Endogenous Pain Inhibition Research Articles

The Relationship Between Neighborhood Disadvantage and Markers of Chronic Pain Risk: Findings From the Oklahoma Study of Native American Pain Risk (OK-SNAP)

Socioeconomic disadvantage contributes to health inequities, including chronic pain. Yet, research examining socioeconomic disadvantage and pain risk in Native Americans (NAs) is scant. This exploratory analysis assessed relationships between socioeconomic position (SEP), ethnicity, and neighborhood disadvantage on pronociceptive processes in 272 healthy, chronic pain-free NAs (n = 139) and non-Hispanic Whites (NHWs, n = 133) from the Oklahoma Study of Native American Pain Risk (OK-SNAP). Neighborhood disadvantage was quantified using the Area Deprivation Index (ADI). Regression models tested whether ADI predicted pain-promoting outcomes (ie, peripheral fiber functionality, pain sensitivity, pain and nociceptive amplification, and endogenous pain inhibition) above-and-beyond SEP and ethnicity. The Ethnicity × ADI interaction was also tested. Of the 11 outcomes tested, 9 were not statistically significant. Of the significant findings, neighborhood disadvantage predicted impaired inhibition of the nociceptive flexion reflex above-and-beyond SEP and ethnicity. Additionally, ethnicity moderated the relationship between ADI and warm detection threshold; disadvantage was associated with higher thresholds for NAs, but not for NHWs. Together, the results suggest neighborhood disadvantage is associated with reduced C-fiber function and impaired spinal inhibition, thus pointing to a role of neighborhood disadvantage in the relationship between the environment and pain inequities. PerspectiveThis study assessed neighborhood socioeconomic disadvantage and pronociceptive processes in chronic pain-free Native Americans (NAs) and non-Hispanic Whites (NHWs). Irrespective of ethnicity, greater neighborhood disadvantage predicted less descending inhibition of spinal nociception. Neighborhood disadvantage was associated with a marker of C-fiber impairment (higher warm detection threshold) in NAs only.

Pupillometry as a Potential Objective Measurement of Pain Assessment in Healthy Volunteers.

Pain leads to activation of the autonomic nervous system and thus, among other things, to pupillary reflex dilation (PRD). Previous studies have already confirmed a correlation between the perception of pain and the pupillary reaction, measured using pupillometry. However, the previous study populations were under the influence of medication for analgesia in perioperative setting or suffered from pain. This study examines the relationship between pupillary reaction and pain perception in healthy controls and addresses the question of whether endogenous pain inhibition, clinically tested by conditioned pain modulation (CPM), can be quantified using pupillometry. Forty-two healthy volunteers (21 females, 21 males, mean age 27.9 ± 5.8 years, range 20-39 years) were included in this study. The PRD, as a measure of the pupillary reaction (variance from the base diameter in percent), was investigated during baseline, heat application and during CPM testing and results compared to the reported pain intensity on the numerical rating scale (NRS). The volunteers showed higher variances under painful conditions compared to the measurement at rest corresponding to higher sympathetic activity during pain. Volunteers with a higher variance, ie a stronger pupillary reaction, gave higher pain ratings than subjects with a lower pupil variance. However, there was no correlation between the NRS and PRD. PRD and pain ratings during CPM were significantly lower compared to heat pain application alone. However, there was no correlation between the calculated CPM effect and the PRD. Pupillometry is capable of objectively reflecting the pain response, eg pain relief through CPM testing. However, the CPM effect calculated from the subjective pain ratings and the objective PRD measurements is not associated suggesting that both measure different aspects of pain perception. It must be discussed whether the CPM effect can be the correct measure for the functionality of the pain system.

Age- and Sex-Dependent Effects of Moderate Exercise on Endogenous Pain Inhibition in Rats.

Diffuse noxious inhibitory controls (DNICs), or the pain inhibits pain phenomenon, refer to reduced pain-like behaviors that are displayed following a noxious conditioning stimulus located far from the test stimulus and have also been referred to as "descending control of nociception" when measured in awake-behaving animals. In this study, we sought to determine the impact of moderate long-term exercise on the DCN response and determine if this effect differed across age and sex. After a six-week exercise program consisting of 30 min of moderate treadmill running 5 days a week, the animals' forepaws were injected with capsaicin, and DCN responses were assessed using thermal withdrawal latencies of the hind paw. Young, exercised male and female rats displayed prolonged DCN responses relative to their sedentary counterparts, with the young exercised male group displaying longer-lasting DCN facilitation than the young exercised females. Exercise did not impact DCN responses in either male or female aged rats. Additionally, the serum testosterone levels did not change following exercise in any group. Importantly, the levels of corticosterone did not change following the exercise program, indicating that changes in the DCN response are not due to stress-induced analgesia. Our findings suggest that moderate exercise can facilitate the DCN response in young animals, even when this exercise does not change the levels of serum testosterone.

Vagal tone, pain sensitivity and exercise-induced hypoalgesia: The effect of physical activity level.

Vagal activity has analgesic effects that are attributed to exercise-induced hypoalgesia (EIH). High vagal tone and low pain sensitivity are reported in individuals who routinely exercise yet, their association is unclear. Furthermore, it is unknown if the heightened vagal tone following high physical activity predicts and intensifies EIH. Fifty-one healthy participants (27 low-moderately physically active; 27 females) underwent a resting-state electrocardiogram followed by heart rate variability analysis. Pain measurements, including pressure (PPT) and heat (HPT) pain thresholds, ratings of tonic heat pain (THP) and conditioned pain modulation (CPM) paradigm, were conducted pre- and post-exercise on a cycle ergometer. The highly active group demonstrated higher vagal tone compared to the low-moderately active (root mean square of successive differences between R-R intervals: 63.96.92 vs. 34.78 ms, p = 0.018; percentage of successive R-R intervals that exceed 50 ms: 24.41 vs. 11.52%, p = 0.012). Based on repeated-measure ANOVA, the highly active group showed higher PPT at pre-exercise, compared to the low-moderately active group (382 kPa vs. 327 kPa; p = 0.007). Post-exercise, both groups demonstrated EIH, increased HPT (p = 0.013) and decreased THP ratings (p < 0.001). Linear regression revealed that only in the low-moderately active group, higher vagal tone was associated with more efficient pre-exercise CPM and a greater reduction in THP ratings post-exercise (p ≤ 0.01). Highly active individuals demonstrate greater vagal tone and lower pain sensitivity but no greater EIH. Vagal tone moderates pain inhibition efficiency and EIH only in low-moderately active individuals. These findings suggest that physical activity level moderates the vagal-pain association via the endogenous analgesia system. Highly physically active individuals exhibit greater vagal tone and reduced sensitivity to experimental pain, yet they do not benefit more from exercise-induced hypoalgesia (EIH) compared to low-moderately active individuals. Moreover, low-moderately active individuals with greater vagal tone exhibited more efficient endogenous pain inhibition and greater EIH, suggestive of the moderation effect of physical activity level on vagal-pain associations.

Psychophysical assessment of pain in adults with moderate and severe haemophilia: A cross-sectional study.

Joint pain is the hallmark of haemophilia; therefore it seems clinically rather a musculoskeletal than a bleeding disorder. Although joint pain in people with haemophilia (PwH) is a complex and multidimensional problem, pain assessment remains primarily focused on the structural evaluation of their joints. Whereas, only few data are available on the potential implication of psychophysical and psychological factors. This study aimed to perform a psychophysical pain assessment including quantitative sensory testing (QST) and an evaluation of psychological factors in a large sample of PwH, to get insight into the individuals' pain system. Ninety-nine adults (36.9±13.5 years) with moderate/severe haemophilia A/B and 46 healthy controls filled in self-reported pain and psychological questionnaires and underwent a QST evaluation including static and dynamic tests. Static tests focused on the determination of thermal detection and pain thresholds and mechanical pressure pain thresholds. Dynamic tests evaluated pain facilitation and the efficacy of endogenous pain inhibition. Besides comparing PwH and healthy controls, between-subgroup differences were studied in PwH based on their pain distribution. The study revealed increased thermal and mechanical pain sensitivity and the presence of unhelpful psychological factors such as anxiety/depression in PwH. Among the subgroups, especially PwH with widespread pain showed altered somatosensory functioning. Enhanced pain facilitation and impaired efficacy of endogenous pain inhibition in PwH could not be observed. Altered somatosensory functioning and unhelpful psychological factors, appear to play an important role in the pathophysiology of pain in PwH, especially in PwH with widespread pain.

Effects of conditioned pain modulation on Capsaicin-induced spreading muscle hyperalgesia in humans.

Muscle pain can be associated with hyperalgesia that may spread outside the area of primary injury due to both peripheral and central sensitization. However, the influence of endogenous pain inhibition is yet unknown. This study investigated how endogenous pain inhibition might influence spreading hyperalgesia in experimental muscle pain. Conditioned pain modulation (CPM) was assessed in 30 male volunteers by cold pressor test at the non-dominant hand as conditioning and pressure pain thresholds (PPT) at the dominant 2nd toe as test stimuli. Subjects were classified as having inhibitory or facilitating CPM based on published reference values. Subsequently, muscle pain and hyperalgesia were induced by capsaicin injection into the non-dominant supraspinatus muscle. Before and 5, 10, 15, 20, 30, 40, 50 and 60 min later, PPTs were recorded at the supraspinatus, infraspinatus and deltoid muscle, ring finger and toe. Compared to baseline, PPTs decreased at the supraspinatus, infraspinatus and deltoid muscle (p≤0.03), and increased at the finger and toe (p<0.001). In facilitating CPM (n=10), hyperalgesia occurred at 5, 10, 15, 20 and 40 min (p≤0.026). In inhibitory CPM (n=20), hyperalgesia only occurred after 10 and 15 min (p≤0.03). At the infraspinatus muscle, groups differed after 5 and 40 min (p≤0.008). The results suggest that facilitating CPM is associated with more spreading hyperalgesia than inhibitory CPM. This implies that poor endogenous pain modulation may predispose to muscle pain and spreading hyperalgesia after injury, and suggest that strategies to enhance endogenous pain modulation may provide clinical benefits.

Effects of Transcranial Direct Current Stimulation (t-DCS) of the Cerebellum on Pain Perception and Endogenous Pain Modulation: a Randomized, Monocentric, Double-Blind, Sham-Controlled Crossover Study

Accumulating evidence demonstrates a role of the cerebellum in nociception. Some studies suggest that this is mediated via endogenous pain modulation. Here, we used t-DCS to test the effects of modulation of cerebellar function on nociception and endogenous pain modulation. Anodal, cathodal, and sham cerebellar t-DCS were investigated in a cross-over design in 21 healthy subjects. The nociceptive flexor (RIII) reflex, conditioning pain modulation (CPM), and offset analgesia (OA) paradigms were used to assess endogenous pain modulation. Somatosensory evoked potentials (SEPs) and pain ratings were used to assess supraspinal nociception and pain perception, respectively. No significant t-DCS effects were detected when including all t-DCS types and time points (baseline, 0, 30, 60 min post t-DCS) in the analysis. Exploratory analysis revealed an increased RIII reflex size immediately after cathodal t-DCS (compared to sham, P = 0.046, η2p = 0.184), in parallel with a trend for a decrease in electrical pain thresholds (P = 0.094, η2p = 0.134), and increased N120 SEP amplitudes 30 min after cathodal compared to anodal t-DCS (P = 0.007, η2p = 0.374). OA was increased after anodal compared to sham stimulation (P = 0.023, η2p = 0.232). Exploratory results suggested that cathodal (inhibitory) cerebellar t-DCS increased pain perception and reduced endogenous pain inhibition while anodal (excitatory) t-DCS increased endogenous pain inhibition. Results are principally compatible with activation of endogenous pain inhibition by cerebellar excitation. However, maybe due to limited t-DCS skull penetration, effects were small and unlikely to be clinically significant.

Enhanced pain facilitation rather than impaired pain inhibition in burning mouth syndrome female patients

BackgroundDeficient endogenous pain modulation has been implicated in the development and exacerbation of chronic orofacial pain. To date, relatively little is known regarding the function of the endogenous pain modulation in patients with burning mouth syndrome (BMS). This case–control study investigated endogenous pain modulation in women with BMS.MethodsConditioned pain modulation (CPM) was assessed upon temporal summation (TSP) of thermal pain. Forty female subjects, 20 BMS patients and 20 age-matched control subjects, were included in a 2 session-protocol. Mechanical and thermal pain thresholds were measured on the forearm and hand. TSP was obtained using repetitive laser-evoked thermal stimuli applied on the non-dominant hand, at an intensity yielding to moderate pain. During TSP, CPM was produced by immersing the contralateral foot in a water bath at painful cold (8 °C) temperature. In control conditions, the foot was immersed in a water bath at not painful (30 °C) temperature.ResultsBMS was not associated with any impairment in thermal as well as mechanical extracephalic pain thresholds. TSP and CPM efficacy were similar in BMS patients and control subjects. However, BMS patients exhibited enhanced extracephalic heat hyperalgesia.ConclusionThis study reveals that there is no impairment of endogenous pain inhibition mechanisms in BMS patients, but rather an increase in pain facilitation.

Altered central pain processing assessed by quantitative sensory testing in patients with failed back surgery syndrome

ObjectiveTo investigate the presence of altered central pain processing in patients with failed back surgery syndrome (FBSS) using quantitative sensory testing (QST). MethodsThis study included 34 patients with FBSS, 102 patients post-lumbar surgery without low back pain (LBP), and 102 healthy subjects. All subjects underwent both pressure pain threshold (PPT) and conditioned pain modulation (CPM) in both local and remote pain-free areas, as well as temporal summation (TS) in a remote pain-free area. All patient subjects were assessed using the Pain Catastrophizing Scale (PCS), Beck Anxiety Inventory (BAI), Beck Depression Index (BDI), Numeric rating pain scale (NRS) and Oswestry Disability Index (ODI). ResultsCompared with both control groups, FBSS patients showed a reduction in both PPT and CPM in both tested areas, along with increased TS in a pain-free area (P < 0.05). Furthermore, the patients with FBSS had a significantly higher prevalence of anxiety, depression and pain catastrophizing thoughts than the patient controls (P < 0.05). In the FBSS patients, there was a significant correlation between LBP at rest and both CPM and TS in the pain-free areas, and QST measurements were also associated with the ODI, PCS and BAI (P < 0.05). ConclusionThese findings support the existence of augmented central pain processing in patients with FBSS, which may be caused by dysfunction of endogenous pain facilitation and inhibition. This central amplification of pain may contribute to both LBP intensity and disability in FBSS patients. Therefore, treatment efforts should take into account functional alterations in the central nervous system of FBSS patients.

Increased pain unpleasantness and pain-related fMRI activation in the periaqueductal gray in Alzheimer's disease.

Pain continues to be underrecognized and undertreated in people with Alzheimer's disease (AD). The periaqueductal gray (PAG) is essential to pain processing and modulation yet is damaged by AD. While evidence exists of altered neural processing of pain in AD, there has not been a focused investigation of the PAG during pain in people with AD. To investigate the role of the PAG in sensory and affective pain processing for people living with AD. Participants from a larger study completed pain psychophysics assessments and then a perceptually-matched heat pain task (warmth, mild, and moderate pain) during a functional MRI scan. In this cross-sectional study, we examined blood oxygenation level-dependent (BOLD) responses in the PAG and other pain-related regions in participants with AD (n = 18) and cognitively intact older adults (age- and sex-matched, n = 18). Associations of BOLD percent signal change and psychophysics were also examined. There were significant main effects of AD status on the temperature needed to reach each perception of warmth or pain, where people with AD reached higher temperatures. Furthermore, participants with AD rated mild and moderate pain as more unpleasant than controls. PAG BOLD activation was greater in AD relative to controls during warmth and mild pain percepts. No significant differences were found for moderate pain or in other regions of interest. Greater PAG activation during mild pain was associated with higher affective/unpleasantness ratings of mild pain in participants with AD but not in controls. Results suggest a role for the PAG in altered pain responses in people with AD. The PAG is the primary source of endogenous opioid pain inhibition in the neuroaxis, thus, altered PAG function in AD suggests possible changes in descending pain inhibitory circuits. People with AD may have a greater risk of suffering from pain compared to cognitively intact older adults.

Offset analgesia is increased intra‐orally

Offset analgesia (OA) is commonly used to quantify endogenous pain inhibition. However, the potential role of afferent inputs and the subsequent peripheral factors from different body areas on the underlying mechanisms are still unclear. The aim of this cross-sectional study was to compare the magnitude of OA in four different body areas representing (a) glabrous and non-glabrous skin, (b) trigeminal and extra-trigeminal areas, and (c) intra- and extra-oral tissue. OA was assessed at the oral mucosa of the lower lip, the skin of the cheek, the forearm and the palm of the hand in 32 healthy and pain-free participants. OA testing included two trials: (1) a constant trial (30 s of constant heat stimulation at an individualised temperature of Pain50 [pain intensity of 50 out of 100]) and (2) an offset trial (10s of individualised Pain50 , followed by 5s at Pain50 + 1°C and 15 s at Pain50 ). Participants continuously rated their pain during each trial with a computerised visual analogue scale. A significant OA response was recorded at the oral mucosa (p < .001, d=1.24), the cheek (p < .001, d=0.84) and the forearm (p < .001, d=1.04), but not at the palm (p=.19, d=0.24). Significant differences were shown for OA recorded at the cheek versus the mucosa (p=.02), and between palm and mucosa (p=.007), but not between the remaining areas (p > .05). This study suggests that intra-oral endogenous pain inhibition assessed with OA is enhanced and supports the role of peripheral mechanisms contributing to the OA response.

Exploring pain mechanisms in hypermobile Ehlers-Danlos syndrome: A case-control study.

The hypermobile type of Ehlers-Danlos syndrome (hEDS) is a heritable connective tissue disorder, associated with joint hypermobility and prominent chronic pain. Because experimental pain testing in hEDS is scarce, the underlying mechanisms are still poorly understood. The present study assesses endogenous pain facilitation and pain inhibition in hEDS, using a protocol for temporal summation of pain (TSP), conditioned pain modulation (CPM) and exercise-induced hypoalgesia (EIH). Twenty women with hEDS and 20 age-matched healthy controls participated. After evaluating thermal and mechanical pain thresholds (PPT), TSP was assessed using 10 repetitive painful pressure stimuli. CPM was provoked using pressure as the test stimulus and hand immersion in hot water (46°) as the conditioning stimulus. EIH was assessed after a submaximal cycling protocol. The hEDS group demonstrated reduced PPTs and showed significantly more TSP after repeated painful stimuli than the control group. In comparison to the healthy control group, the hEDS group demonstrated significantly less EIH at the quadriceps test location. At the trapezius, EIH did not significantly differ between groups. No significant differences were found between the hEDS group and control group in the CPM response. The results demonstrate increased TSP in hEDS, suggesting increased central pain facilitation. EIH should be studied more extensively but may be disturbed when evaluated in the muscles that are activated during exercise. The CPM results are inconclusive and require more research. Studies regarding the mechanisms that underlie pain in hEDS are scarce, although it is the most prevalent and disabling symptom in this patient population. This study demonstrates increased temporal summation in hEDS and suggests that exercise-induced hypoalgesia may be reduced. Because exercise is a cornerstone in the multidisciplinary treatment of heritable connective tissue disorders, gaining knowledge in this field is important. Pressure stimuli were used to facilitate the international usability of the protocols, allowing for future data acquisition in large cohorts.

Increased Periaqueductal Gray Activation and Pain Unpleasantness in People with Alzheimer's Disease

Pain continues to be underrecognized and undertreated in people with Alzheimer's disease (AD). The periaqueductal gray (PAG) is essential to pain processing and modulation yet is damaged by AD. Evidence exists of altered neural processing of pain in AD, but there has not been a focused investigation of the PAG during pain in people with AD. This study aimed to investigate the role of the PAG in sensory and affective pain processing for people living with AD. Participants from a larger study completed psychophysics and then a perceptually matched heat pain task (warmth, mild, and moderate pain) during a functional MRI scan. In this cross-sectional study, we examined BOLD responses in the PAG and other pain-related regions in participants with AD (n=18) and cognitively intact older adults (age- and sex-matched, n=18) with SPM12. Associations of Percent Signal Change and psychophysics were also examined. There were significant main effects of AD status on the temperature need to reach each perception of warmth or pain. Furthermore, participants with AD rated mild and moderate pain as more unpleasant than controls. PAG BOLD activation was greater in AD relative to controls during warmth and mild pain percepts. No significant differences were found for moderate pain or in other regions of interest. Greater PAG activation during mild pain was associated with higher affective/unpleasantness ratings of mild pain in people with AD but not in controls. Results suggest a role for the PAG in altered pain responses in people with AD. The PAG is the primary source of endogenous opioid pain inhibition in the neuroaxis, thus, altered PAG function in AD suggests possible changes in descending pain inhibitory circuits. Therefore, people with AD may have a greater risk of suffering from pain compared to cognitively intact older adults. Grant support from NIH National Institute on Aging grants of co-author Monroe include K23AG046379 and R21AG045735.

Conditioned Pain Modulation in Children: The Effects of Painful and Nonpainful Conditioning Stimuli

Conditioned pain modulation (CPM), a psychophysical measure in which 1 pain stimulus (conditioning stimulus) is used to inhibit another pain stimulus (test stimulus), is an important indicator of endogenous pain inhibition in adults, but is understudied in children. Preliminary evidence suggests that CPM effects are present in healthy children and are more robust in adolescents. However, developmental differences in younger children are not well documented and few studies control for potential distraction effects of the conditioning stimulus (CS). Participants were 54 healthy children aged 6 to 12 years. After a baseline pressure pain threshold (PPT) test, participants underwent 2 conditioning trials in which PPT was assessed while they placed their left hand in a water bath maintained at either 12 °C (painful CS) or 22 °C (nonpainful sham CS) in counterbalanced order. Results revealed a significant CPM effect. PPT values were significantly higher relative to baseline during the painful CS trial; PPT during the nonpainful CS trial did not differ from baseline. There were no significant age differences in magnitude of CPM effect. The results indicate that children as young as 6 years of age demonstrate CPM, suggesting that descending inhibitory pathways may be better developed in young children than previously thought. PerspectiveThis study was successful in producing inhibitory CPM effects in physically healthy children while controlling for sensory distraction. The findings provide strong evidence that the obtained CPM responses cannot be attributed to sensory distraction or other nonspecific effects. Future studies could utilize CPM paradigms to study various aspects of pediatric endogenous pain inhibition, in order to better predict pain responses and improve interventions.

Reliability of conditioned pain modulation in healthy individuals and chronic pain patients: a systematic review and meta-analysis.

Conditioned pain modulation (CPM) is a psychophysical parameter that is used to reflect the efficacy of endogenous pain inhibition. CPM reliability is important for research and potential clinical applications. The aim of this systematic review and meta-analysis was to evaluate the reliability of CPM tests in healthy individuals and chronic pain patients. We searched three databases for peer-reviewed studies published from inception to October 2020: EMBASE, Web of Science and NCBI. Risk of bias and the quality of the included studies were assessed. A meta-analysis with a random effects model was conducted to estimate intraclass correlation coefficients (ICCs). Meta-analysis was performed on 25 papers that examined healthy participants (k=21) or chronic pain patients (k=4). The highest CPM intra-session reliability was with pressure as test stimulus (TS) and ischemic pressure (IP) or cold pressor test (CPT) as conditioning stimulus (CS) in healthy individuals (ICC 0.64, 95% CI 0.45-0.77), and pressure as TS with CPT as CS in patients (ICC 0.77, 95% CI 0.70-0.82). The highest inter-session ICC was with IP as TS and IP or CPT as CS (ICC 0.51, 95% CI 0.42-0.59) in healthy subjects. The only data available in patients for inter-session reliability were with pressure as TS and CPT as CS (ICC 0.44, 95% CI 0.11-0.69). Quality ranged from very good to excellent using the QACMRR checklist. The majority of the studies (24 out of 25) scored inadequate in Kappa coefficient reporting item of the COSMIN-ROB checklist. Pressure and CPT were the TS and CS most consistently associated with good to excellent intra-session reliability in healthy volunteers and chronic pain patients. The inter-session reliability was fair or less for all modalities, both in healthy volunteers and chronic pain patients.

Are Reports of Pain, Disability, Quality of Life, Psychological Factors, and Central Sensitization Related to Outcomes of Quantitative Sensory Testing in Patients Suffering From Chronic Whiplash Associated Disorders?

Chronic whiplash associated disorders (CWAD) are characterized by long-lasting symptoms of neck pain occurring after an acceleration-deceleration injury. Central sensitization (CS) has been suggested as the possible underlying mechanism for these symptoms, and is characterized by changes in the central nervous system. Besides CS, psychological factors are believed to play an important role in the experience of (chronic) pain. Investigatingthe relationships between self-reported pain, disability, quality of life, psychological factors, and symptoms of CS; and electrical-based quantitative sensory testing (QST) outcomesin CWAD patients. Secondly, to investigate the differences in QST between CWAD patients and pain-free controls. Seventy-two individuals with CWAD and 55 pain-free controls underwent electrical stimuli-based QST. Detection and pain thresholds (EPT), temporal summation (TS), and conditioned pain modulation were examined. Spearman correlation and linear mixed models analyses were performed to assess, respectively, the hypothesized associations and group differences in QST. The Pain Catastrophizing magnification subscale correlated with the left wrist EPT (r=-0.332; P=0.004), and the Pain Anxiety Symptom Scale-20 with the left wrist (r=-0.325; P=0.005) and ankle (r=-0.330; P=0.005) EPT. TS at the ankle correlated with the CS inventory (r=0.303; P=0.010), Short Form 36 pain subscale (r=-0.325; P=0.005), and Illness Perception Questionnaire revised consequences subscale (r=0.325; P=0.005). EPTs left (P=0.011) and right wrist (P=0.023) were lower in the CWAD group, but conditioned pain modulation and TS did not differ between groups. QST outcomes relate to psychological constructs, rather than to self-reported pain intensity and distribution. Local hyperalgesia was found in individuals with CWAD, but no differences in endogenous pain facilitation nor inhibition.

Conditioned Pain Modulation Is Not Impaired in Individuals with Frozen Shoulder: A Case-Control Study.

Frozen shoulder (FS) is a poorly understood condition resulting in substantial shoulder pain and mobility deficits. The mechanisms behind FS are not yet fully understood, but, similar to other persistent pain states, central pain mechanisms may contribute to ongoing symptoms in this population. The objective of this research was to investigate conditioned pain modulation (CPM) in people with FS compared with pain-free individuals. A total of 64 individuals with FS and 64 healthy volunteers participated in this cross-sectional study. CPM was assessed by using the pressure pain threshold (PPT) and an occlusion cuff (tourniquet test) as the test and conditioning stimulus, respectively. The absolute and percentage of change in PPT (CPM effect) as well as pain profiles (pro-nociceptive vs. anti-nociceptive) of individuals with FS and healthy controls were calculated. No significant differences in the absolute change in the PPT or CPM effect were found in people with FS compared to pain-free controls. Moreover, no between-group differences in the percentage of subjects with pro-nociceptive and anti-nociceptive pain profiles were observed. These results suggest that endogenous pain inhibition is normally functioning in people with FS. Altered central pain-processing mechanisms may thus not be a characteristic of this population.

Effect of High-definition Transcranial Direct Current Stimulation on Conditioned Pain Modulation in Healthy Adults: A Crossover Randomized Controlled Trial

The disorder of the conditioned pain modulation (CPM) system is one of the main causes of pain perception in individuals. High-definition transcranial direct current stimulation (HD-tDCS) targeting specific brain areas was indicated to have an analgesic effect possibly by activating the endogenous pain inhibition pathway evident in CPM. However, discrepancies were found in previous limited studies of varied homogeneity and quality. Therefore, the present study applied 2 mA HD-tDCS (20 min) in the left primary motor cortex (M1) among 35 healthy adults with a blinded crossover study design, to investigate its effectiveness on optimizing the analgesic effect in healthy individuals through assessing changes of the CPM. The univariate and multivariate general linear models were used to evaluate the intervention effect between-group on the Δ-value (after-intervention minus before-intervention) during CPM (primary outcome), pressure pain threshold (PPT), and cold pressure threshold (CPT) (secondary outcome), respectively. A significant between-group difference in Δ-CPM was found for active stimulation. HD-tDCS significantly improved the analgesic efficiency of Δ-CPM, compared with the sham control, after adjusting the confounding factors including age, gender, psychological status, as well as the sequence effect. The changes of CPM were positively correlated with the total physical activity volume. In conclusion, our findings provide evidence support to the effectiveness of HD-tDCS on endogenous pain modulation among healthy adults. Further studies are required to explore the analgesic effect of tDCS among patients with chronic pain, thereby facilitating optimal chronic pain management.

Advancing our understanding of neuropathic pain in diabetes mellitus using conditioned pain modulation: further considerations for age and testing site.

Neuropathy is common among individuals with diabetes mellitus, and is associated with decreased quality of life, greater comorbidity, and substantial economic burden. However, the mechanisms underlying painful diabetic polyneuropathy has yet to be fully elucidated. While it is recognized that diabetic polyneuropathy places patients at a greater risk for developing neuropathic pain, it is still not clear why some individuals develop pain and others do not. Similar to other chronic pain conditions, painful diabetic neuropathy is likely driven by alterations in both the peripheral and central nervous system. Experimental conditioned pain modulation paradigms have contributed substantially to our current understanding of chronic pain across various disease states. In a new study, researchers have extended this work by examining the efficiency of conditioned pain modulation in patients with painful and non-painful diabetic polyneuropathy. Surprisingly, the results indicate individuals with painful neuropathy experience greater endogenous pain inhibition, which may seem counterintuitive at first blush. Here, we discuss potential explanations and directions for future research, including consideration for age effects, testing site, and disease type, with the goal of further advancing this important line of research.

Functional and Anatomical Characterization of Corticotropin-Releasing Factor Receptor Subtypes of the Rat Spinal Cord Involved in Somatic Pain Relief

Corticotropin-releasing factor (CRF) orchestrates our body’s response to stressful stimuli. Pain is often stressful and counterbalanced by activation of CRF receptors along the nociceptive pathway, although the involvement of the CRF receptor subtypes 1 and/or 2 (CRF-R1 and CRF-R2, respectively) in CRF-induced analgesia remains controversial. Thus, the aim of the present study was to examine CRF-R1 and CRF-R2 expression within the spinal cord of rats with Freund’s complete adjuvant-induced unilateral inflammation of the hind paw using reverse transcriptase polymerase chain reaction, Western blot, radioligand binding, and immunofluorescence confocal analysis. Moreover, the antinociceptive effects of intrathecal (i.t.) CRF were measured by paw pressure algesiometer and their possible antagonism by selective antagonists for CRF-R1 and/or CRF-R2 as well as for opioid receptors. Our results demonstrated a preference for the expression of CRF-R2 over CRF-R1 mRNA, protein, binding sites and immunoreactivity in the dorsal horn of the rat spinal cord. Consistently, CRF as well as CRF-R2 agonists elicited potent dose-dependent antinociceptive effects which were antagonized by the i.t. CRF-R2 selective antagonist K41498, but not by the CRF-R1 selective antagonist NBI35965. In addition, i.t. applied opioid antagonist naloxone dose-dependently abolished the i.t. CRF- as well as CRF-R2 agonist-elicited inhibition of somatic pain. Importantly, double immunofluorescence confocal microscopy of the spinal dorsal horn showed CRF-R2 on enkephalin (ENK)-containing inhibitory interneurons in close opposition of incoming mu-opioid receptor-immunoreactive nociceptive neurons. CRF-R2 was, however, not seen on pre- or on postsynaptic sensory neurons of the spinal cord. Taken together, these findings suggest that i.t. CRF or CRF-R2 agonists inhibit somatic inflammatory pain predominantly through CRF-R2 receptors located on spinal enkephalinergic inhibitory interneurons which finally results in endogenous opioid-mediated pain inhibition.