Inflammation-induced hyperalgesia: Effects of timing,dosage, and negative affect on somatic pain sensitivity in human experimental endotoxemia

BackgroundInflammation-induced pain amplification and hypersensitivity play a role in the pathophysiology of numerous clinical conditions. Experimental endotoxemia has recently been implemented as model to analyze immune-mediated processes in human pain. In this study, we aimed to analyze dose- and time-dependent effects of lipopolysaccharide (LPS) on clinically-relevant pain models for musculoskeletal and neuropathic pain as well as the interaction among LPS-induced changes in inflammatory markers, pain sensitivity and negative affect.MethodsIn this randomized, double-blind, placebo-controlled study, healthy male subjects received an intravenous injection of either a moderate dose of LPS (0.8 ng/kg Escherichia coli), low-dose LPS (0.4 ng/kg), or saline (placebo control group). Pressure pain thresholds (PPT), mechanical pain sensitivity (MPS), and cold pain sensitivity (CP) were assessed before and 1, 3, and 6 h post injection to assess time-dependent LPS effects on pain sensitivity. Plasma cytokines (TNF-α, IL-6, IL-8, IL-10) and state anxiety were repeatedly measured before, and 1, 2, 3, 4, and 6 h after injection of LPS or placebo.ResultsLPS administration induced a systemic immune activation, reflected by significant increases in cytokine levels, body temperature, and negative mood with pronounced effects to the higher LPS dose. Significant decreases of PPTs were observed only 3 h after injection of the moderate dose of LPS (0.8 ng/kg). MPS and CP were not affected by LPS-induced immune activation. Correlation analyses revealed that decreased PPTs were associated with peak IL-6 increases and negative mood.ConclusionsOur results revealed widespread increases in musculoskeletal pain sensitivity in response to a moderate dose of LPS (0.8 ng/kg), which correlate both with changes in IL-6 and negative mood. These data extend and refine existing knowledge about immune mechanisms mediating hyperalgesia with implications for the pathophysiology of chronic pain and neuropsychiatric conditions.     

Elucidating vulnerability to inflammation-induced hyperalgesia: Predictors of increased musculoskeletal pain sensitivity during experimental endotoxemia

Despite broad clinical implications, the mechanisms linking inflammation and pain remain incompletely understood. Using human experimental endotoxemia as a translational model of systemic inflammation, we aimed to elucidate putative vulnerability factors of inflammation-induced musculoskeletal hyperalgesia.We pooled data from three published randomized controlled trials, resulting in a sample of N = 98 healthy volunteers who received either low-dose endotoxin (lipopolysaccharide) or vehicle (saline) intravenously. As measure of musculoskeletal pain sensitivity, pressure pain thresholds (PPTs) were assessed at baseline and 3 h post injection with a handheld algometer for the low back (erector spinae muscle), calf (gastrocnemius muscle), and shoulder region (deltoid muscle). Implementing multiple regression models, we tested the contribution of putative vulnerability factors on musculoskeletal hyperalgesia during systemic inflammation, including acute changes in pro-inflammatory cytokines, state anxiety and mood, as well as pre-existing symptoms of anxiety and depression.Endotoxin application led to significant increases in plasma cytokines, state anxiety, and negative mood, and significantly decreased PPTs for all muscle groups. Regression models revealed that greater M. erector spinae PPT changes were predicted by higher HADS-anxiety scores. Higher TNF-α concentration emerged as predictor for M. gastrocnemius PPT changes, and more pronounced TNF-α increase and higher HADS-anxiety were predictive for M. deltoideus PPTs. HADS scores emerged as predictor for a mean PPT score (computed across all body sites).Together, our results indicate that musculoskeletal hyperalgesia during systemic inflammation is related to pro-inflammatory cytokines, specifically TNF-α. Importantly, subclinical anxiety symptoms (even though in a low and normal range in this cohort of healthy volunteers) may contribute to inflammation-induced hyperalgesia, making individuals more vulnerable to the detrimental effects of systemic inflammation.     

Neural circuitry mediating inflammation-induced central pain amplification in human experimental endotoxemia

Background & aims: To elucidate the brain mechanisms underlying inflammation-induced visceral hyperalgesia in humans, in this functional magnetic resonance imaging (fMRI) study we tested if intravenous administration of lipopolysaccharide (LPS) involves altered central processing of visceral pain stimuli. Methods: In this randomized, double-blind, placebo-controlled fMRI study, 26 healthy male subjects received either an intravenous injection of low-dose LPS (N = 14, 0.4 ng/kg body weight) or placebo (N = 12, control group). Plasma cytokines (TNF-α, IL-6), body temperature, plasma cortisol and mood were assessed at baseline and up to 6 h post-injection. At baseline and 2 h post-injection (test), rectal pain thresholds and painful rectal distension-induced blood oxygen level-dependent (BOLD) responses in brain regions-of-interest were assessed. To address specificity for visceral pain, BOLD responses to non-painful rectal distensions and painful somatic stimuli (i.e., punctuate mechanical stimulation) were also analyzed as control stimuli. Results: Compared to the control group, LPS-treated subjects demonstrated significant and transient increases in TNF-α, IL-6, body temperature and cortisol, along with impaired mood. In response to LPS, rectal pain thresholds decreased in trend, along with enhanced up-regulation of rectal pain-induced BOLD responses within the posterior insula, dorsolateral prefrontal (DLPFC), anterior midcingulate (aMCC) and somatosensory cortices (all FWE-corrected p < 0.05). Within the LPS group, more pronounced cytokine responses correlated significantly with enhanced rectal pain-induced neural activation in DLPFC and aMCC. No significant LPS effects were observed on neural responses to non-painful rectal distensions or mechanical stimulation. Conclusions: These findings support that peripheral inflammatory processes affect visceral pain thresholds and the central processing of sensory-discriminative aspects of visceral pain.     

Intrinsic functional connectivity of insular cortex and symptoms of sickness during acute experimental inflammation

Task-based fMRI has been used to study the effects of experimental inflammation on the human brain, but it remains unknown whether intrinsic connectivity in the brain at rest changes during a sickness response. Here, we investigated the effect of experimental inflammation on connectivity between areas relevant for monitoring of bodily states, motivation, and subjective symptoms of sickness. In a double-blind randomized controlled experiment, 52 healthy volunteers were injected with 0.6 ng/kg LPS (lipopolysaccharide) or placebo, and participated in a resting state fMRI experiment after approximately 2 h 45 min. Resting state fMRI data were available from 48 participants, of which 28 received LPS and 20 received placebo. Bilateral anterior and bilateral posterior insula sections were used as seed regions and connectivity with bilateral orbitofrontal and cingulate (anterior and middle) cortices was investigated. Back pain, headache and global sickness increased significantly after as compared to before LPS, while a non-significant trend was shown for increased nausea. Compared to placebo, LPS was followed by increased connectivity between left anterior insula and left midcingulate cortex. This connectivity was significantly correlated to increase in back pain after LPS and tended to be related to increased global sickness, but was not related to increased headache or nausea. LPS did not affect the connectivity from other insular seeds. In conclusion, the finding of increased functional connectivity between left anterior insula and middle cingulate cortex suggests a potential neurophysiological mechanism that can be further tested to understand the subjective feeling of malaise and discomfort during a sickness response.     

From models to mechanisms: odorant communication as a key determinant of social behavior in rodents during illness-associated states

Pheromones and other social odor cues convey rich information among rodents. Social investigation is described as a key element in olfactory communication, which involves motivated approaches to conspecifics and other socially relevant stimuli. This behavior is activated by the detection of social cues to gather information about conspecifics for subsequent strategies such as avoidance or further approach, thereby determining the extent and nature of physical contact that ensues. This feature indicates a useful way for describing the process of social communication in distance-based manner. In particular, airborne odorant signals in rodent species guide social investigation at a distance, and provide information regarding the health status of the odor donors. In this review, we will address the role of the inflammatory response in the release of odor cues that involve information about several illness-associated conditions (bacterial or parasitic infection, stressor exposure, etc.). We will provide an overview of how sex and developmental epoch in odor donors serve as predictors of subsequent social behavior. We conclude that inflammatory processes have a profound impact on social behavior through a direct effect on the sick individual (i.e., reduced motivation to engage in social interaction), while the release of illness-related, aversive odor cues from the sick individual serves to inhibit social investigation by healthy conspecifics. Together, this dual impact of acute illness is thought to minimize disease transmission across individuals and promote healthy group living.     

Negative affectivity predicts decreased pain tolerance during low-grade inflammation in healthy women

Introduction: Experimental animal studies provided evidence for a synergistic effect of immunological and psychological stressors on subsequent sickness behaviours. Up to now, little corroborating evidence for such synergy exists for humans, in whom it may provide a mechanism leading to the expression of functional somatic symptoms. The aim of the present study was to determine an interaction between stress(-vulnerability) and an immunological activation on experimental pain sensitivity, i.e., pressure pain threshold and tolerance in healthy humans. Methods: In healthy female participants (n = 25, mean age 22.3 years), negative affectivity (NA) and experienced stress were assessed by questionnaire before receiving a Salmonella typhi vaccine or saline control in a randomized blinded cross-over design. Pressure pain threshold was assessed at the lower back and calves and pain tolerance was assessed at the thumbnail, before and six hours after each injection. Results: Vaccination induced leukocytosis (+100%) and increased serum IL-6 (+670%). NA predicted decreased pain tolerance after vaccination (β = −.57, p = .007), but not after placebo (β = .25, p = .26). Post-hoc analyses also demonstrated an association with administration order. Discussion: NA moderated the effects of inflammation on pain tolerance. This finding is consistent with a synergistic model whereby inflammation may lower the threshold for pain reporting in individuals with increased vulnerability for somatic symptom reporting.     

Increased muscular and cutaneous pain sensitivity in cephalic region in patients with chronic tension-type headache

Increased excitability of the central nervous system generated by repetitive and sustained pericranial myofascial nociception may be responsible for transformation of episodic tension-type headache into chronic form. We aimed to compare mechanical and electrical (intramuscular and cutaneous) pain thresholds in trapezius and anterior tibial regions between 20 patients with chronic tension type headache and 20 healthy controls. Pain thresholds to three types of electrical stimulation (single pulse, 2 and 100 Hz) were significantly lower in patients than in controls in trapezius muscle (P < 0.02) and in skin overlying the trapezius muscle (P < 0.05), whilst electrical pain thresholds did not differ between groups in anterior tibial muscle and skin. Quantitative sensory testing revealed increased pain sensitivity in patients as assessed by pressure-controlled manual palpation (local tenderness score, LTS; P < 0.01) and by pressure algometry (mechanical pain thresholds; P < 0.05) in test areas over the trapezius muscle, but not the anterior tibial muscle. In summary, this study demonstrates lower pain thresholds in muscle and skin of the cephalic region but not in lower limb muscle and skin in patients with chronic tension-type headache than in healthy controls. Increased sensitivity in nociceptive pathways from cephalic region may be of importance in the pathophysiology of chronic tension type headache.     

Men and women differ in inflammatory and neuroendocrine responses to endotoxin but not in the severity of sickness symptoms

Impaired mood and increased anxiety represent core symptoms of sickness behavior that are thought to be mediated by pro-inflammatory cytokines. Moreover, excessive inflammation seems to be implicated in the development of mood/affective disorders. Although women are known to mount stronger pro-inflammatory responses during infections and are at higher risk to develop depressive and anxiety disorders compared to men, experimental studies on sex differences in sickness symptoms are scarce. Thus, the present study aimed at comparing physiological and psychological responses to endotoxin administration between men and women. Twenty-eight healthy volunteers (14 men, 14 women) were intravenously injected with a low dose (0.4 ng/kg) of lipopolysaccharide (LPS) and plasma concentrations of cytokines and neuroendocrine factors as well as negative state emotions were measured before and until six hours after LPS administration. Women exhibited a more profound pro-inflammatory response with significantly higher increases in tumor necrosis factor (TNF)-α and interleukin (IL)-6. In contrast, the LPS-induced increase in anti-inflammatory IL-10 was significantly higher in men. The cytokine alterations were accompanied by changes in neuroendocrine factors known to be involved in inflammation regulation. Endotoxin injection induced a significant increase in noradrenaline, without evidence for sex differences. The LPS-induced increase in cortisol was significantly higher in woman, whereas changes in dehydroepiandrosterone were largely comparable. LPS administration also increased secretion of prolactin, but only in women. Despite these profound sex differences in inflammatory and neuroendocrine responses, men and women did not differ in endotoxin-induced alterations in mood and state anxiety or non-specific sickness symptoms. This suggests that compensatory mechanisms exist that counteract the more pronounced inflammatory response in women, preventing an exaggerated sickness response. Disturbance of these compensatory mechanisms by environmental factors such as stress may promote the development of affective disorders in women.     

Autonomic cardiovascular control and responses to experimental pain stimulation in fibromyalgia syndrome

Objective

This study involves a comprehensive investigation of autonomic cardiovascular regulation in fibromyalgia syndrome (FMS) at rest and during painful stimulation and its association with pain indices.

Methods

In 35 patients and 29 healthy controls, electrocardiography, impedance cardiography, and finger continuous blood pressure measurements were conducted. For the purpose of experimental pain induction, a cold pressor test was applied.

Results

FMS patients showed lower pain threshold and tolerance, as well as higher ratings of pain intensity and unpleasantness on visual analogue scales. Resting stroke volume, myocardial contractility, R-R interval, heart rate variability, and sensitivity of the cardiac baroreflex were reduced in the patients, and increases in stroke volume and myocardial contractility during cold pressor stimulation were less pronounced. In the whole sample as well as in the FMS group, baroreflex sensitivity was inversely associated with subjective pain intensity, and a higher number of baroreflex operations per unit of time predicted higher pain tolerance.

Conclusions

The data suggest impaired autonomic cardiovascular regulation in FMS in terms of reduced sympathetic and parasympathetic influences, as well as blunted sympathetic reactivity to acute stress. The association between baroreflex function and pain experience reflects the pain inhibition mediated by the baroreceptor system. Given the reduced baroreflex sensitivity in FMS, one may assume deficient ascending pain inhibition arising from the cardiovascular system, which may contribute to the exaggerated pain sensitivity of FMS.     

Strain and sex differences in the expression of nociceptive behavior and stress-induced analgesia in rats

Evidence indicates that genetic, gender, and emotional/attentional aspects modulate the pain sensation. The present study examined the effect of swim-stress on nociceptive responses in Lewis (LEW) and spontaneously hypertensive (SHR) inbred rats (contrasting for anxiety-related behaviors), as well as in Wistar (WIS) rats of both sexes. Furthermore, we explored possible neurochemical mechanisms involved. In addition, we investigated whether habituation in the hot-plate apparatus could modify the hypoalgesic phenotype of SHR. Male and female LEW, SHR, and WIS rats were tested immediately before and 2 min after a 3-min swim in 15 degrees C water. The swim-stress induced analgesia in LEW and WIS, but not in SHR male rats. The same stressor induced analgesia in females of all three strains. In WIS female rats, the stress-induced analgesia (SIA) seems to involve, at least partially, a nonopioid N-methyl-d-aspartate (NMDA) analgesic system. Moreover, five brief exposures (90 s; 10-min intertrial interval) to the unheated hot-plate apparatus completely abolished the differences in basal hot-plate latencies observed in SHR compared with LEW and WIS strains. The present results demonstrate genetic and gender differences in nociceptive sensitivity and in the activation of endogenous analgesic systems in rats and highlight the influence of emotional reactivity. The SHR's hypoalgesic phenotype seems to involve central cognitive processes. Therefore, the LEW and SHR inbred strains may provide an important tool for study of the molecular bases underlying nociception and its modulation and the relationship with emotional/attentional processes.     

Alexithymia and anxiety sensitivity in patients with non-cardiac chest pain

The aim of this study was to examine independent and combined influences of alexithymia and anxiety sensitivity on chest pain and life interference in patients with non-cardiac chest pain (NCCP). Theories of NCCP posit a central role for emotion in the experience of chest pain, however, studies have not examined how alexithymia characterized by a difficulty identifying or verbalizing emotions, may influence this relationship. This study examined 231 patients (56% females, M age = 50 years) with chest pain seeking cardiac evaluation, who showed no abnormalities during exercise tolerance testing. Forty percent (40%) scored at or above the moderate range of alexithymia. Whereas health care utilization was associated with elevated alexithymia among men, health care utilization was associated with elevated anxiety sensitivity among women. Hierarchical regression analyses revealed that alexithymia and anxiety sensitivity were both uniquely and independently associated with pain severity and life interference due to pain. Alexithymia-pain links were stronger for men compared to women. Secondary analyses conducted with a subsample suggest that alexithymia may be increasingly stable over time (i.e., 18-month follow-up). Findings are largely congruent with theoretical models of NCCP showing that personality and emotional factors are important in this medically unexplained syndrome.     

Immunological and behavioral responses to in vivo lipopolysaccharide administration in young and healthy obese and normal-weight humans

Obesity is associated with an increase prevalence of neuropsychiatric symptoms and diseases, such as depression. Based on the facts that pro-inflammatory cytokines are able to modulate behavior, and that obesity is characterized by a chronic low-grade inflammatory state, inflammation has been hypothesized to contribute to the neuropsychiatric comorbidity in obese individuals. However, a causal link between inflammation and the development of neuropsychiatric symptoms is hard to establish in humans. Here, we used an inflammatory stimulus, i.e. the intravenous injection of lipopolysaccharide (LPS), in a double-blind placebo-controlled design, to determine the vulnerability of obese individuals to inflammation-induced behavioral changes. The hypothesis was that obese individuals would show heightened behavioral response compared to normal-weight subjects for the same inflammatory stimulus, reflecting an increased sensitivity to the behavioral effects of pro-inflammatory cytokines. LPS (dose 0.8 ng/kg body weight, adjusted for estimated blood volume in obese subjects) and placebo (saline) were intravenously injected in 14 obese healthy subjects and 23 normal-weight healthy subjects in a within-subject, randomized, crossover design. LPS administration induced, in both groups, an acute increase in blood concentrations of cytokines (interleukin-6, tumor necrosis factor-α, and IL-10), as well as in body temperature, cortisol, norepinephrine, sickness symptoms, fatigue, negative mood, and state anxiety. There were little differences in the immune and behavioral responses to LPS between obese and normal-weight subjects, but the cortisol response to LPS was strongly attenuated in obese individuals. Higher percentage of body fat was related to a lower cortisol response to LPS. Taken together, the population of young and healthy obese individuals in this study did not exhibit an increased behavioral sensitivity to cytokines, but an attenuated cortisol response to the immune challenge. Future studies will need to determine whether additional physiological and psychological factors interact with the state of obesity to increase the risk for inflammation-induced neuropsychiatric symptoms.     

Alexithymia in fibromyalgia syndrome: Associations with ongoing pain, experimental pain sensitivity and illness behavior

Objective

Alexithymia, a lack of emotional awareness, is common in chronic pain patients. The aim of the study was to investigate the relationship of alexithymia to ongoing pain, experimental pain sensitivity, and illness behavior in patients with chronic musculoskeletal pain.

Methods

Sixty-eight women with fibromyalgia (age: average, 43.4 years; range, 19-72 years) completed self-report measures on alexithymia (20-Item Toronto Alexithymia Scale), ongoing pain [Visual Analogue Scale, Questionario Italiano del Dolore (QUID), Margolis], psychological distress (Center for Epidemiology Studies—Depression Scale, State-Trait Anxiety Inventory Form Y), and illness behavior (Illness Behavior Questionnaire). Psychophysical tests were performed to assess experimental pain sensitivity, including pain thresholds for mechanical (von Frey, tender point count) and thermal (heat, cold) stimuli, and cold pressor pain threshold and tolerance.

Results

Alexithymia “difficulty identifying feelings” (DIF) was related to higher ratings of the affective—but not the sensory—dimensions of ongoing pain (QUID) and to a lower cold pressor pain tolerance, while alexithymia scores were independent of all pain thresholds. Multiple regression demonstrated that alexithymia DIF ceased to uniquely predict affective ongoing pain when psychological distress or illness behavior was separately controlled for. Higher alexithymia DIF scores were predictive of hypochondriacal illness behavior, over and above what was explained by psychological distress and affective pain.

Conclusion

Alexithymia is associated with increased affective pain and hypochondriacal illness behavior. The former relationship is better explained, and possibly mediated, by psychological distress and illness behavior. The hypothesis of a generally increased sensitivity to unpleasant stimuli in alexithymic chronic pain patients is not supported by the data.     

Age differences in nociception and pain behaviours in the rat

Much remains to be learned about the effects of ageing on pain. Studies of life-span changes in nociception and pain behaviours in the rat are equivocal making it difficult to draw firm conclusions. This paper reviews the available data and finds that age differences in nociception may be dependent on the pain test employed. Specifically, reflexive responses to nociceptive stimuli do not change with age while there may be no change or a linear decrease with age on more highly organized tests of nociception. Interestingly, age differences in pain behaviours on models of tissue injury and inflammation may not be linear. It is shown that important changes that begin at mid-life in neuroanatomy, neurochemistry and endogenous pain inhibition may be associated with alterations in pain sensitivity. Several testable hypotheses which might encourage future research in this domain are developed throughout this paper.     

Preoperative inflammatory biomarkers and neurovegetative symptoms in peritoneal carcinomatosis patients

BackgroundInflammation plays a central role in peritoneal carcinomatosis (PC) etiology and progression, and circulating levels of inflammatory biomarkers prior to surgery predict progression-free and overall survival in PC patients. Depression and fatigue are prevalent among PC patients, and experimental research shows that these symptoms may be mediated by proinflammatory cytokines. As yet unstudied is the possibility that the heightened levels of inflammatory markers in PC patients may contribute to their experience of common neurovegetative symptoms.MethodsValidated self-report measures of fatigue, depressive symptoms, and quality of life were administered to 64 patients scheduled to undergo aggressive surgical treatment for PC. Serum samples were collected the morning of surgery, and ELISAs were conducted to quantify circulating IL-6, CRP, and TNF-α levels.ResultsConsistent with hypotheses, higher IL-6 levels were associated with more severe fatigue (β = −.39, p < .01) and neurovegetative symptoms of depression (β = .30, p < .05). IL-6 was also related to poorer physical quality of life (β = −.28, p < .05). CRP showed similar significant relationships with fatigue and physical quality of life. Inflammatory biomarkers were not significantly related to emotional symptoms of depression or to emotional or social functioning aspects of quality of life, and TNF-α levels were not related to patient-reported measures.ConclusionPreoperative inflammatory activity may contribute to patients’ experiences of fatigue and neurovegetative depressive symptoms as well as impaired quality of life. These biological mechanisms warrant consideration in the clinical management of neurovegetative symptoms in PC patients.     

Evidence for an association between an enhanced reactivity of interleukin-6 levels and reduced glucocorticoid sensitivity in patients with fibromyalgia

Pain and fatigue have been identified as core symptoms of fibromyalgia syndrome (FMS). Since both symptoms are also characteristic of hypocortisolemic disorders, reduced cortisol levels have been thought to promote an exacerbation of these FMS core symptoms by an enhanced reactivity of interleukin-6 (IL-6) levels. The aim of the current study was to investigate the pathophysiologic relevance of reduced cortisol levels for manifestation of FMS core symptoms. Twelve female FMS patients with 15 female controls were compared regarding the function of hypothalamus-pituitary-adrenal (HPA) axis and behavioral, endocrine and IL-6 responses after measuring the pressure pain thresholds (PPTs) at tender points. Function of HPA axis was assessed by determining the cortisol awakening response, daytime profile of cortisol secretion, low dose overnight dexamethasone suppression test (DST) and glucocorticoid sensitivity (GC) of inflammatory cytokine production. While endocrine and IL-6 responses were determined by collecting blood and saliva samples behavioral responses were assessed by pain and fatigue recordings of participants before and after PPT measurement using visual analogue scale (VAS). Whereas FMS patients were found not to differ from controls in cortisol awakening response, daytime profile of cortisol secretion and cortisol suppression after overnight DST, they did exhibit a reduced GC sensitivity of inflammatory cytokine production. PPT measurement did induce three times higher cortisol and four times higher IL-6 levels in FMS patients, but no change in their ACTH levels. The enhanced IL-6 reactivity after PPT measurement was accompanied by an increase in the severity of FMS patients' pain and fatigue ratings. The findings of the present study provide evidence for the pathophysiologic relevance of a disturbed glucocorticoid receptor (GR) function, rather than reduced cortisol levels for the maintenance of FMS core symptoms.     

Feasibility and efficacy of remotely supervised cranial electrical stimulation for pain in older adults with knee osteoarthritis: A randomized controlled pilot study

Cranial electrical stimulation (CES) is a noninvasive brain stimulation technique that has been shown to improve pain. However, few studies have investigated the potential benefits associated with remotely supervised CES in older adults with knee osteoarthritis (OA). The aim of this study was to examine the feasibility and preliminary efficacy of remotely supervised CES via secure videoconferencing software on clinical pain severity, experimental pain sensitivity, and pain-related cortical response in older adults with knee OA. Thirty participants with symptomatic knee OA pain were randomly assigned to receive 10 daily sessions (60 min each) of remotely supervised CES (n = 15) or sham CES (n = 15) over two weeks. We measured clinical pain severity via a Numeric Rating Scale, experimental pain sensitivity (e.g., heat pain sensitivity, pressure pain sensitivity, and conditioned pain modulation) using quantitative sensory testing, and pain-related cortical response via functional near-infrared spectroscopy imaging. We also measured participant satisfaction with treatment using the Client Satisfaction Questionnaire. Active CES significantly reduced scores on the Numeric Rating Scale and increased heat pain threshold, pressure pain thresholds, and conditioned pain modulation. We also found significant changes in pain-related cortical hemodynamic activity after CES. Participants tolerated CES well without serious adverse effects and were satisfied with the treatment. Our findings demonstrate promising clinical efficacy of remotely supervised CES for older adults with knee OA.     

Altered cytokine levels in the blood and cerebrospinal fluid of chronic pain patients

This study replicates and extends prior reports of abnormal cytokine levels in chronic pain patients and has correlated the alterations with pain severity. In addition, there appeared to be a need to directly assess cerebrospinal fluid (CSF) because previous findings on cytokine concentrations in peripheral circulation have been inconsistent. CSF and blood specimens were obtained from 14 patients with distal painful non-diabetic polyneuropathy (DPPN) or post-traumatic neuralgia (PTN). Elevated receptor levels for Tumor Necrosis Factor (sTNFr) were the most distinctive abnormality along with low interleukin-10 (IL-10). sTNFr in CSF and blood, and IL-1ß in CSF, were positively associated with pain intensity, whereas IL-10 in both compartments was inversely correlated with pain symptoms. An imbalance of pro- and anti-inflammatory cytokines appears to be a clinically relevant feature, which may contribute to the maintenance of chronic pain.