COMMENTARY

Are there biological markers of neuropathic pain?Commentary on a paper by Saika et al. (2012, this issue)

Funding sourcesNone.

Conflicts of interestNone declared.

Accepted for publication9 May 2012

doi:10.1002/j.1532-2149.2012.00179.x

This is another attempt at identifying biologicalmarkers for pain in humans from skin biopsies, whichends with a negative result, but yields some interestinginformation outside the original research question.Preferably, such a biomarker should result from anoninvasive or minimally invasive test, and MartinSchmelz and colleagues (Schley et al., 2012) employ acomprehensive battery of such tests, including bedsideexamination, quantitative sensory testing, axon reflexflare and the quantification of skin innervation. Incontrast to most previous authors who tried to corre-late skin innervation with pain, they took great carein separating skin nerve fibres into different layersand correlated their quantity with sensory functionlike thermal thresholds or the degree of electricallyinduced pain. They found some – partially unexpected– correlations between structure and function, likecorrelations between pain thresholds and deep dermalinnervation. More expected were the correlation oftemperature thresholds with epidermal nerve fibredensity and of the area of electrically evoked axonreflex flare with calcitonin gene related peptide(CGRP) staining of dermal nerve fibres. None of theparameters showed a close correlation with the painmeasures. Some of the weak correlations identifiedare even counterintuitive. If cold pain thresholds cor-related positively with higher neuronal CGRP stainingin the dermal skin, then less CGRP would mean lowerpain thresholds, thus more pain, in contrast to what isgenerally assumed and to the authors’ hypothesis.

This poses several questions: Would the results havebeen changed if the authors had compared neuropathypatients with pain with neuropathy patients withoutpain (e.g., Üçeyler et al., 2007)? This might have elimi-nated some of the confounding factors caused by thedisease itself. With the present design, most of thedifferences between healthy controls and neuropathicpain patients may be explained by the nerve lesion,like loss of distal nerve fibres and loss of the respectivefunction. The parameters responsible for gain of func-

tion (pain, allodynia) may thus be missed. On theother hand, the structural measures employed may notbe suited to differentiate between a painful and apainless state. For example, nerve fibres may lose thePGP 9.5 immunoreactivity, but may still be presentand active, and might be visualized by a GAP-43 stain(Ragé et al., 2010) or sodium channel immunoreac-tion, or numbers of remaining nerve fibres might playa minor role in determining pain, and the surround-ing microenvironment might be of more importance(Üçeyler et al., 2010). Furthermore, it is possible thatthe pathophysiology of the disorders examined, whichinclude peripheral neuropathy, traumatic nerve lesion,post-herpetic neuralgia and complex regional painsyndrome (CRPS), differs too much to yield consistentfindings when lumping them into one group. Studieswere more homogenous groups were investigated,yielded at least partially stronger correlation betweentheir morphological finding in skin and pain (e.g.,Vlckova-Moravcova et al., 2008; Chao et al., 2010;Casanova-Molla et al., 2012)

The authors conclude that the analysis of neuronalmarkers, such as sodium channel subtypes in painfulneuroma may be a more promising approach to char-acterize the mechanisms of neuropathic pain. I wouldgo even further and propose that not only the typesand numbers of sodium channels, but their activitystate may play a major role, as exemplified by thesodium channel mutations underlying erythromelal-gia (Fischer and Waxman, 2010). Should we thus stopusing those accessible measures in patients to look forpatterns that might help us differentiate painful andpainless states? No, but we should go to differentlevels. The main problem is that most of the ‘objective’measures we have are good at showing loss of func-tion, but are not related to gain of function. Thereseems to be no way around microneurography orother activity markers for C-fibres. Schley and col-leagues have provided a good baseline for such furtherstudies.

1Eur J Pain •• (2012) ••–•• © 2012 European Federation of International Association for the Study of Pain Chapters

Claudia SommerNeurologische Klinik, Universitätsklinikum

Würzburg, Würzburg, GermanyTel.: +49 931 201 23763fax: +49 931 201 23697

E-mail: sommer@uni-wuerzburg.de

References

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Fischer, T.Z., Waxman, S.G. (2010). Familial pain syndromesfrom mutations of the NaV1.7 sodium channel. Ann N Y AcadSci 1184, 196–207.

Ragé, M., Van Acker, N., Facer, P., Shenoy, R., Knaapen, M.W.,Timmers, M., Streffer, J., Anand, P., Meert, T., Plaghki, L.(2010). The time course of CO2 laser-evoked responses and ofskin nerve fibre markers after topical capsaicin in humanvolunteers. Clin Neurophysiol 121, 1256–1266.

Schley, M., Bayram, A., Rukwied, R., Dusch, M., Konrad, C.,Benrath, J., Geber, C., Birklein, F., Hägglöf, B., Sjögren, N.,Gee, L., Albrecht, P.J., Rice, F.L., Schmelz, M. (2012). Skininnervation at different depths correlates with small fiberfunction but not with pain in neuropathic pain patients. Eur JPain (this issue).

Üçeyler, N., Kafke, W., Riediger, N., He, L., Necula, G., Toyka,K.V., Sommer, C. (2010). Elevated proinflammatory cytokineexpression in affected skin in small fiber neuropathy. Neurol-ogy 74, 1806–1813.

Üçeyler, N., Rogausch, J.P., Toyka, K.V., Sommer, C. (2007).Differential expression of cytokines in painful and painlessneuropathies. Neurology 69, 42–49.

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Commentary

2 Eur J Pain •• (2012) ••–•• © 2012 European Federation of International Association for the Study of Pain Chapters