Genetic contributions to pain modulation in sickle cell: A focus on single nucleotide polymorphisms.

Background: Despite recent advances in our knowledge of genetic contributions to the highly variable sickle cell disease (SCD) phenotype, our understanding of genetic factors associated with pain sensitivity in SCD remains limited. Previous studies investigated specific variants in single candidate genes and their association with SCD pain variability. The primary aim of the current study was to expand the genes and polymorphisms tested to discover new risk genes (polymorphisms) associated with central sensitization for individuals with SCD. Methods: Adults with sickle cell disease (n = 59, Mage = 36.8 ± 11.5, 65.8 % female) underwent quantitative sensory testing to examine central sensitization and general pain sensitivity. Participants reported average crisis and non-crisis pain intensities weekly using a 0-100 scale, and provided salivary samples for genotyping. The Hardy-Weinberg equilibrium was verified for controls, and allele distributions were tested with chi-square and odds ratio tests. The Benjamini-Hochberg procedure was used to control for false discovery rate. Regression analyses and Wilcoxon tests were used to test associations for normally distributed and skewed data, respectively. Results: Central sensitization and general pain sensitivity were not associated with hemoglobin genotype (Ps > 0.05). Of 4145 SNPs tested, following false discovery rate adjustments, 11 SNPs (rs11575839, rs12185625, rs12289836, rs1493383, rs2233976, rs3131787, rs3739693, rs4292454, rs4364, rs4678, rs6773307) were significantly associated with central sensitization, and one SNP (rs7778077) was significantly associated with average weekly non-crisis pain. No SNPs were associated with general pain sensitivity. Conclusions: These findings provide insights into genetic variants association with average non-crisis pain and central sensitization for individuals with SCD, and may provide support for genetic predictors of heightened pain experience within SCD.

A myriad of methods to determine temporal summation of pain in people with musculoskeletal pain and healthy participants: a scoping review.

Temporal summation of pain (TSP) is a human proxy for wind-up of dorsal horn neurons as assessed in animals. The common paradigm for eliciting TSP is evoked by repetitive nociceptive stimuli of equal intensity. Various stimulation and assessment protocols have been used. This scoping review aims to provide insight into key elements of TSP stimulation and assessment: modality, instruments, test location, familiarization, train characteristics, and calculations. PubMed, Embase, and Ebsco/CINAHL were searched for studies that measured TSP in adults with musculoskeletal conditions and healthy people. Four hundred six studies were included. Mechanical stimuli were the most commonly used modality (250 studies), followed by thermal stimuli (125 studies). Forty-six different instruments were used. Disregarding studies on widespread musculoskeletal pain and healthy participants, 40 studies evaluated TSP at painful sites, 77 in remote areas, and 66 in both locations. Of the 13 tested locations in patients, the hand (74 studies), lower leg (64 studies), and forearm (59 studies) were most commonly tested. A single practice round was the most common familiarization method (46 studies). Repeated stimuli were applied using 31 different frequencies (0.03-200 Hz) and sustained stimulations ranging from 5 to 1080 seconds were used. Twenty-two different train lengths, 63 different calculations (37 absolute, 19 relative, and 7 alternatives using data directly), and 14 different outcome measures (eg, self-reported pain rating scales and reflex thresholds) were used. Temporal summation of pain protocols vary excessively, hindering the comparison and pooling of results. None of the studies provided substantiation for their protocol choice.

Somatosensory profile in individuals with duchenne muscular dystrophy: A quantitative sensory testing (QST) study.

OBJECTIVE: This study aimed to quantify somatosensory profiles in individuals with Duchenne muscular dystrophy (DMD). METHODS: We included 28 participants with genetically confirmed DMD (aged 8-17 years), 14 with chronic pain (DMD-CP), and 14 without pain (DMD-NP), compared to 13 healthy controls (HC) matched for age and sex. Three quantitative sensory testing (QST) modalities were examined: pressure pain threshold (PPT), temporal summation of pain (TSP) and conditioned pain modulation (CPM). Characteristics related to chronic pain, fatigue, psychological distress, and health-related quality of life were assessed using questionnaires. RESULTS: Decreased PPTs were found in both DMD cohorts across body areas commonly affected by pain (rectus femoris, medial gastrocnemius, paraspinal muscles, upper trapezius), as well as in a less frequently affected remote area (thenar eminence), compared to HCs (p < 0.001). The DMD-CP group exhibited greater TSP compared to HCs (p = 0.025). There were no differences in CPM effects between DMD groups and HCs. No differences were detected in all QST measures between DMD-CP and DMD-NP. SIGNIFICANCE: This study is the first to explore the somatosensory profile in DMD. Preliminary evidence suggests that generalized hyperalgesia may be a common feature in DMD regardless of pain status. QST measures appear to not distinguish individuals with chronic pain from those without and thus are not recommended for assessing pain in DMD or guiding treatment.

Test-retest and inter-rater reliability of two devices measuring tactile mechanical detection thresholds in healthy adults: Semmes-Weinstein monofilaments and the cutaneous mechanical stimulator.

INTRODUCTION/AIMS: Limitations exist in evaluating mechanical detection thresholds (MDTs) due to a lack of dependable electronic instruments designed to assess Aß fibers and measure MDTs across different body areas. This study aims to evaluate the test-retest and inter-rater reliability of the cutaneous mechanical stimulator (CMS), an electronic tactile stimulator, in quantifying MDTs. METHODS: Using a test-retest design, participants underwent assessments of MDTs using Semmes-Weinstein monofilaments (SWM) and the CMS. This study included 27 healthy volunteers (mean age 24.07 ± 3.76 years). Two raters assessed MDTs using SWM and the CMS at two stimulation sites (the left hand and foot) in two experimental sessions approximately 2 weeks apart. RESULTS: MDTs using SWM and the CMS showed excellent reliability on the hand (intraclass correlation coefficient [ICC] = .84) and foot (ICC = .90). A comparison of results obtained at the two sessions showed that MDTs on the hand displayed good reliability for both SWM (ICC = .63) and the CMS (ICC = .73), whereas MDTs on the foot displayed fair reliability for SWM (ICC = .50) and the CMS (ICC = .42). MDTs exhibited good inter-rater reliability with SWM (ICC = .66) and excellent inter-rater reliability with the CMS (ICC = .82) on the hand, as well as showing fair inter-rater reliability with SWM (ICC = .53) and good inter-rater reliability with the CMS (ICC = .60) on the foot. DISCUSSION: The CMS showed superior inter-rater reliability, indicating its potential as a valuable tool for assessing tactile sensitivity in research and clinical settings.

Altered Sensory Processing in People Attending Specialist Orthopaedic Consultation for Management of Persistent Shoulder Pain: An Observational Cross-Sectional Study.

OBJECTIVES: The primary objective was to compare sensory processing measures in people attending specialist orthopaedic consultation for management of persistent shoulder pain with control participants. The secondary objective was to compare the groups' sociodemographic, clinical, general health and lifestyle, and psychological characteristics. DESIGN: Observational cross-sectional. METHODS: Participants with shoulder pain for ≥3 months, who attended a public hospital orthopaedic department (n = 119), and community participants without shoulder pain (n = 44) underwent a standardized quantitative sensory testing protocol, measuring pressure pain threshold, temporal summation, and conditioned pain modulation. Sociodemographic, clinical, general health and lifestyle, and psychological characteristics were also collected. RESULTS: Participants with shoulder pain had significantly lower pressure pain thresholds at all sites (ie, local and widespread mechanical hyperalgesia) and significantly decreased conditioned pain modulation effect (ie, descending inhibition of nociception) than control participants. There was no significant difference between groups for temporal summation. Participants with shoulder pain had decreased general health and function, less healthy lifestyles, and poorer psychological health compared with controls. CONCLUSION: People referred to specialist orthopaedic care for management of persistent shoulder pain had clinical signs of altered sensory processing and poor health outcomes. J Orthop Sports Phys Ther 2024;54(10):1-10. Epub 25 July 2024. doi:10.2519/jospt.2024.12512.

Feasibility and acceptability of remote administration of the cold pressor test.

Objective: Quantitative sensory testing is often used to investigate pain in the context of experimental and clinical research studies. However, many of the devices used for QST protocols are only available in resource rich environments, thereby inadvertently limiting the possible pool of participants. Development of remote protocols for appropriate QST measures has the potential to reduce barriers to participation in research. Methods: Participants with insomnia and Crohn's disease were recruited as part of a clinical trial. We adapted a remote version of the cold pressor test for use during telehealth-based study assessments. Herein, we present data from the baseline assessments including an assessment of feasibility and acceptability of the task. Results: 100% of participants (N = 28) were able to complete the remote cold pressor test using a combination of materials from their homes and mailed by the study team. Temperature changes during the test were minimal and fairly evenly balanced between increases and decreases. Correlations between submersion time and both general and disease specific pain trended toward significance. Conclusions: We demonstrated that a remote version of the cold pressor test is feasible and acceptable in a clinical population and provided a step-by-step protocol for administration to facilitate use in other studies.

Idiopathic Distal Sensory Polyneuropathy and Fibromyalgia Syndrome: A Comparative Phenotyping Study.

INTRODUCTION: Painful idiopathic distal sensory polyneuropathy (IDSP) and fibromyalgia syndrome (FMS) are cryptogenic chronic pain syndromes. The contribution of small fibre pathology (SFP) in FMS remains controversial. This study aims to quantify small nerve pathology in participants with IDSP and FMS and identify relationships of SFP with sensory phenotypes. METHODS: In this study, 73 individuals (FMS: 25, IDSP: 23, healthy volunteers: 25) underwent comprehensive assessment, including neurological exams, questionnaires, sensory tests, and corneal confocal microscopy. RESULTS: IDSP participants displayed lower wind-up ratio (WUR) relative to FMS (p < 0.001), loss of function to thermal and mechanical stimuli and elevated neuropathy disability scores compared to FMS and healthy volunteers (all p < 0.001). FMS participants demonstrated gain of function to heat and blunt pressure pain responses relative to IDSP, and healthy volunteers (heat: p = 0.002 and p = 0.003; pressure: both p < 0.001) and WUR (both p < 0.001). FMS participants exhibited reduced corneal nerve fibre density (p = 0.02), while IDSP participants had lower global corneal nerve measures (density, branch density, and length) relative to healthy volunteers (all p < 0.001). Utilising corneal nerve fibre length, SFP was demonstrated in 66.6% of participants (FMS: 13/25; IDSP: 22/23). CONCLUSION: Participants with SFP, in both FMS and IDSP, reported symptoms indicative of small nerve fibre disease. Although distinctions in pain distributions are evident between individuals with FMS and IDSP, over 50% of participants between the two conditions displayed both a loss and gain of thermal and mechanical function suggestive of shared mechanisms. However, sensory phenotypes were associated with the presence of SFP in IDSP but not in FMS.

In people with painful idiopathic neuropathy (pain related to nerve damage where the cause of nerve damage is unknown), fibromyalgia syndrome (a long-term condition causing widespread pain), and healthy volunteers, the small nerve fibres of the peripheral nervous system, which may be involved in generating pain were assessed. These nerve fibres can be measured at the front of the eye (cornea) which can provide details on whether they are damaged in the body. The response to temperature, light touch, pressure and pinprick stimuli can also be used to determine if there is a loss or gain of sensation, which may contribute to pain. The aim of this study was to identify the degree of damage to these nerve fibres and to determine whether this damage is associated with a loss (cannot feel or requires more intense stimulus to feel) or gain (stimulus is felt earlier or is painful earlier at lower intensity) of sensory function. The pattern of loss or gain in sensory function is known as a sensory phenotype. It was found that people with painful idiopathic neuropathy had more severe nerve damage, loss of function to temperature and touch, and fewer small nerve fibres in the cornea compared to those with fibromyalgia syndrome and healthy volunteers. People with fibromyalgia syndrome were more sensitive to heat and pressure and had fewer corneal nerve fibres relative to healthy volunteers. The presence of corneal nerve fibre damage was associated with sensory phenotypes (types of sensation felt) in painful idiopathic neuropathy but not in fibromyalgia syndrome.

Pain Is Modulated Differently Between Females with and without Patellofemoral Pain: Factors Related to Sensitization.

CONTEXT: Patellofemoral pain (PFP) has poor long-term recovery outcomes. Central sensitization describes central nervous system changes altering pain modulation, which can complicate recovery (poorer prognosis, worse function). Signs of central sensitization include amplified pain facilitation, pain hypersensitivity, and impaired pain inhibition, which can be measured with temporal summation of pain (TSP), pressure pain thresholds (PPTs) and conditioned pain modulation (CPM), respectively. Sex differences exist for these test responses, but female-only PFP investigations of sensitization are uncommon. Understanding pain modulation in females with PFP could improve treatment protocols. OBJECTIVE: To determine whether females with PFP exhibit signs of central sensitization (greater TSP, lower PPTs, reduced CPM) compared to pain-free females. DESIGN: Cross-sectional Setting: Laboratory Patients or Other Participants: Thirty-three females [(20 PFP, 13 pain-free); Age: PFP 29.2 ± 7 years, pain-free 28 ± 7 years; Height: PFP 166.7 ± 5.9cm, pain-free 166 ± 9.5cm, Mass: PFP 66.7 ± 9.6kg, pain-free 69.3 ± 7.5kg). MAIN OUTCOME MEASURES: TSP was assessed with ten punctate stimuli applied to the knee and calculated by the difference in pain intensity between beginning and end responses. PPTs were tested at four sites [3 for local hypersensitivity (knee), 1 for widespread hypersensitivity (hand)]. CPM was conducted by comparing PPTs during two conditions (baseline, ice immersion). CPM response was defined as the percent difference between conditions. Between-group differences in TSP response were analyzed with a Welch's test. Separate Welch's tests analyzed group comparisons of PPTs and CPM responses at four sites. RESULTS: Females with PFP exhibited greater TSP response (P=0.019) and lower CPM response at patella center (P=0.010) and hand sites (P=0.007) than pain-free females. PPT group differences were not observed at any site (P>0.0125). CONCLUSIONS: Females with PFP modulate pain differently than pain-free females. Clinicians should recognize signs of central sensitization and their potential impact on treatment options.

A multi-modal evaluation of experimental pain and psychological function in women with carpometacarpal osteoarthritis.

Objective: Thumb carpometacarpal osteoarthritis (CMC1 OA) is a prevalent and debilitating condition that lacks effective treatments. Understanding the multidimensional pain experience across CMC1 OA disease stages is crucial to improving treatment outcomes. This study examined how radiographic CMC1 OA severity is associated with physical, psychological, and somatosensory function. Method: Thirty-one women with early-stage (Eaton-Littler 1-2) or end-stage (Eaton-Littler 3-4) radiographic CMC1 OA completed validated questionnaires to assess pain, disability, and psychological function. Additionally, experimental pain was measured in each participant using quantitative sensory testing (QST) (mechanical, pressure, vibratory, thermal) at seven body sites (thenar, hypothenar, brachioradialis bi-laterally; quadriceps on affected side). Cohort differences (early-vs. end-stage) across all variables were analyzed using a multivariable modeling approach that included fixed effects and interactions; notably, age was controlled as a confounder. Results: End-stage CMC1 OA participants had higher scores in the pain (p â€‹= â€‹0.01) and function (p â€‹= â€‹0.02) portions of the AUSCAN assessment, self-reported disability of the DASH questionnaire (p â€‹= â€‹0.04), and painDETECT scores (p â€‹= â€‹0.03), indicating greater pain and disability compared to early-stage participants. Additionally, end-stage CMC1 OA participants demonstrated reduced vibratory detection and heat pain thresholds at multiple body sites (p's â€‹< â€‹0.05), with significant interactions observed across the mechanical and cold stimuli. Conclusion: Findings revealed women with end-stage CMC1 OA exhibited increased neuropathic pain characteristics and somatosensory loss compared to those with early-stage CMC1 OA. These results underscore the importance of addressing both peripheral and centralized pain mechanisms and the need for multimodal approaches in the treatment of CMC1 OA.

Temporal summation does not predict the acupuncture response in patients with chronic non-specific low back pain.

Introduction: Previously, we had observed that immediate pain reduction after one acupuncture treatment was associated with high temporal summation of pain (TS) at a pain free control site and younger age in a mixed population of chronic pain patients. The aim of the present study was to verify these results in chronic non-specific low back pain (LBP) and to collect pilot data on the association between TS and the response to an acupuncture series. Methods: TS at a pain free control site (back of dominant hand) and at the pain site was quantified by the pin-prick induced wind-up ratio (WUR) in 60 LBP patients aged 50 years or younger. Response to one acupuncture treatment was assessed by change in pain intensity and pressure pain threshold (PPT) at the pain site. The primary hypothesis was that a high TS (WUR > 2.5) would be associated with a clinically relevant reduction in pain intensity of at least 30%. In study part two, 26 patients received nine additional treatments. Response to the acupuncture series was assessed by the pain intensity during the last week, the PPT and the Hannover functional ability questionnaire (FFbH-R). Results: An immediate reduction in pain intensity of at least 30% was frequent irrespective of TS at the control site (low vs. high TS 58% vs. 72%, p = 0.266). High TS at the pain site was also not significantly associated with a clinically relevant immediate reduction in pain intensity (low vs. high TS 46% vs. 73%, p = 0.064). The PPT was not changed after one acupuncture treatment. Study part two did not reveal a consistent association between TS at the control site and any of the outcome measures but also a trend toward a higher chance for a clinically relevant response along with low TS at the pain site. Conclusion: Our results do not suggest an important role of TS for predicting a clinically important acupuncture effect or the response to a series of 10 acupuncture treatments in patients with chronic non-specific LBP. Overall high response rates imply that acupuncture is a suitable treatment option for LBP patients irrespective of their TS.

Sensory dysfunction in SMA type 2 and 3 - adaptive mechanism or concomitant target of damage?

BACKGROUND: The motor neuron survival protein performs numerous cellular functions; hence, spinal muscular atrophy (SMA) is considered to be a multi-organ disease with possible sensory system damage. The controversy surrounding the presence of sensory disturbances, prompted us to conduct standard electrophysiological studies and assess the sensory thresholds for different modalities in adults with SMA types 2 and 3. The study group consisted of 44 adult SMA patients (types 2 and 3). All patients underwent neurological examination using the Hammersmith Functional Motor Scale - Expanded (HFMSE). Standard sensory electrophysiological studies in the ulnar nerve and the estimation of vibratory, temperature, and warm- and cold-induced pain thresholds with temperature dispersion assessment were performed using quantitative sensory testing (QST). RESULTS: The most repeatable result was the high amplitude of the sensory nerve action potentials (SNAP) in SMA patients compared to controls. This was higher in type 2 patients compared to type 3a and 3b patients and patients with low HFSME scores. Patients with SMA, especially type 3b presented a longer sensory latency and slower conduction velocity than did controls. Cold pain threshold was higher and warm dispersion larger in SMA. The vibratory limit was higher in patients with high HFSME scores. CONCLUSIONS: A high SNAP amplitude suggests sensory fibre hyperactivity, which may be based on overactivation of metabolic pathways as an adaptive mechanism in response to SMN protein deficiency with additionally coexisting small C- and A-delta fibre damage. SMA patients seem to have a concomitant, mild demyelinating process present at the early SMA stage.

Effects of therapeutic exercise on pain processing in people with chronic non-specific neck pain - A systematic review and meta-analysis.

BACKGROUND: Emerging evidence suggests that individuals with chronic non-specific neck pain may experience altered sensory processing, potentially contributing to the modest response to therapeutic exercise treatments. OBJECTIVE: This systematic review aims to explore the effect of therapeutic exercise on pain processing among patients with chronic non-specific neck pain. METHODS: A systematic search was conducted in multiple databases (PubMed, EMBASE, CINAHL, PEDro, SportDiscus, and Cochrane CENTRAL) from inception to June 2023. Inclusion criteria included randomized controlled trials (RCT) comparing therapeutic exercise to non-exercise treatments or no treatment. The screening and data extraction was conducted by two reviewers. The methodological quality was evaluated using the PEDro scale and the certainty of evidence using GRADE. The primary outcomes assessed were pressure pain threshold (PPT), temporal summation, and conditioned pain modulation. RESULTS: Thirteen trials included a total of 948 participants, with 586 in the exercise therapy group and 362 in the non-exercise group. The therapeutic exercise was not superior to non-exercise treatments for both local and PPT in the immediate (MD = 0.13, 95%CI = -0.18 to 0.43), and short-term follow-up (MD = 0.17, 95%CI = -0.27 to 0.61). In the medium term, therapeutic exercise demonstrated a small effect size in increasing local PPT (Kg/cm2) (MD = 0.64, 95%CI = 0.08 to 1.19) compared to non-exercise interventions. The certainty of evidence for these outcomes was very low. CONCLUSIONS: There is very low certainty of evidence that therapeutic exercise is not superior than non-exercise treatment on pain processing in patients with chronic non-specific neck pain.

Words matter: Effects of instructional cues on pressure pain threshold values in healthy people.

BACKGROUND: Pressure pain threshold (PPT) measurements require standardised verbal instructional cues to ensure that the increasing pressure is stopped at the correct time consistently. This study aimed to compare how PPT values and their test-retest reliability were affected by different instructional cues. METHODS: At two separate sessions, two PPT measurements were taken at the anterior knee for each of four different instructional cues: the cue of the German Neuropathic Research Network instructions ('DFNS'), the point where pressure first feels uncomfortable ('Uncomfortable'), 3/10 on the numerical pain rating scale ('3NPRS'), and where pain relates to an image from the pictorial-enhanced NPRS scale ('Pictorial'). Linear mixed modeling was used to quantify differences between pairs of instructional cues. Test-retest reliability was estimated using intraclass correlation coefficients (ICC[2,1] and ICC[2,k]). RESULTS: Twenty participants were recruited. The cue resulting in greatest PPT value was DFNS (394.32 kPa, 95%CI [286.32 to 543.06]), followed by Pictorial (342.49 kPa, 95%CI [248.68 to 471.68]), then Uncomfortable (311.85 kPa, 95%CI [226.43 to 429.48]), and lastly 3NPRS (289.78 kPa, 95%CI [210.41 to 399.09]). Five of six pairwise contrasts were statistically significant. Regardless of the cues, the point estimates of ICC (2,1) ranged from 0.80 to 0.86, and the ICC (2,k) values ranged from 0.89 to 0.93. No statistically significant differences were found between any pairwise contrasts of reliability indices. CONCLUSION: Words matter when instructing people when to stop testing in pressure algometry. Clinicians should use the same instructional cue when assessing pain thresholds to ensure reliability.

Assessment of small nerve fiber function as an early marker of peripheral neuropathy in children and adolescents with type 1 diabetes mellitus (T1DM).

PURPOSE: This study aimed to assess subclinical peripheral diabetic neuropathy (PDN) in adolescents with type 1 diabetes mellitus (T1DM). METHODS: Subjects included 53 T1DM patients (age (mean ± SE): 15.8 ± 0.54 years, disease duration: 6.0 ± 0.51 years and HbA1c: 7.9 ± 0.19%), and 37 healthy gender matched controls (age: 15.6 ± 0.52 years). PDN was assessed by vibration perception threshold (VPT) and by quantitative sensory testing (QST). In controls, 95% confidence intervals were calculated. RESULTS: Among patients, VPT prevalence of abnormality ranged from 60-73.4% on different sites. Higher VPT was found in patients on all examined sites (p < 0.01). In controls, VPT correlated with height (r = 0.48, p = 0.05). Regarding QST prevalence of abnormality, cold detection threshold (CDT) ranged 7.3-39.0%, cold pain threshold (CPT) ranged 22.22-29.63%, hot detection threshold (HDT) ranged 34.14-63.41%, and hot pain threshold (HPT) ranged 15.79-36.84%. In patients, CPT correlated with BMI (r = 0.42, p = 0.05) and diabetes duration, (r = 0.40, p = 0.05), HPT correlated with age (r = 0.36, p = 0.05) and height (r = 0.35, p = 0.05), while in controls with BMI (r = 0.51, p = 0.05). No correlation of VPT or QST with HbA1c was observed. CONCLUSION: Adolescents with T1DM in this study, although asymptomatic, showed a high prevalence of impaired indices of PDN, highlighting potential clinical implications of early identification of PDN.

Early detection of altered cold perception in elderly with type 2 diabetes using a novel Quantitative Sensory Testing method.

AIM: To compare the effectiveness of two methods for measuring cold detection thresholds in screening for temperature-perception deficits in elderly individuals with type 2 diabetes (T2 diabetes). METHODS: Cold threshold measurements were performed on seven body regions of participants with diabetes without neuropathy (n = 30; mean age, 70.9 ± 6.5 years) and healthy participants (n = 73; mean age, 68 ± 5 years). Two protocols applying the Levels Method were used: the first used skin temperature as the starting point; the second used 40 °C. RESULTS: Cold detection thresholds were significantly higher in subjects with diabetes, particularly on the foot. For CDT TSk, values were -2.22 ± 1.91 °C in non-diabetic and -3.27 ± 3.33 °C in diabetic groups (p = 0.023); for CDT 40, values were -9.82 ± 3.5 °C and -12.18 ± 4.5 °C (p = 0.003). However, after adjusting for age, the group effect on cold threshold with skin temperature as baseline disappeared. Sensory screens showed that the Area Under Curve of the method using a 40 °C baseline was 0.69 (p = 0.002). CONCLUSION: Measuring the cold detection threshold on the foot with a 40 °C baseline is more effective than using skin temperature as a baseline for screening sensory alterations in elderly subjects with type 2 diabetes before neuropathy onset. SIGNIFICANCE: These findings highlight the importance of selecting the appropriate cold detection threshold method for elderly individuals with type 2 diabetes. The optimal method can facilitate early identification of sensory changes, minimizing complications and improving overall well-being.

Predictive and concurrent validity of pain sensitivity phenotype, neuropeptidomics and neuroepigenetics in the MI-RAT osteoarthritic surgical model in rats.

Background: Micro-RNAs could provide great insights about the neuropathological mechanisms associated with osteoarthritis (OA) pain processing. Using the validated Montreal Induction of Rat Arthritis Testing (MI-RAT) model, this study aimed to characterize neuroepigenetic markers susceptible to correlate with innovative pain functional phenotype and targeted neuropeptide alterations. Methods: Functional biomechanical, somatosensory sensitization (peripheral-via tactile paw withdrawal threshold; central-via response to mechanical temporal summation), and diffuse noxious inhibitory control (via conditioned pain modulation) alterations were assessed sequentially in OA (n = 12) and Naïve (n = 12) rats. Joint structural, targeted spinal neuropeptides and differential expression of spinal cord micro-RNAs analyses were conducted at the sacrifice (day (D) 56). Results: The MI-RAT model caused important structural damages (reaching 35.77% of cartilage surface) compared to the Naïve group (P < 0.001). This was concomitantly associated with nociceptive sensitization: ipsilateral weight shift to the contralateral hind limb (asymmetry index) from -55.61% ± 8.50% (D7) to -26.29% ± 8.50% (D35) (P < 0.0001); mechanical pain hypersensitivity was present as soon as D7 and persisting until D56 (P < 0.008); central sensitization was evident at D21 (P = 0.038); pain endogenous inhibitory control was distinguished with higher conditioned pain modulation rate (P < 0.05) at D7, D21, and D35 as a reflect of filtrated pain perception. Somatosensory profile alterations of OA rats were translated in a persistent elevation of pro-nociceptive neuropeptides substance P and bradykinin, along with an increased expression of spinal miR-181b (P = 0.029) at D56. Conclusion: The MI-RAT OA model is associated, not only with structural lesions and static weight-bearing alterations, but also with a somatosensory profile that encompasses pain centralized sensitization, associated to active endogenous inhibitory/facilitatory controls, and corresponding neuropeptidomic and neuroepigenetic alterations. This preliminary neuroepigenetic research confirms the crucial role of pain endogenous inhibitory control in the development of OA chronic pain (not only hypersensitivity) and validates the MI-RAT model for its study.

Characterization of the neuropathic pain component contributing to myalgia in patients with myotonic dystrophy type 1 and 2.

Introduction: Chronic muscle pain is common in myotonic dystrophies (DM). Little is known about its pathophysiology. We aimed to investigate the characteristics of the neuropathic pain component contributing contributes to the pathogenesis of chronic pain in DM. Methods: Twenty-one DM1 and 32 DM2 patients completed pain questionnaires (Brief pain inventory-BPI, PAIN-DETECT, pain disability index-PDI) and underwent neurological examination, nerve conduction studies (NCS), quantitative sensory testing (QST, dorsum of the right hand and right thigh) and skin biopsy to determine the intraepidermal nerve fiber density (IENFD, distal and proximal site of lower extremity). NCS and QST results at the thigh were compared to 27 healthy controls and IENFD and QST at the dorsum of the hand to published reference values. Results: The sensory profile of DM2 patients was characterized by a loss in thermal and mechanical detection, while DM1 patients showed reduced mechanical and heat pain thresholds and higher mechanical pain sensitivity. Both DM groups showed pressure hyperalgesia. IENFD was reduced in 63% of DM1 patients and 50% of DM2. The slightly higher pain interference and disability found in DM2 was rather due to age difference than disease. Conclusion: Similar pain mechanisms likely occur in both DM1 and DM2, even though a tendency toward more pain sensitivity was observed in DM1 and more sensory loss in DM2. Both QST and reduced IENFD highlight the presence of peripheral nerve damage in DM. This must be considered for the best pain management strategies.

Test-retest and interrater reliability of experimental within-subject variability of pain reports as assessed by the focused analgesia selection test.

Introduction: Within-subject variability (WSV) of pain intensity reports has been shown to predict the placebo response. The focused analgesia selection test (FAST), which allows to experimentally assess WSV of pain reports, has been used as a screening tool to identify participants who are likely to have a strong placebo response in drug-development clinical trials. Yet, the reliability of FAST has not been reported. Objectives: To assess test-retest and interrater reliability of the FAST outcomes. To mimic pharma-sponsored clinical trials, we enlisted inexperienced assessors who underwent limited training. Methods: Healthy volunteers performed the FAST twice within a week and were randomly assigned to either the test-retest group or the interrater group. T-tests, partial Pearson correlations, intraclass correlations (ICC), and Bland-Altman plots were generated to assess FAST outcomes' reliability. Results: Sixty-three participants completed the study and were assigned to the test-retest (N = 33) or interrater (N = 30) arms. No statistically significant differences in the FAST outcomes were detected between the 2 sessions, except for the FAST covariance (FAST CoV) in the interrater assessment (P = 0.009). Test-retest reliabilities of the FAST-main outcomes were r = 0.461, ICC = 0.385 for the FAST R 2 and r = 0.605, ICC = 0.539 for the FAST ICC and in the interrater cohort, they were FAST R 2: r = 0.321, ICC = 0.337 and FAST ICC: r = 0.355, ICC = 0.330. Conclusion: Using inexperienced assessors, the FAST outcomes test-retest ranged from moderate to strong, whereas the interrater reliability ranged from weak to poor. These results highlight the importance of adequately training study staff members before using this tool in multicentre clinical trials.

Preoperative Temporal Summation is Associated with Impaired Recovery Following Hip Arthroscopy for Femoroacetabular Impingement Syndrome .

Objectives: Chronic pain is a risk factor for worse outcomes following hip arthroscopy for femoroacetabular impingement syndrome (FAIS). Pain sensitization involves the central nervous system perceiving previously innocuous stimuli as noxious. Temporal summation can provide a surrogate measure of sensitization, and may be a clinical tool to identify patients at a higher risk for poor post-hip arthroscopy outcomes. Therefore, we aimed to 1) identify the prevalence of temporal summation in patients undergoing hip arthroscopy for FAIS, 2) determine if there a difference in postoperative improvement between individuals with and without preoperative temporal summation, and 3) examine preoperative predictors of poor postoperative recovery. Methods: 51 participants undergoing hip arthroscopy for FAIS underwent preoperative temporal summation testing. Three months postoperatively, 38 participants completed the 12-item International Hip Outcome Tool (iHOT-12) and reported their overall symptomatic improvement (0% to 100%, with 100% being normal). Participants were categorized on the presence ( Numeric Pain Rating Scale; NPRS   2) or absence (  NPRS < 2) of temporal summation. A Mann-Whitney U test was used to determine the difference in improvement between groups (temporal summation: temporal summation (TS), no temporal summation (NTS), and a linear regression was used to explore predictors of improvement. Results: 23 (45.1%) of 51 participants displayed preoperative temporal summation. In participants with postoperative data, those with temporal summation reported less improvement than those without (TS: 62.8%   29.7%; NTS: 82.7%   13.9%; p = 0.01; Cohen's d = -0.86). Temporal summation (Beta = -0.48; 95% CI -36.6, -8.7) and mental health disorder (Beta = -0.30; 95% CI -28.0, -0.48) predicted 28.1% of the variance in postoperative improvement (p = 0.002). Conclusion: The presence of preoperative temporal summation is common and related to worse postoperative recovery after hip arthroscopy for FAIS.

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.