Cold Pain Thresholds Research Articles

New diagnostic measures of oxaliplatin-induced peripheral sensory neuropathy

ObjectiveOxaliplatin-induced peripheral neuropathy (OIPN) is an unwanted side effect of oxaliplatin chemotherapy treatment. OIPN manifests in an acute phase that lasts a few days after injection and a persistent phase that may become chronic. Currently, there is no consensus about a clinically applicable, quantitative, and objective measure of OIPN. MethodsSeventeen patients treated with oxaliplatin containing adjuvant chemotherapy for stage III colon cancer, but otherwise healthy, were tested with six quantitative sensory tests (QST) and five large fibre perception threshold tracking (PTT) measures (quantified by, e.g., rheobase and electrotonus threshold) one hour before each of the 12 chemotherapy cycles given at two weeks’ intervals. These measures were repeated at 3, 6, and 12-month follow-ups. The temporal development of OIPN assessed by the Common Terminology Criteria for Adverse Events (CTCAE) scale, QST, and PTT measures was calculated by linear regression. ResultsThe CTCAE score showed a tri-phasic increase during the treatment and remained increased during the follow-up. The vibration threshold (R = 0.25, p<0.001), the cold pain threshold (R = 0.17, p = 0.02), and the rheobase (R = 0.28, p < 0.001) increased during treatment, whereas the cold detection threshold (R=-0.16, p = 0.002) decreased. The cold pain threshold and the rheobase remained increased, and the cold detection and heat pain threshold remained decreased during follow-up. ConclusionsIncreased cold pain sensitivity and decreased large fibre sensitivity (increased rheobase) correlate to the persistent OIPN, whereas the CTCAE score assesses both acute and persistent OIPN. Furthermore, the novel PTT method assessed the nerve excitability changes caused by the oxaliplatin.

Correlation between the perceived pain intensity and psychophysical tests in patients with chronic pain

Introduction. Pain perception varies due to many factors. Quantitative sensory testing is a panel of diagnostic tests used to assess somatosensory function. The aim of the study was to determine how psychophysical variables are related to the perceived pain intensity in patients with chronic pain. Material and Methods. The cross-sectional study included 88 subjects (average age 51.3 ? 9.4 years, 76 (86.4%) women) diagnosed with chronic pain syndrome and fibromyalgia or chronic neuropathic pain associated with lumbosacral radiculopathy. Current and average pain intensities in the past 4 weeks were rated on a numerical rating scale. Quantitative sensory testing included pressure pain thresholds, heat pain thresholds, and cold pain thresholds. Patients filled out the Fear Avoidance Component Scale, a questionnaire that examines the fear avoidance phenomenon. Results. The highest correlations were found between the Fear Avoidance Component Scale scores and current and average pain intensity (r = 0.438 and r = 0.253, respectively); between pain duration and current and average pain intensity in the past 4 weeks (r = 0.340 and r = 0.308, respectively). Moderate and negative correlations were found between pressure pain thresholds and current and average pain intensity (r = - 0.233 and r = -0.300, respectively). Conclusion. Low to moderate, significant positive correlations were found between fear-avoidance and pain intensity. Significant but low negative correlations were found between pressure pain threshold and current pain intensity, as well as between pressure pain threshold and average pain intensity.

Pain mechanisms in carpal tunnel syndrome: a systematic review and meta-analysis of quantitative sensory testing outcomes.

Carpal tunnel syndrome (CTS) is the most common nerve compression in the arm. A mix of peripheral and central contributions on quantitative sensory testing (QST) has been reported in the literature. Thus, this systematic review or meta-analysis aimed to identify the dominant sensory phenotype and draw conclusive evidence about the presence of central sensitization (CS) in CTS. Based on an a priori published protocol and using PRISMA guidelines, 7 databases were searched (Embase, Web of Science, Scopus, PubMed, SAGE, EBSCOhost, and ProQuest). Eligible studies compared the QST findings of individuals with subacute and chronic CTS with those of healthy controls through thermal, mechanical, and vibration detection thresholds; thermal, pressure, and mechanical pain thresholds; mechanical pain sensitivity; presence of allodynia; wind-up ratio; and conditioned pain modulation. Thirty-seven studies were included in the qualitative analysis. Results showed a significant loss of all detection thresholds of hand median nerve territories and hand extramedian areas (little finger and hand dorsum) in CTS ( P < 0.05) but no significant difference ( P > 0.05) in wind-up ratio, cold, heat, or mechanical pain thresholds of the median nerve territories. Furthermore, there was a significant increase in mechanical pain sensitivity in median nerve territories and remotely in the forearm ( P < 0.05) and a significant gain in pressure and heat pain thresholds in the carpal area ( P < 0.05). Conditioned pain modulation was impaired in CTS. Hypoesthesia and increased thermal and mechanical pain ratings are the dominant sensory phenotype with inconclusive evidence about CS in CTS due to the heterogenous results of thermal and mechanical pain thresholds.

Relationship between pressure and thermal pain threshold, pain intensity, catastrophizing, disability, and skin temperature over myofascial trigger point in individuals with neck pain

The objective of the study was to correlate the thermal pain threshold (heat and cold) on myofascial trigger points with measurements of pain and skin temperature in patients with chronic neck pain. This is a cross-sectional study. We included participants of both genders, aged between 18-45 years, with chronic neck pain (>90 days), and with active bilateral myofascial trigger point centrally located in the upper trapezius muscle. Neck Disability Index, Numerical Rating Scale, Pain-Related Catastrophizing Thoughts Scale, algometry, infrared thermography, and quantitative sensory testing were used for the evaluation. A significant, weak, and negative association was observed between pain intensity and heat pain threshold on the myofascial trigger point to the right (rho -0.381, p=0.022) and to the left (rho -0.334, p=0.049), and a significant, weak, and positive association was observed between pain intensity and cold pain threshold on the myofascial trigger point to the right (rho 0.471, p=0.004) and to the left (rho 0.339, p=0.043). Thermal pain threshold (heat and cold) on myofascial trigger points is associated with pain intensity in individuals with chronic neck pain.

Pain sensitivity in men who have never experienced a headache: an observer blinded case control study

BackgroundHeadache affects 90–99% of the population. Based on the question “Do you think that you never ever in your whole life have had a headache?” 4% of the population say that they have never experienced a headache. The rarity of never having had a headache suggests that distinct biological and environmental factors may be at play. We hypothesized that people who have never experienced a headache had a lower general pain sensitivity than controls.MethodsWe included 99 male participants, 47 headache free participants and 52 controls, in an observer blinded nested case-control study. We investigated cold pain threshold and heat pain threshold using a standardized quantitative sensory testing protocol, pericranial tenderness with total tenderness score and pain tolerance with the cold pressor test. Differences between the two groups were assessed with the unpaired Student’s t-test or Mann-Whitney U test as appropriate.ResultsThere was no difference in age, weight or mean arterial pressure between headache free participants and controls. We found no difference in pain detection threshold, pericranial tenderness or pain tolerance between headache free participants and controls.ConclusionOur study clearly shows that freedom from headache is not caused by a lower general pain sensitivity. The results support the hypothesis that headache is caused by specific mechanisms, which are present in the primary headache disorders, rather than by a decreased general sensitivity to painful stimuli.Trial registrationRegistered at ClinicalTrials.gov (NCT04217616), 3rd January 2020, retrospectively registered.

Heritability of musculoskeletal pain and pain sensitivity phenotypes: 2 generations of the Raine Study.

There is a need to better understand biological factors that increase the risk of persistent musculoskeletal (MSK) pain and heightened pain sensitivity. Knowing the heritability (how genes account for differences in people's traits) can enhance the understanding of genetic vs environmental influences of pain and pain sensitivity. However, there are gaps in current knowledge, including the need for intergenerational studies to broaden our understanding of the genetic basis of pain. Data from Gen1 and Gen2 of the Raine Study were used to investigate the heritability of MSK pain and pressure and cold pain sensitivity. Participants included parents (Gen1, n = 1092) and their offspring (Gen2, n = 688) who underwent a battery of testing and questionnaires including pressure and cold pain threshold testing and assessments of physical activity, sleep, MSK pain, mental health, and adiposity. Heritability estimates were derived using the Sequential Oligogenic Linkage Analysis Routines software. Heritability estimates for MSK pain and pressure pain sensitivity were significant, accounting for between 0.190 and 0.289 of the variation in the phenotype. By contrast, heritability of cold pain sensitivity was not significant. This is the largest intergenerational study to date to comprehensively investigate the heritability of both MSK pain and pain sensitivity, using robust statistical analysis. This study provides support for the heritability of MSK pain and pain sensitivity to pressure, suggesting the need for further convergence of genetic and environmental factors in models for the development or maintenance of these pain disorders.

The effect of high-definition transcranial direct current stimulation on pain processing in a healthy population: A single-blinded crossover controlled study

Transcranial direct current stimulation (tDCS) is increasingly used in pain treatment. tDCS targeting both primary motor cortex (M1) and dorsolateral prefrontal cortex (DLPFC) may modulate the descending pain inhibitory system, however, it remains controversial regarding the optimal stimulation region for pain modulation. Therefore, this study aimed to explore the effects of high-definition anodic stimulation of M1 and DLPFC on conditioned pain modulation (CPM) and pain thresholds and establish a preferred stimulation setting. Twenty-six healthy adults were randomly assigned to M1-tDCS, DLPFC-tDCS, or sham-tDCS groups. During the three sessions, each participant received an active or sham stimulation of 2 mA for 20 min, with at least 3 days’ interval between sessions. Quantitative sensory tests were performed to obtain pressure pain threshold (PPT), cold pain threshold (CPT), and CPM before and after the tDCS intervention. Only M1-tDCS significantly increased CPM in healthy individuals compared with sham control (P = 0.004). No statistically significant difference was found in PPT and CPT between tDCS vs. sham control (P > 0.05). Our findings further support the important role of M1 as a target in pain regulation. Further large-scale, multicenter studies in chronic pain populations are needed to validate the alterations of distinct target brain regions related to pain and thus for an optimal target stimulation strategy in pain management.

Evaluation of Cold Sensitivity in Patients With Upper Extremity Nerve Compression Syndromes: A Scoping Review

The aim of this study was to review the literature to determine the prevalence of cold sensitivity in upper extremity nerve compression syndromes and the impact of treating nerve compression syndromes on cold sensitivity. Following a standardized scoping review protocol, this study included interventional and observational study designs assessing patients with cold sensitivity and upper extremity nerve compression syndromes. Review articles, case reports, and small case series (n < 5) were excluded. The abstracts and eligible full texts were screened by 2 independent reviewers. Data were extracted and reported according to PRISMA extension for scoping reviews statement. Three databases were searched (Ovid MEDLINE, Ovid EMBASE, and CINAHL on EBSCO); 274 references were reviewed. Fifteen studies from the database search and 8 studies from the reference search were eligible for this review (n= 23). Two interventional and 21 observational studies were identified. The most common method for assessing cold sensitivity was cold pain threshold testing (n= 12), followed by subjective patient reporting (n= 4). The Cold Intolerance Symptom Severity questionnaire was the most common validated patient-reported outcome questionnaire used in the studies (n= 3). Cold sensitivity was most commonly reported in carpal tunnel syndrome (96% of the studies). The prevalence of cold sensitivity in nerve compression syndromes ranged from 20% to 69%. Nerve decompression improved the severity of cold sensitivity in 5 of 6 studies where cold sensitivity was studied. There is heterogenicity in the studies assessing cold sensitivity in nerve compression syndromes. Despite moderate prevalence in patients with carpal tunnel syndrome, cold sensitivity is understudied. Within the limitations of eligible studies reviewed, surgical decompression improved the severity of cold sensitivity in some studies. Therapeutic IV.

Quantitative sensory testing in patients with the muscle pain subtype of temporomandibular disorder: a systemic review and meta-analysis.

This meta-analysis aimed to evaluate quantitative sensory testing (QST) evidence for pain processing in patients with the muscle pain subtype of temporomandibular disorders (mTMD). A comprehensive systematic electronic search strategy was performed in online literature databases. All full-text observational studies published up to July 2021 with the aim of investigating pain sensitization in humans with mTMD using QST measures were eligible for inclusion. Meta-analysis of QST data was performed using a random effects model, which included results comparing patients with mTMD to healthy controls, and standard mean difference (SMD) results were analyzed. Twelve studies with 732 participants (371 patients with mTMD and 361 healthy controls) were analyzed following screening and quality appraisal. Compared with healthy controls, patients with mTMD had significantly lower pressure pain threshold (SMD - 1.10, 95% confidence interval [CI] - 1.52 to - 0.68) with high heterogeneity (Tau2 = 0.61, I2 = 86%), and significantly lower mechanical pain threshold (SMD - 0.64, 95% CI - 0.95 to - 0.32) with no heterogeneity (Tau2 = 0.00, I2 = 0%). No difference was observed in the cold pain threshold (SMD 0.16, 95% CI - 0.13 to 0.45), heat pain threshold (SMD - 0.13, 95% CI - 0.40 to 0.15), and wind-up ratio (SMD 0.63, 95% CI - 0.11 to 1.38) between patients with mTMD and healthy controls. Other QST parameters were also discussed. The study results suggest that the pain processing of deep tissues is likely sensitized in mTMD and calls for more QST studies with standard procedures to reduce inter-study heterogeneity. The major findings of this meta-analysis support using PPT to examine the pain processing in patients with mTMD in clinical scenario.

Potential differences in somatosensory function during premenopause and early and late postmenopause in patients with burning mouth syndrome: An observational case–control study

Background/purposeBurning mouth syndrome (BMS) is a chronic condition presenting as intraoral burning or dysesthesia, with a high preponderance in menopausal women. This study aimed to examine the association between somatosensory dysfunction and BMS in premenopausal, early postmenopausal, and late postmenopausal patients, using a standardized Quantitative Sensory Testing (QST) protocol, and to determine the predictive value of thermal or mechanical perception by QST for detecting BMS. Materials and methodsAn observational case–control study was performed with 36 female participants with BMS (12 premenopausal, 10 early postmenopausal, and 14 late postmenopausal) and 42 age- and sex-matched healthy volunteers (21 premenopausal, 10 early postmenopausal, and 11 late postmenopausal). Neurophysiological tests were used to evaluate somatosensory dysfunction at the tongue. ResultsZ-score in the late postmenopausal BMS group revealed a gain of function for the cold pain threshold and heat pain threshold (Z = 2.08 and 3.38, respectively). In the multiple regression analysis with the Visual Analog Scale as the dependent variable, the vibration detection threshold predicted the severity of burning mouth sensation in the premenopausal group. ConclusionLate postmenopausal patients with BMS showed an increased response of the tongue to noxious thermal stimuli. This supports the theory that changes in sex hormones may affect trigeminal somatosensory function, particularly during the late postmenopausal stage in patients with BMS.

Pain sensitivity does not differ between obese and healthy weight individuals.

There is emerging evidence suggesting a relationship between obesity and chronic pain. The aim of this study was to determine whether pain-free obese individuals display altered pain responses to acute noxious stimuli, thus raising the possibility of greater pain sensitivity and potential susceptibility for chronic pain development. Psychophysical and anthropometric data were collected from 38 individuals with an obese body mass index (BMI) classification (BMI ≥ 30) and 41 age/sex-matched individuals of a healthy BMI (BMI < 24.9). Because BMI may be an inaccurate index of obesity, additional anthropometric parameters of central adiposity and percent body fat were examined. Pain responses to suprathreshold noxious heat and cold stimuli were examined. Subjects provided pain intensity and unpleasantness ratings to noxious heat (49°C) applied at varying durations and locations (ventral forearm/lower leg). Cold pain ratings, thresholds, and tolerances were obtained after immersion of the hand in a cold-water bath (0-2°C). Between-group differences in pain responses, as well as relationships between pain responses and obesity parameters, were examined. Importantly, confounds that may influence pain such as anxiety, depression, impulsivity, sleepiness, and quality of life were assessed. No between-group differences in pain sensitivity to noxious heat and cold stimuli were found. No relationships were found between central adiposity or body fat (percentage or distribution) and pain responses to noxious heat or cold stimuli. Obesity has minimal influence on pain sensitivity. Accordingly, it is unlikely that obesity alone increases susceptibility for chronic pain development through amplification of nociceptive processes.

Quantitative sensory testing of mandibular somatosensory function following orthognathic surgery-A pilot study in Chinese with class III malocclusion.

Somatosensory changes after sagittal split ramus osteotomy (SSRO) have not been fully studied in Chinese patients by the latest technologies. To provide a comprehensive analysis of somatosensory function at the lower lip and chin at different time points following SSRO in a Chinese population. A total of 22 patients (18-27years; nine men) with skeletal III malocclusion and scheduled for SSRO were recruited. Quantitative sensory testing (QST) was performed at pre-operation (baseline), 1week (1W), 1, 3 and 6months (1M, 3M, 6M) post-operatively. Cold detection threshold (CDT), warm detection threshold (WDT), cold pain threshold (CPT), heat pain threshold (HPT), mechanical detection threshold (MDT), mechanical pain threshold (MPT), pressure pain threshold (PPT) and two-point discrimination threshold (2PD) were tested at the lower lip and chin. Except for PPT at both test sides at 1W and 1M, all QST values indicated a significantly reduced sensitivity (p<.05). All values had returned to baseline values at 3M with exception of HPT at the right chin which, however, had recovered at 6M (p>.05). Somatosensory function at the lower lip and chin appears to be fully recovered in the majority of young Chinese adults 6months after SSRO for skeletal class III malocclusion.

Sensory recovery and oral health-related quality of life following tongue reconstruction using non-innervated radial forearm free flaps

ObjectivesThis study aimed to monitor the recovery of somatosensory function and oral health-related quality of life after tongue reconstruction using a non-innervated radial forearm free flap (RFFF). MethodsTwenty patients (9 men, age: 42–67 years) underwent tongue reconstruction with non-innervated RFFFs, and twenty age- and sex-matched controls were included in this study. Quantitative sensory testing (QST), including cold, warm, and mechanical detection thresholds (CDT, WDT, MDT); cold, heat, and mechanical pain thresholds (CPT, HPT, MPT); and static two-point, sharp/blunt, and direction discrimination (S2-PD, S/BD, DD) were determined 9 months and 18 months after surgery on the surgical (9 M, 18 M) and contralateral sides (9Mc, 18Mc). Oral Health Impact Profile-49 (OHIP-49) was used to determine the oral-related quality of life of participants. ResultsAll parameters showed significantly lower sensitivity at 9 M and 18 M (p < 0.001) compared to those for the controls and the contralateral side, except for DD (p = 0.101). In addition, the parameters showed a significant decrease in sensitivity for 9Mc and 18Mc (p ≤ 0.043) compared to those for the controls, except for MPT, HPT, S/SD, and DD (p ≥ 0.453). Findings on WDT, MPT, S2-PD, and DD (p ≤ 0.046) indicated significantly higher somatosensory function at 18 M than that at 9 M. MDT and MPT (p ≤ 0.038) showed significantly higher sensitivity at 18Mc than at 9Mc. Scores for all dimensions of OHIP-49 were significantly higher in patients (decrease in quality of life, p ≤ 0.002) than in controls, except for physical discomfort (p = 0.51). However, the scores were significantly higher at 18 M than at 9 M (p ≤ 0.011), except for handicap (p = 0.36). Postoperative chemotherapy was significantly correlated with impaired thermal sensitivity of the flaps (WDT, p = 0.049). ConclusionThe present findings showed significant impairment in somatosensory function on both the surgical and contralateral sides of patients with RFFFs. However, a significant increase in somatosensory function was observed on both sides over time. Somatosensory disturbances observed after surgery were associated with poor oral health-related quality of life.

Cold and Mechanical Hypersensitivity Is Exacerbated during Acute Pain in Children and Adolescents with Sickle Cell Disease

▪Background: Sickle cell disease (SCD) pain is associated with colder temperatures, touch and increased wind speed suggesting thermal and mechanical pain nociceptors may be activated during and/or precipitate acute SCD pain. Patients with SCD and SCD mice display features of nervous system sensitization during baseline health as evidenced by hypersensitivity to thermal and mechanical pain. In SCD mice, this pain hypersensitivity is exacerbated with hypoxia-reoxygenation that mimics acute vaso-occlusive crises. However, it is unknown if exacerbations of thermal and mechanical pain hypersensitivity occur during acute pain in SCD patients. Thus, we sought to quantify thermal and mechanical pain sensitivity differences between SCD patients in baseline health and during pain. We hypothesized SCD patients will experience increased hypersensitivity to thermal and mechanical pain during acute pain as compared to baseline health.Methods: We conducted a prospective cohort study of SCD patients ≥ 7 yrs assessed in baseline health and during hospitalization for pain to detect patients' sensitivity to thermal and mechanical stimuli as measured by quantitative sensory testing (QST). We excluded patients with pain phenotype other than SCD, known overt/silent stroke or those chronically transfused. Patients underwent QST to thermal (cold/heat) and mechanical stimuli during baseline health and within 48 hrs of hospitalization for pain. QST detects sensory loss (hyposensitivity) or gain (hypersensitivity). Thermal testing was done with a Thermal Sensory Analyzer (Medoc;Israel), a computer-assisted device that delivers cold/warm stimuli via a skin thermode (starting temperature, 32ºC; range, 0-50ºC). Mechanical testing was done using graded vonFrey filaments (force range 0.026-110 g). Testing sites were the thenar eminence of non-dominant hand (glabrous skin) and lateral dorsum of foot (hairy skin). Primary outcomes were: 1) Cold Pain Threshold (ºC), 2) Heat Pain Threshold (ºC) and 3) Mechanical Pain Threshold (g) assessed by “method of limits” where patients pushed a button (thermal) or spoke (mechanical) when the progressive stimulus was painful. The final outcome was the median of 3 (thermal) and 5 (mechanical) tests. Patient-report of pain precipitators related to temperature was collected. Descriptive statistics were performed and comparison of medians between baseline and pain was done with Wilcoxon-signed rank due to non-normally distributed data. Linear effect model with repeated measure analysis was done to adjust for age, gender and hydroxyurea use. Statistical significance was set at p<0.05.Results: We enrolled 24 SCD patients that were tested both in baseline health and when hospitalized for pain. The median age of baseline testing was 10.5 (IQR 9-14.8) yrs, 66.7% were female and 91.7% were on hydroxyurea. Median time between baseline and pain testing was 15.8 (IQR 5.1-22.1) mos. Genotypes were 62.5% HbSS, 29.2% HbSC, 4.2% HbSβ+thal, and 4.2% HbSOArab. SCD patients had significantly increased cold pain sensitivity in the hand during pain as compared to baseline health and also had significantly increased mechanical pain sensitivity in the foot during pain as compared to baseline health (Table 1). There were no differences in heat pain sensitivity during pain (Table 1). Significant changes in cold (1.6 ºC, p=0.03) and mechanical (-6.6g, p=0.002) pain sensitivity persisted after adjusting for age, gender and hydroxyurea use. Significantly more patients reported temperature change from warm to cold exacerbates their pain as compared to change from cold to warm (63.2% vs. 26.3%, p=0.03; McNemar Test).Conclusions: SCD patients experience exacerbations of cold and mechanical pain sensitivity during hospitalization for pain, however, no changes in heat pain sensitivity. This differential pattern is consistent with patient reports of cold temperatures exacerbating pain, hypersensitivity to touch during pain events and heat providing pain relief. The exacerbation of mechanical and cold pain emulate findings in the SCD mouse model and suggest cold and mechanical pain nociceptors may contribute to SCD pain biology. Modulation of these pathways could be novel therapeutic targets to treat and/or prevent SCD pain. Investigation into why these pain nociceptors are activated in SCD patients could lead to increased understanding of SCD pain biology and additional therapeutic targets. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Quantitative Sensory Testing in Children with Sickle Cell Disease

▪Background: Quantitative Sensory Testing (QST) is used in a variety of pain disorders such as arthritis and neuropathic pain syndromes, to characterize pain and predict prognosis and response to specific therapies. QST evaluates sensory function using a set of psychophysical procedures to measure subjective somatosensory responses to various physical stimuli. In Sickle Cell Disease (SCD) the painful vasoocclusive crisis is the most difficult management challenge and factors underlying the transition from acute to chronic pain and the wide interpatient variability in the pain experience are poorly understood. Optimal management for this complex pain syndrome remains unclear despite over three decades of basic and clinical research in the field.In this study, we aimed to duplicate results in the literature documenting altered QST thresholds in SCD and test the reproducibility of results over time to validate QST as a therapeutic endpoint for use in clinical trials evaluating novel preventative pain therapies.Objectives: Primary objectives were to test thermal thresholds in children with SCD versus African American controls and determine consistency over 6 months. Exploratory objectives were to correlate QST with clinical factors and select biomarkers and assess pressure pain thresholds (PPTs).Methods: Fifty-seven SCD and 60 control subjects aged 8-20 years underwent heat (wdt) and cold (cdt) detection and pain (hpt and cpt) threshold testing using a Medoc TSAII. A thermal composite score (TCS) was constructed by averaging the wdt, cdt, hpt, and cpt threshold responses from the testing instrument's starting temperature of 32°C. All participants were tested at baseline and 3 months; SCD subjects were additionally tested at 6 months and blood collected for future biomarker assessment. PPTs were performed using an SBMedic algometer. A single individual performed all QST. Descriptive statistics were computed and covariate-adjusted differences in thresholds within and between groups evaluated over time by mixed effects regression models with random intercepts and linear contrast tests. The intraclass correlation coefficient (ICC) from these models was used to assess within-subject consistency and Spearman's correlation was used to evaluate associations between thresholds and biomarkers. In addition, as a nested pseudo-intervention study, we analyzed a subset of “new” hydroxyurea (HU) users consisting of SCD subjects in whom HU was initiated within a few weeks prior to, or shortly after baseline testing. Significance was set at 0.05.Results: There were no significant differences in mean thermal or PPTs between SCD and control participants at baseline (Table 1) or month 3. QST measurements were consistent in SCD and control subjects for cpt, wdt, hpt and TCS (each ICC>0.55), but not necessarily for cdt (ICC = 0.37). Although generally internally consistent, there was some variability in mean thermal thresholds among SCD subjects over time, but the only significant difference between the 3 and 6 month means was for hpt (+0.67°C; 95% CI 1.15, 0.19). There was no association between mean thermal thresholds and chronic transfusion therapy. The group in whom HU was initiated shortly after baseline testing (n=6) demonstrated significant reductions in all thermal sensitivity and pain threshold measurements following HU initiation (Table 2).Conclusions: In contrast to Brandow's study (Brandow, American Journal Hematology, 2012), which documented thermal hypersensitivity in SCD, we have not demonstrated significant differences in thermal thresholds between SCD and control subjects. This could be due, in part, to differences in body sites used for testing. Results between second and third test sessions were highly consistent, indicating that reliability may improve once subjects have experience with QST. Subjects on whom HU was initiated shortly after baseline testing (new HU users) exhibited progressive and significant decreases in both cold and heat sensitivity from baseline to 6 months, suggesting that thermal testing is sensitive to effective therapy to prevent vasoocclusive pain. These findings are of critical importance to inform the planning of future SCD related clinical trials using QST as an endpoint in the evaluation of preventative pain therapies.Supported by National Institute of General Medical Sciences National Institutes of Health Award P20GM109021 and U54GM104941 [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Quantitative sensory testing can effectively predict cardiovascular autonomic neuropathy in patients with type 2 diabetes mellitus.

Cardiovascular autonomic neuropathy (CAN) is one of the most serious types of diabetic autonomic neuropathy and is a class of small fibre neuropathy. Among many inspection methods, quantitative sensory testing is an effective and convenient method for diagnosing diabetic small fibre neuropathy. This cross-sectional study aimed to identify the correlation between the development of cardiovascular autonomic neuropathy and quantitative sensory testing parameters in patients with type 2 diabetes mellitus. A total of 266 participants with type 2 diabetes mellitus from Nanjing Drum Tower Hospital were enrolled in this study, and each of them received cardiovascular reflex tests (CARTs) and quantitative sensory testing, including testing of cold, warm, cold pain, and heat pain detection thresholds (CDT, WDT, CPT, and HPT, respectively). The results of CARTs were compared with the thermal detection thresholds in quantitative sensory testing by using SPSS 26.0. A total of 266 participants were divided into the CAN group, early CAN (ECAN) group, and without CAN (NCAN) group. There were significant differences in quantitative sensory testing parameters among three groups, and CARTs presented a positive correlation with the WDT and HPT and a negative correlation with the CDT. Moreover, after adjusting for age, sex, diabetes duration, and other influencing factors, WDT, HPT, and CDT were independent risk factors for cardiovascular autonomic neuropathy. The thermal detection thresholds, including cold, warm, and heat pain detection thresholds, in quantitative sensory testing were found to be significantly related to the results of CARTs. Some thermal detection thresholds were independent risk factors for cardiovascular autonomic neuropathy. Therefore, this study showed that quantitative sensory testing has a reliable predictive ability for the occurrence and development of cardiovascular autonomic neuropathy.

The Microglial Activation Inhibitor Minocycline, Used Alone and in Combination with Duloxetine, Attenuates Pain Caused by Oxaliplatin in Mice.

The antitumor drug, oxaliplatin, induces neuropathic pain, which is resistant to available analgesics, and novel mechanism-based therapies are being evaluated for this debilitating condition. Since activated microglia, impaired serotonergic and noradrenergic neurotransmission and overexpressed sodium channels are implicated in oxaliplatin-induced pain, this in vivo study assessed the effect of minocycline, a microglial activation inhibitor used alone or in combination with ambroxol, a sodium channel blocker, or duloxetine, a serotonin and noradrenaline reuptake inhibitor, on oxaliplatin-induced tactile allodynia and cold hyperalgesia. To induce neuropathic pain, a single dose (10 mg/kg) of intraperitoneal oxaliplatin was used. The mechanical and cold pain thresholds were assessed using mouse von Frey and cold plate tests, respectively. On the day of oxaliplatin administration, only duloxetine (30 mg/kg) and minocycline (100 mg/kg) used alone attenuated both tactile allodynia and cold hyperalgesia 1 h and 6 h after administration. Minocycline (50 mg/kg), duloxetine (10 mg/kg) and combined minocycline + duloxetine influenced only tactile allodynia. Seven days after oxaliplatin, tactile allodynia (but not cold hyperalgesia) was attenuated by minocycline (100 mg/kg), duloxetine (30 mg/kg) and combined minocycline and duloxetine. These results indicate a potential usefulness of minocycline used alone or combination with duloxetine in the treatment of oxaliplatin-induced pain.

Establishing abdominal QST reference values for healthy adults and adolescents

Debilitating abdominal and pelvic pain conditions are highly prevalent in adults and adolescents. Assessing sensory functioning among people with painful conditions is important in understanding the disease. Reference values for Quantitative Sensory Testing (QST), used to assess sensory perception, are well established for other regions but not the abdomen. The aim of this study was to establish QST reference values for the abdomen in a diverse group of males and female adults and adolescents. In this cross-sectional study, 181 healthy, pain-free males and females from age 12-50 years completed a comprehensive QST battery in upper and lower abdomen and a control site. The QST battery consisted of: Dynamic Mechanical Touch (DMT), Light Touch Detection (LTD), Sharp Prick Detection (SPD), Pressure Pain Threshold (PPT), Temporal Summation of Pain (TSP), Cool and Warmth Detection Thresholds (CDT, WDT), and Cold and Heat Pain Thresholds (CPT, HPT). Participants also answered pain-related questionnaires including the Pain Catastrophizing Scale, 36-Item Short Form Survey, Pain Sensitivity Questionnaire (PSQ). Mean and standard deviation values were calculated for each QST sub-test and separated by age, sex, and body site (upper and lower abdomen, and control site). Results of RMANOVAs indicated that pain sensitivity differed by site and modality, with no consistent pattern indicating one area was generally more sensitive than others. There were also effects of sex with males experienced less sensitivity to pressure and cold pain than females. Self-reported pain sensitivity (PSQ) was associated with greater abdominal sensitivity to punctate, cold, and heat pain. This paper successfully established reference QST values for the upper and lower abdominal sites for healthy, pain-free male and female adolescents and adults which will be critical in understanding somatosensory nervous system function among patients with abdominal and pelvic pain. These data will be critical in understanding nociceptive processing in the abdominal region. Boston Center for Endometriosis/Marriott Family Foundation Investigator Grant Office of Faculty Developtment at Boston Children's Hospital.

Abnormal sensory thresholds of dystonic patients are not affected by deep brain stimulation.

Unlike motor symptoms, the effects of deep brain stimulation (DBS) on non-motor symptoms associated with dystonia remain unknown. The objective of this study was to assess the effects of DBS on evoked experimental pain and cutaneous sensory thresholds in a crossover, double-blind on/off study and compare these results with those of healthy volunteers (HV). Sixteen patients with idiopathic dystonia (39.9±13years old, n=14 generalized) with DBS of the globus pallidus internus underwent a battery of quantitative sensory testing and assessment using a pain top-down modulation system (conditioned pain modulation, CPM). Results for the more and less dystonic body regions were compared in on and off stimulation. The patients' results were compared to age- and sex-matched HV. Descending pain modulation CPM responses in dystonic patients (on-DBS, 11.8±40.7; off-DBS, 1.8±22.1) was abnormally low (defective) compared to HV (-15.6±23.5, respectively p=.006 and p=.042). Cold pain threshold and cold hyperalgesia were 54.8% and 95.7% higher in dystonic patients compared to HV. On-DBS CPM correlated with higher Burke-Fahn-Marsden disability score (r=0.598; p=.014). While sensory and pain thresholds were not affected by DBS on/off condition, pain modulation was abnormal in dystonic patients and tended to be aggravated by DBS. The analgesic effects after DBS do not seem to depend on short-duration changes in cutaneous sensory thresholds in dystonic patients and may be related to changes in the central processing of nociceptive inputs.

Can within-subject comparisons of thermal thresholds be used for diagnostic purposes?

ObjectiveQuantitative thermal testing (QTT) is a psychophysical assessment method of small nerve fibers that relies on reference material to assess function. Normal limits for within-subject comparisons of thermal thresholds are scarce, and their association with age, height and sex is not fully elucidated. The aim of this study was to investigate the normal limits for distal-proximal– and contralateral homologous comparisons of thermal thresholds with QTT, and their association with age, sex or height. MethodsFifty healthy volunteers ages 20–79 participated in the experiment. Cold detection thresholds (CDT), warm detection thresholds (WDT), heat pain thresholds (HPT), and cold pain thresholds (CPT) were measured bilaterally at the thenar eminence, anterior thigh, distal medial leg and foot dorsum. Sample normal limits were calculated as (mean) ± 2 SD. ResultsForty-eight subjects were included in the analysis. CPT was excluded from all analyses due to a large floor-effect. Sample normal limits for side-differences ranged from 1.8 to 7.2 °C for CDT, 2.4–6.8 °C for WDT and 3.2–4.0 °C for HPT, depending on anatomical site. For distal-proximal comparisons, sample normal limits ranged from 4.0 to 8.7 °C for CDT, 6.0–14.0 °C for WDT and 4.2–9.0 °C for HPT, depending on the pairs compared. Age was associated with side-differences for CDT in the thenar eminences (p < 0.001) and distal medial legs (p < 0.002), and with 11 of 18 distal-proximal comparisons (p < 0.01). ConclusionsThe normal limits for distal-proximal- and contralateral homologous thermal thresholds were wide, and thus of limited use in a clinical setting, although the reported values may be somewhat inflated by low sample-size and consequent age-pooling. Age, but not sex or height, was associated with contralateral differences in CDT in the thenar eminences and distal medial legs, and with most distal-proximal differences. SignificanceDue to wide normal limits, we advise caution when utilizing relative comparisons of thermal thresholds for diagnostic purposes.