Supplemental Digital Content is Available in the Text. Validated questionnaires revealed a shift of attention from chronic pain towards the COVID-19 pandemic in patients with chronic painful polyneuropathy.
Chronic pain is a constantly recurring and persistent illness, presenting a formidable healthcare challenge for patients and physicians alike. Current first‐line analgesics offer only low‐modest efficacy when averaged across populations, further contributing to this debilitating disease burden. Moreover, many recent trials for novel analgesics have not met primary efficacy endpoints, which is particularly striking considering the pharmacological advances have provided a range of highly relevant new drug targets. Heterogeneity within chronic pain cohorts is increasingly understood to play a critical role in these failures of treatment and drug discovery, with some patients deriving substantial benefits from a given intervention while it has little‐to‐no effect on others. As such, current treatment failures may not result from a true lack of efficacy, but rather a failure to target individuals whose pain is driven by mechanisms which it therapeutically modulates. This necessitates a move towards phenotypical stratification of patients to delineate responders and non‐responders in a mechanistically driven manner. In this article, we outline a bench‐to‐bedside roadmap for this transition to mechanistically informed personalised pain medicine. We emphasise how the successful identification of novel analgesics is dependent on rigorous experimental design as well as the validity of models and translatability of outcome measures between the animal model and patients. Subsequently, we discuss general and specific aspects of human trial design to address heterogeneity in patient populations to increase the chance of identifying effective analgesics. Finally, we show how stratification approaches can be brought into clinical routine to the benefit of patients.image
Background The serotonin receptor 2A (HTR2A) has been described as an important facilitation mediator of spinal nociceptive processing leading to central sensitization (CS) in animal models of chronic pain. However, whether HTR2A single nucleotide variants (SNVs) modulate neuropathic pain states in patients has not been investigated so far. The aim of this study was to elucidate the potential association of HTR2A variants with sensory abnormalities or ongoing pain in neuropathic pain patients. Methods At total of 240 neuropathic pain patients and 253 healthy volunteers were included. Patients were phenotypically characterized using standardized quantitative sensory testing (QST). Patients and controls were genotyped for HTR2A g.‐1438G > A (rs6311) and c.102C > T (rs6313). Genotype‐related differences in QST parameters were assessed considering QST profile clusters, principal somatosensory components and sex. Results There was an equal distribution of rs6313 and linked rs6311 between patients and controls. However, the rs6313 variant was significantly associated with a principal component of pinprick hyperalgesia and dynamic mechanical allodynia, indicating enhanced CS in patients with sensory loss (−0.34 ± 0.15 vs. +0.31 ± 0.11 vs., p < .001). In this cluster, the variant allele was also associated with single QST parameters of pinprick hyperalgesia (MPT, +0.64 ± 0.18 vs. −0.34 ± 0.23 p = .002; MPS, +0.66 ± 0.17 vs. −0.09 ± 0.23, p = .009) and ongoing pain was increased by 30%. Conclusions The specific association of the rs6313 variant with pinprick hyperalgesia and increased levels of ongoing pain suggests that the HTR2A receptor might be an important modulator in the development of CS in neuropathic pain. Significance This article presents new insights into serotonin receptor 2A‐mediating mechanisms of central sensitization in neuropathic pain patients. The rs6313 variant allele was associated with increased mechanical pinprick sensitivity and increased levels of ongoing pain supporting a contribution of central sensitization in the genesis of ongoing pain providing a possible route for mechanism‐based therapies.
Background and Objectives Reduced laser‐evoked potential (LEP) habituation indicates abnormal central pain processing. But the paradigm (four stimulation blocks a 25 stimuli) is time consuming and potentially omits important information on the exact habituation time course. This study examined whether a high temporal resolution (HTR) analysis (dividing the four stimulation blocks into 12 analysis blocks) can answer the following questions: (a) After how many stimuli does LEP habituation occur? (b) Is there a difference in LEP habituation in younger versus older subjects? (c) Is HTR applicable on radiculopathy patients? Methods EEG data of 129 subjects were included. Thirty‐four young healthy and 28 advanced‐aged healthy subjects were tested with LEPs on the hand dorsum. Thirty‐seven radiculopathy patients and 30 controls were tested with LEPs on the L3 dermatome. The EEG data of the hand dorsa have been analysed conventionally and with HTR analysis. The applicability of HTR has been tested on radiculopathy patients and respective controls. Results HTR was well feasible in young healthy subjects and revealed a strong habituation effect during the first 25 stimuli (i.e. within the first 5 min). After approximately 48 stimuli, no further significant habituation was detectable. LEP amplitudes were higher in young subjects. HTR was unsuitable for elderly subjects and middle‐aged radiculopathy patients. Conclusions In young healthy subjects, HTR allows a shortening of the test protocol while providing a detailed information on the time course of LEP habituation. A shorter protocol might be useful for the applicability of the LEP paradigm for clinical and experimental settings as well as pharmacological studies. Significance The usage of high temporal resolution (HTR) analysis in young healthy subjects enables a short test protocol and provides the exact time course of laser‐evoked potential habituation. This can be useful for the examination of neurological conditions affecting younger patients and for pharmacological studies. HTR was inapplicable in advanced‐aged subjects and patients with radiculopathy.
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