A diminished sciatic nerve structural integrity is associated with distinct peripheral sensory phenotypes in individuals with type 2 diabetes.

AIMS/HYPOTHESIS: Quantitative sensory testing (QST) allows the identification of individuals with rapid progression of diabetic sensorimotor polyneuropathy (DSPN) based on certain sensory phenotypes. Hence, the aim of this study was to investigate the relationship of these phenotypes with the structural integrity of the sciatic nerve among individuals with type 2 diabetes. METHODS: Seventy-six individuals with type 2 diabetes took part in this cross-sectional study and underwent QST of the right foot and high-resolution magnetic resonance neurography including diffusion tensor imaging of the right distal sciatic nerve to determine the sciatic nerve fractional anisotropy (FA) and cross-sectional area (CSA), both of which serve as markers of structural integrity of peripheral nerves. Participants were then assigned to four sensory phenotypes (participants with type 2 diabetes and healthy sensory profile [HSP], thermal hyperalgesia [TH], mechanical hyperalgesia [MH], sensory loss [SL]) by a standardised sorting algorithm based on QST. RESULTS: Objective neurological deficits showed a gradual increase across HSP, TH, MH and SL groups, being higher in MH compared with HSP and in SL compared with HSP and TH. The number of participants categorised as HSP, TH, MH and SL was 16, 24, 17 and 19, respectively. There was a gradual decrease of the sciatic nerve's FA (HSP 0.444, TH 0.437, MH 0.395, SL 0.382; p=0.005) and increase of CSA (HSP 21.7, TH 21.5, MH 25.9, SL 25.8 mm2; p=0.011) across the four phenotypes. Further, MH and SL were associated with a lower sciatic FA (MH unstandardised regression coefficient [B]=-0.048 [95% CI -0.091, -0.006], p=0.027; SL B=-0.062 [95% CI -0.103, -0.020], p=0.004) and CSA (MH ß=4.3 [95% CI 0.5, 8.0], p=0.028; SL B=4.0 [95% CI 0.4, 7.7], p=0.032) in a multivariable regression analysis. The sciatic FA correlated negatively with the sciatic CSA (r=-0.35, p=0.002) and markers of microvascular damage (high-sensitivity troponin T, urine albumin/creatinine ratio). CONCLUSIONS/INTERPRETATION: The most severe sensory phenotypes of DSPN (MH and SL) showed diminishing sciatic nerve structural integrity indexed by lower FA, likely representing progressive axonal loss, as well as increasing CSA of the sciatic nerve, which cannot be detected in individuals with TH. Individuals with type 2 diabetes may experience a predefined cascade of nerve fibre damage in the course of the disease, from healthy to TH, to MH and finally SL, while structural changes in the proximal nerve seem to precede the sensory loss of peripheral nerves and indicate potential targets for the prevention of end-stage DSPN. TRIAL REGISTRATION: ClinicalTrials.gov NCT03022721.

A multidimensional appraisal of early menstrual pain experience.

BACKGROUND: Symptomatic dysmenorrhea is a global problem, affecting more than 40% of menstruating persons. Cross-sectional studies have implicated psychosocial, biological, and sensory factors in dysmenorrhea but the mechanisms are not fully understood. Only a few prospective longitudinal studies have evaluated such factors in relation to the emergence and course of dysmenorrhea at menarche. OBJECTIVE: This study aimed to describe the initial menstruation experience and to evaluate the association of premenarchal psychosocial and sensory factors with the intensity of dysmenorrhea during the period in the fourth month. STUDY DESIGN: This was a prospective cohort study of adolescents who completed premenarchal assessments and postmenarchal daily menstrual diaries for their first (n=149) and fourth month periods (n=114). They were recruited shortly before menarche and completed baseline assessments, including psychosocial questionnaires and experimental pain sensitivity (pressure testing, bladder provocation), and their parents completed related pain questionnaires. The relation between the hypothesized premenarchal factors and month 4 dysmenorrhea intensity was evaluated using Kruskal-Wallis and chi-square tests for low (<3 on a 0-10 scale) vs higher (≥3) menstrual pain groups based on maximal pain ratings recorded in a daily diary. RESULTS: Low levels of dysmenorrhea characterized the first (median, 1; interquartile range, 0-2) and fourth month periods (1; 0-3). Maximal pain ratings increased from the first to the fourth period (3; 1-5 vs 4; 1-6; P=.007). The distribution of dysmenorrhea was multimodal at month 4 with 31.6% of the participants having low levels of maximal pain (1; 0-1) and 68.4% having higher levels (5; 4-6; Hartigan's dip test P<.001). The baseline demographic, psychosocial, and parental pain characteristics were not associated with the development of worse dysmenorrhea. The baseline experimental pain sensitivity, based on pressure pain thresholds, did not differ between the low (15.7 N; 12.5-22.3) and higher (15.0 N; 10.9-21.4]) level dysmenorrhea groups. Baseline bladder pain at first urge also did not differ (low, 6; 0-20 vs higher, 7; 0-19). CONCLUSION: By their fourth month period, two-thirds of adolescents fell into the higher group for maximal dysmenorrhea, half reported some related impairments in physical activity, and one-seventh reported some related school absence. Premenarchal factors (experimental pain sensitivity, psychosocial profile, parental pain experience) linked to chronic pain emergence in the adult literature did not predict dysmenorrhea intensity, suggesting the dominant factor at menarche may be peripheral afferent activation. Further research is needed to understand the evolution of psychosocial and sensory mechanisms in the development and course of dysmenorrhea.

Circadian functional changes of pain-processing brainstem nuclei and implications for cluster headache: A 7 Tesla imaging study.

BACKGROUND: Pain thresholds and primary headaches, including cluster headache attacks, have circadian rhythmicity. Thus, they might share a common neuronal mechanism. OBJECTIVE: This study aimed to elucidate how the modulation of nociceptive input in the brainstem changes from noon to midnight. Insights into the mechanism of these fluctuations could allow for new hypotheses about the pathophysiology of cluster headache. METHODS: This repeated measure observational study was conducted at the University Hospital Zurich from December 2019 to November 2022. Healthy adults between 18 and 85 years of age were eligible. All participants were examined at noon and midnight. We tested the pain threshold on both sides of the foreheads with quantitative sensory testing, assessed tiredness levels, and obtained high-field (7 Tesla) and high-resolution functional magnetic resonance imaging (MRI) at each visit. Functional connectivity was assessed at the two visits by performing a region-of-interest analysis. We defined nuclei in the brainstem implicated in processing nociceptive input as well as the thalamus and suprachiasmatic nucleus as the region-of-interest. RESULTS: Ten people were enrolled, and seven participants were included. First, we did not find statistically significant differences between noon and midnight of A-delta-mediated pain thresholds (median mechanical pain threshold at noon: left 9.2, right 9.2; at night: left 6.5, right 6.1). Second, after correction for a false discovery rate, we found changes in the mechanical pain sensitivity to have a statistically significant effect on changes in the functional connectivity between the left parabrachial nucleus and the suprachiasmatic nucleus (T = -40.79). CONCLUSION: The MRI data analysis suggested that brain stem nuclei and the hypothalamus modulate A-delta-mediated pain perception; however, these changes in pain perception did not lead to statistically significantly differing pain thresholds between noon and midnight. Hence, our findings shed doubt on our hypothesis that the physiologic circadian rhythmicity of pain thresholds could drive the circadian rhythmicity of cluster headache attacks.

Clinical, histologic, and immunologic signatures of Small Fiber Neuropathy in Systemic Lupus Erythematosus.

BACKGROUND AND OBJECTIVES: Systemic Lupus Erythematosus (SLE) often causes damage to small nerve fibers, leading to distressing painful and autonomic symptoms. Despite this, Small Fiber Neuropathy (SFN) remains an underrecognized complication for SLE patients. In this cross-sectional study, we aimed to assess SFN in patients with SLE and to explore its correlations with immunologic disease features and clinical manifestations. METHODS: We recruited 50 SLE patients (1 male to 12.5 females, aged 20-80 years) reporting painful disturbances. We conducted a comprehensive clinical and neurophysiological evaluation, using Nerve Conduction Studies and Quantitative Sensory Testing. Additionally, we carried out an extensive laboratory assessment of disease-related serological parameters. We also performed a thorough skin biopsy analysis, investigating somatic and autonomic innervation while detecting complement and inflammatory cell infiltrates within the skin. RESULTS: Out of 50 patients, 19 were diagnosed with SFN, primarily characterized by a non-length-dependent distribution; 7 had a mixed neuropathy, with both large and small fiber involvement. Patients with SFN were younger than patients with a mixed neuropathy (p = .0143); furthermore, they were more likely to have a history of hypocomplementemia (p = .0058) and to be treated with cyclosporine A (p = .0053) compared to patients without neuropathy. However, there were no significant differences in painful and autonomic symptoms between patients with and without SFN. DISCUSSION: This study highlights the relevant frequency of SFN with a non-length-dependent distribution among SLE patients experiencing painful symptoms. Indeed, SFN emerges as an early manifestation of SLE-related neuropathy and is closely associated with hypocomplementemia, suggesting a potential pathogenic role of the complement system. Moreover, SFN may be influenced by disease-modifying therapies. However, the precise role of SFN in shaping painful and autonomic symptoms in patients with SLE remains to be fully elucidated.

Effects of taxane-induced peripheral neuropathy on hand dexterity impairment: evaluation of quantitative and subjective assessments.

PURPOSE: Chemotherapy-induced peripheral neuropathy (CIPN) commonly involves hand dexterity impairment. However, the factors affecting hand dexterity impairment are unknown and there is currently no established treatment. The purpose of the current study was to clarify factors influencing hand dexterity impairment in taxane-induced peripheral neuropathy using subjective and objective assessments. METHODS: We assessed patient characteristics, treatment-related factors, subjective symptoms of CIPN (Patient Neurotoxicity Questionnaire [PNQ]), psychological symptoms, and upper limb dysfunction (Quick Disabilities of the Arm, Shoulder and Hand [Quick DASH]). Quantitative assessments were pinch strength, sensory threshold, hand dexterity impairment, and grip force control. Multiple regression analysis was performed using hand dexterity impairment as the dependent variable and age and PNQ, Quick DASH, and control of grip force as independent variables. RESULTS: Forty-three breast cancer patients were included in the analysis. Hand dexterity impairment in taxane-induced peripheral neuropathy patients was significantly correlated with age, grip force control, and PNQ sensory scores (p < 0.008). Multiple regression analysis demonstrated that PNQ sensory scores and grip force control were significantly associated with hand dexterity impairment (p < 0.01). CONCLUSION: Subjective symptoms (numbness and pain) and grip force control contributed to impaired hand dexterity in taxane-induced peripheral neuropathy.

The Known Biology of Neuropathic Pain and Its Relevance to Pain Management.

Patients with neuropathic pain are heterogeneous in pathophysiology, etiology, and clinical presentation. Signs and symptoms are determined by the nature of the injury and factors such as genetics, sex, prior injury, age, culture, and environment. Basic science has provided general information about pain etiology by studying the consequences of peripheral injury in rodent models. This is associated with the release of inflammatory cytokines, chemokines, and growth factors that sensitize sensory nerve endings, alter gene expression, promote post-translational modification of proteins, and alter ion channel function. This leads to spontaneous activity in primary afferent neurons that is crucial for the onset and persistence of pain and the release of secondary mediators such as colony-stimulating factor 1 from primary afferent terminals. These promote the release of tertiary mediators such as brain-derived neurotrophic factor and interleukin-1ß from microglia and astrocytes. Tertiary mediators facilitate the transmission of nociceptive information at the spinal, thalamic, and cortical levels. For the most part, these findings have failed to identify new therapeutic approaches. More recent basic science has better mirrored the clinical situation by addressing the pathophysiology associated with specific types of injury, refinement of methodology, and attention to various contributory factors such as sex. Improved quantification of sensory profiles in each patient and their distribution into defined clusters may improve translation between basic science and clinical practice. If such quantification can be traced back to cellular and molecular aspects of pathophysiology, this may lead to personalized medicine approaches that dictate a rational therapeutic approach for each individual.

Impact of different CRPS phenotypes and diagnostic criteria on quantitative sensory testing outcomes: systematic review and meta-analysis.

OBJECTIVES: This review and meta-analysis evaluated the impact of diagnostic criteria and clinical phenotypes on quantitative sensory testing (QST) outcomes in patients with complex regional pain syndrome (CRPS). METHODS: Eight databases were searched based on a previously published protocol. Forty studies comparing QST outcomes between CRPS-I vs II, warm vs cold CRPS, upper vs lower limb CRPS, males vs females, or using Budapest vs older IASP criteria were included. RESULTS: Studies investigating QST differences between CRPS-I vs II (n = 4), between males vs females (n = 2), and between upper and lower limb CRPS (n = 2) showed no significant differences. Four studies compared QST outcomes in warm vs cold CRPS, showing heat hyperalgesia in warm CRPS, with thermal and mechanical sensory loss in cold CRPS. Although CRPS diagnosed using the Budapest criteria (24 studies) vs 1994 IASP criteria (13 studies) showed similar sensory profiles, there was significant heterogeneity and low quality of evidence in the latter. CONCLUSIONS: Based on the findings of this review, classifying CRPS according to presence or absence of nerve lesion into CRPS-I and II, location (upper or lower limb) or according to sex might not be clinically relevant as all appear to have comparable sensory profiles that might suggest similar underlying mechanisms. In contrast, warm vs cold phenotypes exhibited clear differences in their associated QST sensory profiles. To the extent that differences in underlying mechanisms might lead to differential treatment responsiveness, it appears unlikely that CRPS-I vs II, CRPS location, or patient sex would prove useful in guiding clinical management.

Altered pain processing and sensitization in sickle cell disease: a scoping review of quantitative sensory testing findings.

OBJECTIVES: Over 50% of adults living with sickle cell disease (SCD) have chronic pain, but the underlying mechanisms of chronic pain in this population remain unclear. Quantitative sensory testing is an important measurement tool for understanding pain and sensory processing. This scoping review summarizes quantitative sensory testing methodologies used in sickle cell studies and the evidence for central sensitization in this population. METHODS: We conducted a systematic search of PubMed, Embase, and CINAHL to identify studies using quantitative sensory testing in individuals living with sickle cell disease. Search strategies were based on variations of the terms "sickle cell disease," and "quantitative sensory testing." Eligible studies were observational or experimental studies in human participants living with SCD that reported findings and detailed methodology for at least 1 quantitative sensory testing modality. RESULTS: Our search yielded a total of 274 records; 27 of which are included in this scoping review. Of the 27 studies, 17 were original studies (with combined total of 516 adult and 298 pediatric participants), and 10 were secondary or subgroup analyses of these prior studies. Significant variation existed in quantitative sensory testing methodologies across studies, including testing locations, type and intensity of stimuli, and interpretation of findings. Of the identified studies, 22% (2/9 studies) reported sensory abnormalities in mechanical sensitivity and thresholds, 22% (2/9 studies) reported abnormal pressure pain thresholds, 46% (6/13 studies) reported sensory abnormalities in thermal pain thresholds and tolerance (cold and warm), and 50% (2/4 studies) reported abnormalities in temporal summation. CONCLUSION: Future studies should use standardized quantitative sensory testing protocols with consistent and operationalized definitions of sensitization to provide clear insight about pain processing and central sensitization in sickle cell disease.

Individuals with fibromyalgia report greater pain sensitivity than healthy adults while listening to their favorite music: the contribution of negative affect.

OBJECTIVE: We investigated the impact of favorite music on pain processing among individuals with fibromyalgia. We also examined differences in pain processing between individuals with fibromyalgia and healthy controls (HC) while listening to favorite music and explored whether psychosocial factors contributed to these differences. METHODS: Individuals with fibromyalgia and HC completed baseline psychosocial questionnaires and then underwent quantitative sensory testing (QST) during 3 randomized music conditions (meditative music, favorite music, white noise). Among individuals with fibromyalgia, Friedman tests were used to investigate differences in QST across conditions. Analyses of Covariance were used to examine group (HC vs fibromyalgia) differences in QST during favorite music. Correlations were conducted to explore associations of baseline psychosocial factors with QST during favorite music. Mediation analyses were conducted to explore whether psychosocial factors contributed to greater pain sensitivity among individuals with fibromyalgia compared to HC during favorite music. RESULTS: Individuals with fibromyalgia were less sensitive to pressure pain while listening to their favorite music compared to white noise. Compared to HC, individuals with fibromyalgia reported higher baseline negative affect and lower pain thresholds and tolerances during favorite music. Negative affect partially mediated the relationship between pain status (HC vs fibromyalgia) and pain sensitivity during favorite music. CONCLUSIONS: Individuals with fibromyalgia were less pain sensitive while listening to favorite music than white noise, although they were more sensitive than HC. Greater negative affect endorsed by individuals with fibromyalgia contributed to their greater pain sensitivity. Future studies should explore the impact of favorite music on clinical pain. CLINICAL TRAILS REGISTRATION: This study was registered with ClinicalTrials.gov (NCT04087564) and began on 6/13/2019.

Evaluation of Central Sensitisation in Bladder Pain Syndrome: A Systematic Review.

INTRODUCTION AND HYPOTHESIS: Bladder pain syndrome (BPS) is a debilitating condition characterised by exaggerated bladder sensations and altered bladder function. It is still unknown whether the condition is a peripheral sensory problem or due to abnormal central sensory processing as seen in central sensitisation. This systematic review, which followed a published and Prospective Register of Systematic Reviews-registered protocol (CRD42021229962), is aimed at establishing the scope of central sensitisation in patients with BPS to aid optimal management and treatment. METHODS: Four databases were searched, and appraisal of the identified studies was conducted by two independent reviewers based on eligibility criteria: patients with BPS being investigated for central sensitisation with or without comparison of controls, English-language articles, full text and publication in a peer-reviewed journal. The Methodological Index for non-Randomised Studies was used to determine study quality. We identified 763 papers in total, with 15 studies included in the final analysis. All studies were observational and had a low risk of bias. Measures included in the evaluation of CS were questionnaires, urodynamics, and quantitative sensory testing methods. RESULTS: There was evidence of central sensitisation in patients with BPS in all papers evaluated (15 out of 15). In addition, more significant central sensitisation correlated with severe disease presentation (3 out of 3 papers) and concomitant chronic pain conditions (5 out of 5 papers). CONCLUSIONS: Central sensitisation plays an integral role in BPS patient pathology. Many secondary measures are used to evaluate this condition. Stratification of patients based on their pathology (peripheral, central or a combination of the two) will aid in implementing an individualised management strategy.

Profiling migraine patients according to clinical and psychophysical characteristics: clinical validity of distinct migraine clusters.

AIMS: Investigate if different clinical and psychophysical bedside tools can differentiate between district migraine phenotypes in ictal/perictal (cohort 1) and interictal (cohort 2) phases. METHOD: This observational study included two independent samples in which patients were subgrouped into distinct clusters using standardized bedside assessment tools (headache frequency, disability, cervical active range of motion, pressure pain threshold in different areas): (A) cohort 1-ictal/perictal migraine patients were subgrouped, based on previous studies, into two clusters, i.e., Cluster-1.1 No Psychophysical Impairments (NPI) and Cluster-1.2 Increased Pain Sensitivity and Cervical Musculoskeletal Dysfunction (IPS-CMD); (B) cohort 2-interictal migraine patients were subgrouped into three clusters, i.e., Cluster-2.1 NPI, Cluster-2.2 IPS, and Cluster-2.3 IPS-CMD. Clinical characteristics (multiple questionnaires), somatosensory function (comprehensive quantitative sensory testing (QST)), and cervical musculoskeletal impairments (cervical musculoskeletal assessment) were assessed and compared across headache clusters and a group of 56 healthy controls matched for sex and age. RESULTS: Cohort 1: A total of 156 subjects were included. Cluster-1.2 (IPS-CMD) had higher headache intensity (p = 0.048), worse headache-related (p = 0.003) and neck-related disability (p = 0.005), worse quality of life (p = 0.003), and higher symptoms related to sensitization (p = 0.001) and psychological burden (p = 0.005) vs. Cluster-1.1(NPI). Furthermore, Cluster-1.2 (IPS-CMD) had (1) reduced cervical active and passive range of motion (p < 0.023), reduced functionality of deep cervical flexors (p < 0.001), and reduced values in all QST(p < 0.001) vs. controls, and (2) reduced active mobility in flexion, left/right lateral flexion (p < 0.045), and reduced values in QST (p < 0.001) vs. Cluster-1.1 (NPI). Cohort 2: A total of 154 subjects were included. Cluster-2.3 (IPS-CMD) had (1) longer disease duration (p = 0.006), higher headache frequency (p = 0.006), disability (p < 0.001), and psychological burden (p = 0.027) vs. Cluster-2.2 (IPS) and (2) higher headache-related disability (p = 0.010), neck-related disability (p = 0.009), and higher symptoms of sensitization (p = 0.018) vs. Cluster-2.1 (NPI). Cluster-2.3(IPS-CMD) had reduced cervical active and passive range of motion (p < 0.034), and reduced functionality of deep cervical flexors (p < 0.001), vs. controls, Custer-2.1 (NPI), and Cluster-2.2 (IPS). Cluster-2.2 (IPS) and 2.3 (IPS-CMD) had reduced QST values vs. controls (p < 0.001) and Cluster-2.1 (p < 0.039). CONCLUSION: A battery of patient-related outcome measures (PROMs) and quantitative bedside tools can separate migraine clusters with different clinical characteristics, somatosensory functions, and cervical musculoskeletal impairments. This confirms the existence of distinct migraine phenotypes and emphasizes the importance of migraine phases of which the characteristics are assessed. This may have implications for responders and non-responders to anti-migraine medications.

Serum neurofilament light chain levels correlate with small fiber related parameters in patients with hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN).

BACKGROUND: Recent evidence suggests that both serum neurofilament light chain (sNfL) levels and small fiber related diagnostic variables may be valuable disease biomarkers of hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN). Our study aimed to explore the relations between sNfL and small fiber related skin biopsy and quantitative sensory testing (QST) parameters in a cohort of ATTRv-PN patients and pre-symptomatic carriers. METHODS: We retrospectively analyzed data from 13 ATTRv patients and 21 pre-symptomatic carriers who underwent sNfL dosage, skin biopsy, and QST, and analyzed correlations between sNFL, intraepidermal nerve fiber density (IENFD), and cold (CDT) and warm detection thresholds (WDT). RESULTS: Both sNfL and small fiber related parameters significantly differed between carriers and patients (sNfL: p < 0.0001; IENFD: p = 0.0008; CDT, WDT: < 0.0001). sNFL levels were normal in all carriers, altered in 85% of patients, negatively correlated with distal IENFD (r = -0.47, p = 0.005), and significantly correlated with CDT (r = -0.68; p < 0.0001) and WDT (r = 0.57; p < 0.0001). CONCLUSIONS: Our study showed that sNfL reliably discriminates symptomatic ATTRv-PN patients from pre-symptomatic carriers, and found significant relations between sNfL, skin biopsy, and QST small fiber related parameters, suggesting that sNfL might be a valuable biomarker of peripheral nerve involvement in ATTRv-PN and a supportive criterion for symptomatic disease transition.

Altered central pain processing in patients with degenerative lumbar diseases and its association with low physical activity levels after lumbar spinal surgeries: a retrospective cohort analysis.

PURPOSE: To investigate the occurrence of altered central pain modulation in patients with degenerative lumbar diseases (DLDs) and to analyze its association with physical activity (PA) 3 years after lumbar decompression and fusion. METHODS: Preoperative assessments of pressure pain thresholds (PPTs), temporal summation (TS), conditioned pain modulation (CPM) and pain were, respectively, recorded in 304 patients. These patients further underwent International Physical Activity Questionnaire (IPAQ) and both pain-related and psychological assessments 3 years post-operation. RESULTS: Preoperatively, the patients had lower PPTs in both local pain and pain-free areas and lower CPM and higher TS in pain-free areas than healthy subjects (P < 0.05). Postoperatively, 53.9% (164/304) patients showed PA below healthy-related thresholds (< 600 MET min/w). Low PA group showed a greater postoperative weight gain and bone loss and a higher postoperative prevalence of both moderate anxiety and marginal depression than high PA group (P < 0.05). All covariates with differences between the high and low PA groups were subjected to multivariate logistic regression, and long preoperative disease duration, low preoperative PPT in pain-free area, high preoperative TS, revision surgery, severe postoperative low back pain and significant postoperative pain catastrophizing thought were independently associated with low postoperative PA (P < 0.05). CONCLUSIONS: This study supports the existence of central sensitization (CS) caused by abnormal central pain modulation in DLDs. Pre-existing CS in these patients may be associated with low PA after lumbar surgeries, and this low-activity lifestyle may predispose patients to multiple adverse health outcomes. Preoperative dynamic quantitative sensory testing may provide information for the identification of at-risk patients.

Mechanisms of neurodynamic treatments (MONET): a protocol for a mechanistic, randomised, single-blind controlled trial in patients with carpal tunnel syndrome.

BACKGROUND: Physiotherapeutic management is the first-line intervention for patients with entrapment neuropathies such as carpal tunnel syndrome (CTS). As part of physiotherapy, neurodynamic interventions are often used to treat people with peripheral nerve involvement, but their mechanisms of action are yet to be fully understood. The MONET (mechanisms of neurodynamic treatment) study aims to investigate the mechanisms of action of neurodynamic exercise intervention on nerve structure, and function. METHODS: This mechanistic, randomised, single-blind, controlled trial will include 78 people with electrodiagnostically confirmed mild or moderate CTS and 30 healthy participants (N = 108). Patients will be randomly assigned into (1) a 6-week progressive home-based neurodynamic exercise intervention (n = 26), (2) a steroid injection (= 26), or (3) advice (n = 26) group. The primary outcome measure is fractional anisotropy of the median nerve at the wrist using advanced magnetic resonance neuroimaging. Secondary outcome measures include neuroimaging markers at the wrist, quantitative sensory testing, electrodiagnostics, and patient reported outcome measures. Exploratory outcomes include neuroimaging markers at the cervical spine, inflammatory and axonal integrity markers in serial blood samples and biopsies of median nerve innervated skin. We will evaluate outcome measures at baseline and at the end of the 6-week intervention period. We will repeat questionnaires at 6-months. Two-way repeated measures ANCOVAs, followed by posthoc testing will be performed to identify differences in outcome measures among groups and over time. DISCUSSION: This study will advance our understanding of the mechanisms of action underpinning neurodynamic exercises, which will ultimately help clinicians to better target these treatments to those patients who may benefit from them. The inclusion of a positive control group (steroid injection) and a negative control group (advice) will strengthen the interpretation of our results. TRIAL REGISTRATION: NCT05859412, 20/4/2023.

The effectiveness of a combined exercise and psychological treatment programme on measures of nervous system sensitisation in adults with chronic musculoskeletal pain - a systematic review and meta-analysis.

BACKGROUND: Quantitative sensory testing (QST) offers information regarding underlying mechanisms contributing to chronic pain (CP) in adults with musculoskeletal disorders. This review examined the use of QST measures in adults with CP following participation in a combined exercise and psychological intervention. METHODS: The review was conducted in accordance with the PRISMA guidelines. Five databases were searched from inception to November 2022. All study designs which evaluated the effects of a combined exercise and psychological treatment on measures of nervous system sensitivity in adults with chronic musculoskeletal pain were included. RESULTS: A total of 13 studies met the selection criteria, 10 of which were included in a meta-analysis. Local pressure pain thresholds were the most frequently used measure (n = 12 studies). Meta-analysis revealed statistically significantly improvements in favour of the combined exercise and psychological intervention group, compared to a control group, for local pressure pain threshold measures [SMD = 0.44, 95% CI 0.08-0.81, I2 = 84%], pain intensity scores [SMD=-0.89, 95% CI -1.66- -0.13, I2 = 94%] and the Central Sensitisation Inventory [SMD=-0.69, 95% CI -1.37- -0.02, I2 = 87%]. There were no significant differences found between groups for remote pressure pain thresholds, temporal summation or conditioned pain modulation. CONCLUSIONS: The results suggest that a combined exercise and psychological intervention may lead to greater improvements in local pressure pain threshold, pain intensity and Central Sensitisation Inventory scores when compared to a control intervention in adults with CP, however these findings must be interpreted with caution as a large degree of heterogeneity was present in these results (I2: 84-94%). Further large, longitudinal studies are required using standardised QST measurement procedures and patient reported outcome measures to explore changes in nervous system sensitisation. TRIAL REGISTRATION: This systematic review is registered with PROSPERO, ID Number CRD42022380464.

Effects of Nature-Based Multisensory Stimulation on Pain Mechanisms in Women with Fibromyalgia Syndrome: A Randomized Double-Blind Placebo-Controlled Trial.

BACKGROUND: The term "nature-based sensory stimuli" refers to the sensory information produced by biotic and abiotic agents from natural environments. The literature has reported the beneficial effects of these agents on various pain dimensions in non-clinical populations. AIMS: To evaluate the potential analgesic effects of nature-based multisensory stimulation in women with fibromyalgia syndrome. METHODS: A randomized, double-blind, placebo-controlled, parallel-group trial with a 1:1 allocation ratio was conducted. Forty-two women with fibromyalgia syndrome interacted with either different plant species with flowers, stones, and soil organic matter or their synthetic imitations for 30 minutes. Outcome measurements were performed before and after the intervention, including clinical pain intensity using the Numeric Rating Scale, cold pain thresholds using the Cold Pressor Test, mechanical hyperalgesia and wind-up using a monofilament, and pressure pain thresholds using a pressure algometer. RESULTS: Analyses revealed group × time interactions for clinical pain intensity (F = 7.915, p = .008), cold-water immersion time (F = 7.271, p = .010), mechanical hyperalgesia (F = 4.701, p = .036), and pressure pain threshold (p ≤ .017). Between-group differences were found in clinical pain intensity (p = .012), cold pain thresholds (p = .002), and pressure pain thresholds (p < .05). The experimental group exhibited reduced clinical pain intensity (p = .001) and increased pressure pain thresholds (p ≤ .034). CONCLUSIONS: Women with fibromyalgia syndrome may benefit from multisensory stimulation using biotic and abiotic agents from natural environments for 30 minutes. Interacting with flowering plants and soil components appears to induce analgesic effects.

Psychophysical and Functional Outcomes in Chemotherapy-induced Peripheral Neuropathy After Spinal Cord Stimulation: A Narrative Review and Case Series.

OBJECTIVES: Chemotherapy-induced peripheral neuropathy (CIPN) is a complication that may occur after treatment with various anticancer drugs. In refractory CIPN cases, spinal cord stimulation (SCS) has garnered increased attention. The use of gait analysis and psychophysical quantitative sensory testing (QST) as an objective measurement of CIPN-related damage has burgeoned; however, these changes have not been reported for patients with CIPN after SCS implantation using either burst or tonic stimulation. MATERIALS AND METHODS: This manuscript encompasses two parts: 1) a presentation of pain improvement in a series of patients who underwent tonic vs burst SCS for CIPN measured by gait and QST analysis and 2) a narrative review on gait and psychophysical QST outcomes between burst and tonic SCS stimulation pertaining to pain and the extrapolation to CIPN-related sequalae. RESULTS: In these cases, gait scores improved in both patients. Touch thresholds were higher before SCS whereas skin temperatures were lower at the dorsal foot, subtalus, and posterior calf. Sharpness detection was drastically improved after SCS. In the review, the patients aligned with pain relief, suggesting good response to interventional outcomes with SCS. QST outcomes, particularly touch, sharpness, heat, and cold stimuli, however, were not fully corroborated. Similarly to other non-CIPN SCS gait studies, both tonic and burst studies provided positive outcomes on spatiotemporal gait parameters, gait form, and standardized gait scales. CONCLUSION: We emphasize the use of different SCS waveforms as a therapy for CIPN management and the use of psychophysical testing as a measure for diagnosis and monitoring CIPN's progress in our case series and review.

Quantitative Sensory Testing in Spinal Cord Stimulation: A Narrative Review.

OBJECTIVES: Quantitative sensory testing (QST) has been used for decades to study sensory abnormalities in multiple conditions in which the somatosensory system is compromised, including pain. It is commonly used in pharmacologic studies on chronic pain but less so in conjunction with neuromodulation. This review aims to assess the utility of QST in spinal cord stimulation (SCS) protocols. MATERIALS AND METHODS: For this narrative review, we searched PubMed for records of studies in which sensory testing has been performed as part of a clinical study on SCS from 1975 onward until October 2023. We focused on studies in which QST has been used to explore the effect of SCS on neuropathic, neuropathic-like, or mixed pain. RESULTS: Our search identified 22 useful studies, all small and exploratory, using heterogeneous methods. Four studies used the full battery of validated German Research Network on Neuropathic Pain QST. There is emerging evidence that assessment dynamic mechanical allodynia (eight studies), and mechanical/thermal temporal summation of pain (eight studies) may have a role in quantifying the response to various SCS waveforms. There also were sporadic reports of improvement of sensory deficits in a proportion of patients with neuropathic pain that warrant further study. CONCLUSIONS: We recommend the adoption of QST into future clinical research protocols, using either the full QST protocol or a less time-demanding short-form QST.

Visual psychosocial profiling of Chinese temporomandibular disorder pain patients and correlations with somatosensory function.

BACKGROUND: Psychosocial function of Chinese temporomandibular disorders (TMD) pain patients and the correlation with somatosensory function has not been sufficiently studied. OBJECTIVE: The study aims at assessing the psychosocial function of Chinese TMD pain patients by visualisation method and evaluating the correlations with somatosensory function quantitatively. METHODS: The Symptom Checklist 90 (SCL-90) questionnaire and standardised quantitative sensory testing (QST) were administered to 70 Chinese TMD pain patients and age- and gender-matched healthy controls (HCs). Of these, 40 TMD arthralgia patients received QST before and after medication. Psychosocial and somatosensory parameters were transformed into standardised scores. Differences within groups were assessed through t tests. Correlations between psychosocial and somatosensory profiles were explored through correlation analyses with Bonferroni correction for multiple comparisons. RESULTS: 100% of the Chinese TMD pain patients exhibited psychosocial distress in contrast to HCs. Anger and hostility showed negative correlation with the thermal nonnociceptive parameter (thermal sensory limen, p =.002) and nociceptive parameters (cold pain threshold and pain pressure threshold, p<.001). Correlation analysis indicated that cold detection threshold was negatively correlated with somatization and mechanical pain sensitivity had a negative correlation with anger and hostility through medical treatment (p <.001). CONCLUSIONS: Visual psychosocial profiles provided an easy overview of psychosocial function in Chinese TMD pain patients. Anger and hostility was associated with increased thermal nonnociceptive and nociceptive sensitivity to stimuli. Psychosocial distress might be negatively associated with TMD treatment response which indicated a possible need for psychological intervention during treatment.

[Neuropathic pain as a symptom in autonomic neuropathies and other rare diseases : Small fiber neuropathy: its recognition, diagnosis, and treatment]. / Neuropathische Schmerzen als Symptom bei autonomen Neuropathien und anderen seltenen Erkrankungen : Kleinfaserneuropathie erkennen, diagnostizieren und behandeln.

BACKGROUND: Neuropathic pain is difficult to diagnose and treat. Small fiber neuropathy (SFN) flies under the radar of nerve conduction studies. OBJECTIVES: The importance of a structured patient history and physical examination in the context of neuropathic pain is emphasized. Describing SFN as an important cause, the authors consider rare but partially treatable differential diagnoses. They conclude that autonomic symptoms are frequently associated, often presenting with diverse symptoms. METHODS: A selective literature research to present SFN symptoms as well as differential diagnostic and therapeutic steps in the context of SFN and rare diseases focusing on the autonomic nervous system. RESULTS: Neuropathic pain significantly reduces quality of life. To shorten the time until diagnosis and to initiate therapy, the authors recommend a structured patient history including sensory plus and minus symptoms and non-specific autonomic signs. If the initial search for the cause is not successful, rare causes such as treatable transthyretin (ATTR) amyloidosis and Fabry's disease or autoimmune causes should be considered, particularly in the case of progressive and/or autonomic symptoms. CONCLUSION: The diagnosis and therapy of rare SFN requires interdisciplinary collaboration and, in many cases, a referral to specialized centers to achieve the best patient care.