Neuropathic pain (NeP) can result from sources as varied as nerve compression, channelopathies, autoimmune disease, and incision. By identifying the neurobiological changes that underlie the pain state, it will be clinically possible to exploit mechanism-based therapeutics for maximum analgesic effect as diagnostic accuracy is optimized. Obtaining sufficient knowledge regarding the neuroadaptive alterations that occur in a particular NeP state will result in improved patient analgesia and a mechanism-based, as opposed to a disease-based, therapeutic approach to facilitate target identification. This will rely on comprehensive disease pathology insight; our knowledge is vastly improving due to continued forward and back translational preclinical and clinical research efforts. Here we discuss the clinical aspects of neuropathy and currently used drugs whose mechanisms of action are outlined alongside their clinical use. Finally, we consider sensory phenotypes, patient clusters, and predicting the efficacy of an analgesic for neuropathy.

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.

Introduction: Patients suffering from fibromyalgia syndrome (FMS) are heterogenous. They often present with sensory abnormalities and comorbidities. Objectives:We aimed to answer the following questions: (1) Is there a specific somatosensory profile in our patient cohort? (2) Can we detect subgroups characterized by a specific combination of sensory and psychological features? and (3) Do psychological parameters influence sensory signs? Methods: In 87 patients with FMS quantitative sensory testing was performed on the hand and evaluated in combination with questionnaire results regarding pain, psychological comorbidities, sleep, and functionality. Results: Patients presented different somatosensory patterns, but no specific subgroups regarding sensory signs and psychological features were detected. Hypersensitivity for noxious mechanical and thermal stimuli and hyposensitivity for nonnoxious mechanical stimuli were the most prominent features. Thirty-one percent of patients showed signs of central sensitization as indicated by abnormally increased pinprick hyperalgesia or dynamic mechanical allodynia. Central sensitization was associated with higher pain intensities (P , 0.001). Only a small influence of psychiatric comorbidities on mechanical pain sensitivity (P 5 0.044) and vibration detection (P 5 0.028) was found, which was partly associated with high pain intensities. A small subgroup of patients (11.4%) demonstrated thermal hyposensitivity (loss of small-fiber function). Conclusion: Patients with FMS showed various somatosensory abnormalities. These were not significantly influenced by psychological comorbidities. Signs for central sensitization were detected in about one-third of patients and associated with higher pain intensities. This supports the notion of central sensitization being a major pathophysiological mechanism in FMS, whereas small-fiber loss may be less important.

Objective:To test whether contralateral sensory abnormalities in the clinically unaffected area of patients with unilateral neuropathic pain are due to the neuropathy or pain mechanisms.Methods:We analyzed the contralateral clinically unaffected side of patients with unilateral painful or painless neuropathy (peripheral nerve injury, PNI; postherpetic neuropathy, PHN; radiculopathy) by standardized quantitative sensory testing following a validated protocol. Primary outcome was the independent contribution of the following variables on the contralateral sensory function using generalized linear regression models: pain intensity, disease duration, etiology, body area, and sensory patterns in the most painful area.Results:Among 424 patients (PNI: n=256; PHN: n=78, radiculopathy: n=90) contralateral sensory abnormalities were frequent in both painful (n=383) and painless (n=41) unilateral neuropathy, demonstrating sensory loss for thermal and mechanical non-painful stimuli and both sensory loss and gain for painful test stimuli. Analysis by etiology revealed contralateral pinprick hyperalgesia in PHN and PNI. Analysis by ipsilateral sensory phenotype demonstrated mirror-image pinprick hyperalgesia in both mechanical and thermal hyperalgesia phenotypes. Pain intensity, etiology and affected body region predicted changes in only single contralateral somatosensory parameters. Disease duration had no impact on the contralateral sensory function.Conclusion:Mechanisms of sensory loss seems to spread to the contralateral side in both painful and painless neuropathies. Contralateral spread of pinprick hyperalgesia was restricted to the two ipsilateral phenotypes that suggest sensitization; this suggest a contribution of descending net facilitation from supraspinal areas, which was reported in rodent models of neuropathic pain, but not yet in human patients.

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.

Hereditary transthyretin amyloidosis is caused by pathogenic variants (ATTRv) in the TTR gene. Alongside cardiac dysfunction, the disease typically manifests with a severely progressive sensorimotor and autonomic polyneuropathy. Three different drugs, tafamidis, patisiran, and inotersen, are approved in several countries, including the European Union and the United States of America. By stabilizing the TTR protein or degrading its mRNA, all types of treatment aim at preventing amyloid deposition and stopping the otherwise fatal course. Therefore, it is of utmost importance to recognize both onset and progression of neuropathy as early as possible. To establish recommendations for diagnostic and therapeutic procedures in the follow-up of both pre-symptomatic mutation carriers and patients with manifest ATTRv amyloidosis with polyneuropathy, German and Austrian experts elaborated a harmonized position. This paper is further based on a systematic review of the literature. Potential challenges in the early recognition of disease onset and progression are the clinical heterogeneity and the subjectivity of sensory and autonomic symptoms. Progression cannot be defined by a single test or score alone but has to be evaluated considering various disease aspects and their dynamics over time. The first-line therapy should be chosen based on individual symptom constellations and contra-indications. If symptoms worsen, this should promptly implicate to consider optimizing treatment. Due to the rareness and variability of ATTRv amyloidosis, the clinical course is most importantly directive in doubtful cases. Therefore, a systematic follow-up at an experienced center is crucial to identify progression and reassure patients and carriers.

Supplemental Digital Content is Available in the Text.An easy to use bedside test was developed to detect sensitization mechanisms in chronic painful knee osteoarthritis or chronic pain after total knee replacement.

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