Paradoxical heat sensation as a manifestation of thermal hypesthesia: a study of 1090 patients with lesions of the somatosensory system.

ABSTRACT: Paradoxical heat sensation (PHS) is the perception of warmth when the skin is cooled. Paradoxical heat sensation rarely occurs in healthy individuals but more frequently in patients suffering from lesions or disease of the peripheral or central nervous system. To further understand mechanisms and epidemiology of PHS, we evaluated the occurrence of PHS in relation to disease aetiology, pain levels, quantitative sensory testing parameters, and Neuropathic Pain Symptom Inventory (NPSI) items in patients with nervous system lesions. Data of 1090 patients, including NPSI scores from 404 patients, were included in the analysis. We tested 11 quantitative sensory testing parameters for thermal and mechanical detection and pain thresholds, and 10 NPSI items in a multivariate generalised linear model with PHS, aetiology, and pain (yes or no) as fixed effects. In total, 30% of the neuropathic patients reported PHS in contrast to 2% of healthy individuals. The frequency of PHS was not linked to the presence or intensity of pain. Paradoxical heat sensation was more frequent in patients living with polyneuropathy compared with central or unilateral peripheral nerve lesions. Patients who reported PHS demonstrated significantly lower sensitivity to thermal perception, with lower sensitivity to normally painful heat and cold stimuli. Neuropathic Pain Symptom Inventory scores were lower for burning and electric shock-like pain quality for patients with PHS. Our findings suggest that PHS is associated with loss of small thermosensory fibre function normally involved in cold and warm perception. Clinically, presence of PHS could help screening for loss of small fibre function as it is straightforward to measure or self-reported by patients.

Beyond biopsychosocial: The keystone mechanism theory of pain.

Pain is a deeply personal experience, with interindividual differences in its chronification and treatment presenting a formidable healthcare challenge. The biopsychosocial model (BPSm) has been hugely influential within nascent attempts at precision pain medicine, steering the field away from a reductionist biomechanical viewpoint and emphasising complex interactions of biological, psychological, and social factors which shape the individuality of pain. However, despite offering a strong theoretical foundation and holistic perspective, we contend that the BPSm remains limited in its capacity to deliver truly mechanistically informed treatment of pain. We therefore propose the keystone model of pain which offers a pragmatic balance between the dimensionality expansive BPSm and overly reductive approaches, providing both theoretical and practical advantages for the transition from treating populations to individual people.

Cutaneous nerve fiber and peripheral Nav1.7 assessment in a large cohort of patients with postherpetic neuralgia.

ABSTRACT: The mechanisms of pain in postherpetic neuralgia (PHN) are still unclear, with some studies showing loss of cutaneous sensory nerve fibers that seemed to correlate with pain level. We report results of skin biopsies and correlations with baseline pain scores, mechanical hyperalgesia, and the Neuropathic Pain Symptom Inventory (NPSI) in 294 patients who participated in a clinical trial of TV-45070, a topical semiselective sodium 1.7 channel (Nav1.7) blocker. Intraepidermal nerve fibers and subepidermal Nav1.7 immunolabeled fibers were quantified in skin punch biopsies from the area of maximal PHN pain, as well as from the contralateral, homologous (mirror image) region. Across the entire study population, a 20% reduction in nerve fibers on the PHN-affected side compared with that in the contralateral side was noted; however, the reduction was much higher in older individuals, approaching 40% in those aged 70 years or older. There was a decrease in contralateral fiber counts as well, also noted in prior biopsy studies, the mechanism of which is not fully clear. Nav1.7-positive immunolabeling was present in approximately one-third of subepidermal nerve fibers and did not differ on the PHN-affected vs contralateral sides. Using cluster analysis, 2 groups could be identified, with the first cluster showing higher baseline pain, higher NPSI scores for squeezing and cold-induced pain, higher nerve fiber density, and higher Nav1.7 expression. While Nav1.7 varies from patient to patient, it does not seem to be a key pathophysiological driver of PHN pain. Individual differences in Nav1.7 expression, however, may determine the intensity and sensory aspects of pain.

Improving neuropathic pain treatment - by rigorous stratification from bench to bedside.

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.

Test-retest reliability of a simple bedside-quantitative sensory testing battery for chronic neuropathic pain.

Introduction: The sensory phenotype is believed to provide information about the underlying pathophysiological mechanisms and to be used in the diagnosis and treatment of chronic neuropathic pain. However, the use of standardized quantitative sensory testing (QST) protocols is limited due to high expenditures of time and costs. Thus, a simple bedside-QST battery was recently developed showing good agreement when compared with laboratory QST. The aim of this study was to preliminary validate this bedside-QST protocol. Methods: Patients experiencing chronic pain with neuropathic features (n = 60) attended 3 visits. During the first visit, laboratory QST and bedside-QST were performed by the same trained investigator. Three hours and 3 weeks later, bedside-QST was repeated. Patients completed questionnaires regarding their pain (intensity, quality), depression/anxiety, and quality of life. Test-retest reliability and convergent/divergent validity were investigated. Results: Most of the bedside-QST parameters, including also those recommended in our first study as being indicative for sensory phenotypes, revealed a moderate to excellent test-retest reliability. Overall, results for short-term reliability and interval-scaled parameters were slightly better. Most of the bedside-QST parameters did not correlate with the depression and anxiety score, suggesting a good divergent validity. Conclusions: Bedside-QST has good criterion and divergent validity as well as reliability. This battery consists of 5 low-cost devices that can be quickly and easily used to characterize the sensory phenotype of patients with neuropathic pain. A combination of bedside-QST parameters can be used to investigate patients' subgroups with specific pathophysiological mechanisms and to identify treatment responders.

Patient Reported Outcome Measures in Chronic Neuropathic Pain Clinical Trials - A Systematic Literature Review.

In neuropathic pain clinical trials, the patient's perspective is often insufficiently reflected focusing mainly on pain intensity. Comparability of outcome assessment is limited due to heterogenous patient reported outcome measures (PROMs). The MEDLINE, CENTRAL, and Embase databases and reference lists of published meta-analyses were searched. Randomized controlled studies assessing treatment efficacy of drugs for chronic neuropathic pain were included. PROMs were assigned to recommended IMMPACT/NeuPSIG domains: pain intensity, pain other aspects, physical functioning, emotional functioning, global improvement and satisfaction, adverse events, participant disposition. Domains and PROMs were compared regarding the publication year and methodological quality of the studies. Within the 251 included studies 200 PROMs were used with 27 being recommended by IMMPACT/NeuPSIG. The number of domains was higher in high/moderate quality studies. The (sub-) domains 'physical functioning', 'global improvement and satisfaction', and 'neuropathic pain quality' were assessed more frequently in high/moderate quality studies and those published after 2011. Recent studies and those of better quality more often used the recommended PROMs. Although neuropathic assessment via PROMs has improved, there is still a high heterogeneity. A standardized core set of outcome domains and should be defined to improve neuropathic pain treatment and to achieve better comparability of clinical trials. Perspective: This systematic literature review assesses the use of patient reported outcome measures (PROMs) in chronic neuropathic pain. The results show that there is still a high heterogeneity, highlighting the need for a standardized core set of outcome domains and PROMs to improve comparability of clinical trials and neuropathic pain treatment.

Capsaicin treatment in neuropathic pain: axon reflex vasodilatation after 4 weeks correlates with pain reduction.

ABSTRACT: Capsaicin, an agonist at the transient receptor potential vanilloid 1, is used for the topical treatment of peripheral neuropathic pain. Reversible receptor defunctionalization and degeneration and subsequent regeneration of cutaneous nociceptors are discussed as its mechanism of action. Here, we hypothesize an accelerated functional recovery of a subclass of nociceptive afferents, the peptidergic vasoactive nociceptors, as the potential cause of capsaicin analgesia. In this noninterventional exploratory trial, 23 patients with peripheral neuropathic pain were treated with one topical high-concentration capsaicin application. Baseline pain ratings, comorbidities, and quality of life were assessed. Functional laser speckle contrast analysis (heat-evoked neurogenic vasodilatation to assess functional properties of peptidergic nociceptors) and quantitative sensory testing were performed in the affected skin. Four weeks after treatment, functional laser speckle contrast analysis and questionnaires were repeated. Telephone interviews were conducted at weeks 2, 10, and 12. Topical capsaicin treatment induced a significant reduction in pain intensity with a maximum at 4 weeks. At the same time, heat-evoked neurogenic vasodilatation was on average similar to pretreatment values. Half of the patients not only showed a functional recovery but also an improvement in vasodilatation, indicating regeneration of nerve fibers. Patients with improved heat-evoked neurogenic vasodilatation at week 4 showed a greater pain reduction than those with deterioration. The degree of vasodilatation significantly correlated with pain reduction. These findings suggest that (1) regeneration of peptidergic nociceptors may be the mechanism behind capsaicin-induced analgesia and (2) that a disease-modifying effect of capsaicin on these fibers already occurs 4 weeks after application.

The pandemic's effect on a patient cohort with painful polyneuropathy in 2020: A longitudinal study on pain, mood, and everyday life.

In the early phase of the COVID pandemic 2020, we demonstrated how patients with painful polyneuropathy, against our expectations, did not experience a deterioration of their neuropathic pain. We hypothesized that our assessed measures, that is, pain intensity and characteristics, emotional wellbeing, and everyday life, would deteriorate in the further course of the pandemic according to the phases of disaster management. Thus, the aim of our study was to investigate patients repeatedly under varying pandemic conditions from March until December 2020. Sixty-three patients were investigated with validated questionnaires (brief pain inventory [BPI], neuropathic pain symptom inventory [NPSI], pain catastrophizing scale [PCS], patient-reported outcomes measurement information system [PROMIS] pain interference/sleep disturbance/fatigue/ depression/anxiety, EuroQol 5 dimensions 5 level version [EQ-5D-5L]) and a pandemic-specific, self-designed questionnaire. The data from the beginning of the pandemic with severe restrictions, during summer with loosened regulations and from December 2020 with reinstalled, severe restrictions were compared with an observational design. Patients reported higher pain severity when restrictions were lower. Sleep, mood, and quality of life did not change in the course of the pandemic in the validated measures. Pain interference significantly decreased during the study independent from restrictions. Patients who reported medical disadvantages had a lower quality of life upon EuroQol 5 dimension (EQ-5D) and were significantly more worried about their health. The perception of pain intensity was dependent on pandemic severity. Sleep, mood, and quality of life did not change significantly in validated measures. Continued medical care seems decisive to prevent worsening of pain and quality of life.

Neuropsychiatric Symptoms and Their Association With Sex, Age, and Enzyme Replacement Therapy in Fabry Disease: A Systematic Review.

Patients suffering from Fabry disease (FD) have an increased risk of developing neuropsychiatric symptoms (NPS), mostly impairment in cognitive performance and depression. Single cases of psychosis have been reported, however, their association with FD can be coincidental. Furthermore, deficits in social functioning and adaptation as well as specific coping styles in FD patients were observed. Recent studies focused on a longitudinal course of the disease and identified risk factors associated with specific NPS. Since 2001, enzyme replacement therapy (ERT) has been available and in preliminary studies seems to improve cognitive impairment and adaptive skills. In this systematic review, we analyze the available literature on the NPS in FD and investigate if there are any differences in their distribution between males and females, children/adolescents and adults, and individuals treated with ERT and untreated. We discuss the role of the psychological, environmental, and molecular alterations and their correlation to psychiatric manifestations in FD. Finally, we would like to increase awareness of the spectrum of NPS in FD.

A modality-specific somatosensory evoked potential test protocol for clinical evaluation: A feasibility study.

OBJECTIVE: We aimed to establish an objective neurophysiological test protocol that can be used to assess the somatosensory nervous system. METHODS: In order to assess most fiber subtypes of the somatosensory nervous system, repetitive stimuli of seven different modalities (touch, vibration, pinprick, cold, contact heat, laser, and warmth) were synchronized with the electroencephalogram (EEG) and applied on the cheek and dorsum of the hand and dorsum of the foot in 21 healthy subjects and three polyneuropathy (PNP) patients. Latencies and amplitudes of the modalities were assessed and compared. Patients received quantitative sensory testing (QST) as reference. RESULTS: We found reproducible evoked potentials recordings for touch, vibration, pinprick, contact-heat, and laser stimuli. The recording of warm-evoked potentials was challenging in young healthy subjects and not applicable in patients. Latencies were shortest within Aß-fiber-mediated signals and longest within C-fibers. The test protocol detected function loss within the Aß-fiber and Aδ-fiber-range in PNP patients. This function loss corresponded with QST findings. CONCLUSION: In this pilot study, we developed a neurophysiological test protocol that can specifically assess most of the somatosensory modalities. Despite technical challenges, initial patient data appear promising regarding a possible future clinical application. SIGNIFICANCE: Established and custom-made stimulators were combined to assess different fiber subtypes of the somatosensory nervous system using modality-specific evoked potentials.

Revealing the time course of laser-evoked potential habituation by high temporal resolution analysis.

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.

The early influence of COVID-19 pandemic-associated restrictions on pain, mood, and everyday life of patients with painful polyneuropathy.

INTRODUCTION: The SARS-Cov-2 pandemic requires special attention on its psychological effects and the impact on patients with chronic pain. OBJECTIVES: This study aimed at examining the influence of the COVID-19 pandemic-associated regulations initiated by the German government on pain intensity and characteristics, emotional well-being, and everyday life of patients with painful polyneuropathy. METHODS: Forty-three patients (well assessed with questionnaires before the pandemic and without change of their health status between baseline and current assessment) were investigated with validated, self-reported questionnaires and COVID-19-specific items 2 weeks after the regulations came into effect. RESULTS: Pain intensity remained stable or even improved like the neuropathic pain symptom inventory total score (t0: 33.54 ± 20.48 vs t1: 27.38 ± 16.16, P = 0.008). Only 11.6% reported a pandemic-associated pain worsening. Rumination scores of the Pain Catastrophizing Scale were lower during t1 compared to before the pandemic regulations (t0: 7.81 ± 4.70, t1: 6.49 ± 4.39; P = 0.030). Interestingly, pain ratings for the last 7 days were higher in patients with a changed social life compared to those without (-1.63 ± 1.60 vs 0.31 ± 1.83; P = 0.01). Quality of life was decreased and helplessness increased in those with higher pain ratings. CONCLUSION: Results suggest a shift of attention from the chronic pain condition towards the imminent threat of a global pandemic. As the impacts of the pandemic are persistent and evolving, the development of the measured parameters in the forthcoming weeks will be of great interest.

Bridging the Gap Between Vessels and Nerves in Fabry Disease.

PURPOSE: Fabry disease frequently includes pain as an early disease feature, which was characterized as a dysfunctional processing of somatosensory information in various studies. The pathomechanism involves the mutation in the x-chromosomal GLA-gene and a consequent reduction of the α-galactosidase. This results in an insufficient reduction of globotriaosylceramide (GL3). Interestingly, an accumulation of GL3 was shown in both vascular endothelial cells and nerve tissue. This implicates that both an endothelial and nerve-dependent dysfunction may be considered as prominent mechanisms in pain pathogeneses. PATIENTS AND METHODS: The exploration of endothelial and C-fiber-dependent microcirculatory changes was conducted in a healthy cohort (n = 22) and in patients with polyneuropathy (n = 21) and Fabry disease (n = 15). Microcirculatory measurements were conducted using a laser speckle contrast analysis (LASCA) in combination with a thermoprobe controlling system, which applied a constant heat stimulus (42°C). Additionally, nerve fiber function was assessed via Quantitative Sensory Testing and heart rate variability (HRV). RESULTS: The results indicated a characteristic perfusion profile in the control group as well as both patient groups. Fabry patients had the smallest increase of endothelial-dependent perfusion as compared to the others [% increase as compared to Fabry: control + 129% (p = 0.002), PNP + 126% (p = 0.019)]. The sensory testing indicated a dysfunctional processing of A-delta fibers in Fabry disease as compared to healthy controls [cold detection threshold (CDT): p = 0.004, mechanical pain threshold (MPT): p = 0.007] and PNP patients (MPT: p = 0.001). CONCLUSION: Our results point to both an endothelial and a nerve-dependent dysfunction in Fabry disease. Therefore, not only direct changes in nerve fiber tissue may contribute to an altered sensory processing. Indeed, evidence of a perfusion change in vasa nervorum could also contribute to the dysfunctional processing of sensory information, which likely occurs under physical stress.

Stratification of patients with unclassified pain in the FabryScan database.

PURPOSE: Fabry disease belongs to lysosomal storage disorders and can be successfully treated today. On the contrary, the correct diagnostic classification of its symptoms can be challenging and most patients suffer from pain for years, until they are diagnosed correctly. The aim of this project was to characterize patients with unclassified extremity pain and to present a simple algorithm for a retrospective stratification approach. PATIENTS AND METHODS: The FabryScan includes a bedside-test and a questionnaire, consisting of 10 symptom-orientated and anamnestic questions. For the stratification of patients according to the likelihood for Fabry disease two different approaches were conducted. First, a prospective subgrouping based on the previously invented FabryScan evaluation system was conducted. The second retrospective approach consisted of a factor analysis and a subsequent two-way cluster analysis. Further on, 4 patients diagnosed with Fabry disease were stratified according to both approaches. RESULTS: In total, 183 completed datasets were included in the statistical analysis. The first approach prospectively classified patients into 3 subgroups (n=40 [likely], n=96 [possible], n=47 [unlikely]) according to the FabryScan evaluation system. The second approach retrospectively stratified patients into 3 subgroups (n=47 [cluster 1], n=95 [cluster 2], n=41 [cluster 3]). Finally, the Fabry patients were sorted to the subgroups, indicative for the highest possibility of Fabry disease in both stratification approaches A and B. CONCLUSION: Both stratification approaches sorted patients with confirmed Fabry disease to the subgroups, indicative for the highest likelihood for Fabry. These results indicate validity of the initially selected FabryScan outcome parameters.

Cold-evoked potentials versus contact heat-evoked potentials-Methodological considerations and clinical application.

BACKGROUND: Previous studies investigated cold-evoked potentials (CEPs) for the assessment of the integrity of cold-mediating A-delta fibres and the spinothalamic tract. Nevertheless, several methodological questions remained unanswered to proceed to clinical application. How do latencies and amplitudes vary between CEPs and contact heat-evoked potentials (CHEPs)? Are there differences between variable and fixed thermode positions or between glabrous and hairy skin? Are CEPs recordable in patients with abnormal cold processing? METHODS: A total of 16 healthy subjects were tested with CEPs and CHEPs at the face, hand and foot. Variable and fixed thermode positions, hairy and glabrous skin were compared. Three patients with abnormal cold processing were tested with CEPs and quantitative sensory testing. RESULTS: Compared to CEPs, CHEPs latencies were significantly longer at all locations, amplitudes were significantly larger at the face and the hand whilst comparable at the foot. CEPs and CHEPs did not differ significantly between variable and fixed thermode positions using inter stimulus intervals of 8-12 s. CEP latencies were increased by around 20% at the glabrous skin. Patients with known abnormal cold processing (central pain, polyneuropathy, Fabry's disease) showed increased N2 latencies as compared to normal controls. CONCLUSIONS: Inter stimulus intervals of 8-12 s allow the use of a fixed thermode position for reliable CEPs/CHEPs recording. Hairy skin stimulation results in faster latencies as compared to glabrous skin, without influencing EP amplitudes. In patients with abnormal cold processing, CEPs are recordable and increased latencies may be expected as compared to healthy controls and the healthy contralateral side. SIGNIFICANCE: Cold-evoked potentials are an innovative, non-invasive technique to assess cold detection and processing objectively. This study shows that CEP can be recorded from the hairy and glabrous skin, regardless of using fixed or variable thermode positions. Loss of A-delta fibre function leads to an increased CEP latency, consistent with loss of cold detection in the QST.