Pathophysiological mechanisms of neuropathic pain: comparison of sensory phenotypes in patients and human surrogate pain models

Abstract

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.

Pain‐autonomic interaction: A surrogate marker of central sensitization

“…Pinprick hyperalgesia was indicated by a decreased MPT in the secondary area of hyperalgesia. This gain of function sign is similar to findings after the application of other human surrogate models of central sensitization (e.g., high-frequency stimulation and intradermal capsaicin injections) (Vollert et al, 2018), and as described in a cluster of patients presenting mainly with mechanical hyperalgesia (Baron et al, 2017;Vollert et al, 2017…”

Cold‐evoked potentials versus contact heat‐evoked potentials—Methodological considerations and clinical application

“…Previous studies reported cold sensation loss in 40% of polyneuropathy, 63% of postherpetic neuralgia, 50% of peripheral nerve injury and 49% of central pain patients (Maier et al, 2010). In various multi-centre studies, QST was validated for the assessment of all known sensory fibre classes, including non-noxious and noxious cold-mediating fibres (Rolke, Baron et al, 2006;Vollert et al, 2018Vollert et al, ,2017. QST is a psychophysical test procedure, which relays on patients' compliance and preserved cognitive function.…”

Sensory bedside testing: a simple stratification approach for sensory phenotyping

“…In fact, these clusters presented similar patterns to those induced by neuropathic surrogate models in healthy volunteers. 17 The exact stratification algorithm was not applied in clinical trials, yet but responders of recent studies can be tentatively assigned to each cluster: the sodium channel blocker oxcarbazepine showed significant pain relief in a subgroup of patients with an irritable nociceptor phenotype (cluster 2), whereas in the remaining group, there was no effect. 6 Another study indirectly hypothesized that patients with sensory loss (cluster 1) had good response to opioids.…”