipment for PREP analysis.
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