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Pathophysiological mechanisms of neuropathic pain

comparison of sensory phenotypes in patients and human surrogate pain models

Vollert, Jana,b,*; Magerl, Walterb; Baron, Ralfc; Binder, Andreasc; Enax-Krumova, Elena K.a,d; Geisslinger, Gerde,f; Gierthmühlen, Jannec; Henrich, Florianb; Hüllemann, Philippc; Klein, Thomasb; Lötsch, Jörne; Maier, Christopha; Oertel, Brunof; Schuh-Hofer, Sigridb; Tölle, Thomas R.g; Treede, Rolf-Detlefb

doi: 10.1097/j.pain.0000000000001190
Research Paper
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Global Year 2018

As an indirect approach to relate previously identified sensory phenotypes of patients suffering from peripheral neuropathic pain to underlying mechanisms, we used a published sorting algorithm to estimate the prevalence of denervation, peripheral and central sensitization in 657 healthy subjects undergoing experimental models of nerve block (NB) (compression block and topical lidocaine), primary hyperalgesia (PH) (sunburn and topical capsaicin), or secondary hyperalgesia (intradermal capsaicin and electrical high-frequency stimulation), and in 902 patients suffering from neuropathic pain. Some of the data have been previously published. Randomized split-half analysis verified a good concordance with a priori mechanistic sensory profile assignment in the training (79%, Cohen κ = 0.54, n = 265) and the test set (81%, Cohen κ = 0.56, n = 279). Nerve blocks were characterized by pronounced thermal and mechanical sensory loss, but also mild pinprick hyperalgesia and paradoxical heat sensations. Primary hyperalgesia was characterized by pronounced gain for heat, pressure and pinprick pain, and mild thermal sensory loss. Secondary hyperalgesia was characterized by pronounced pinprick hyperalgesia and mild thermal sensory loss. Topical lidocaine plus topical capsaicin induced a combined phenotype of NB plus PH. Topical menthol was the only model with significant cold hyperalgesia. Sorting of the 902 patients into these mechanistic phenotypes led to a similar distribution as the original heuristic clustering (65% identity, Cohen κ = 0.44), but the denervation phenotype was more frequent than in heuristic clustering. These data suggest that sorting according to human surrogate models may be useful for mechanism-based stratification of neuropathic pain patients for future clinical trials, as encouraged by the European Medicines Agency.

Sensory profiles of human surrogate models of neuropathic pain and neuropathy underline the mechanistic relevance of heuristically found sensory phenotypes in patients suffering from neuropathic pain.

aDepartment of Pain Medicine, BG University Hospital Bergmannsheil GmbH, Ruhr-University Bochum, Bochum, Germany

bCenter of Biomedicine and Medical Technology Mannheim (CBTM), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

cDivision of Neurological Pain Research and Therapy, Department of Neurology, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Kiel, Germany

dDepartment of Neurology, BG University Hospital Bergmannsheil GmbH, Ruhr-University Bochum, Bochum, Germany

eInstitute of Clinical Pharmacology, Pharmazentrum Frankfurt/ZAFES, University Hospital of Goethe-University, Frankfurt am Main, Germany

fFraunhofer Institute for Molecular Biology and Applied Ecology (IME), Project Group Translational Medicine and Pharmacology (TMP), Frankfurt am Main, Germany

gDepartment of Neurology, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany

Corresponding author. Address: Neurophysiologie, Zentrum für Biomedizin und Medizintechnik Mannheim, Medizinische Fakultät Mannheim, der Universität Heidelberg, Ludolf-Krehl-Str.13-17, 68167 Mannheim, Germany. Tel.: +49 621/383-9926; fax: +49 621/383-9921. E-mail address: Jan.Vollert@rub.de (J. Vollert).

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Received October 09, 2017

Received in revised form January 26, 2018

Accepted February 14, 2018

© 2018 International Association for the Study of Pain
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