Osteoarthritis patients exhibit an autonomic dysfunction with indirect sympathetic dominance.

BACKGROUND: Osteoarthritis (OA) is a chronic degenerative joint disease causing limited mobility and pain, with no curative treatment available. Recent in vivo studies suggested autonomic alterations during OA progression in patients, yet clinical evidence is scarce. Therefore, autonomic tone was analyzed in OA patients via heart rate variability (HRV) measurements. METHODS: Time-domain (SDRR, RMSSD, pRR50) and frequency-domain (LF, HF, LF/HF) HRV indices were determined to quantify sympathetic and parasympathetic activities. In addition, perceived stress, WOMAC pain as well as serum catecholamines, cortisol and dehydroepiandrosterone-sulphate (DHEA-S) were analyzed. The impact of the grade of disease (GoD) was evaluated by linear regression analysis and correlations with clinical data were performed. RESULTS: GoD significantly impacted the autonomic tone in OA patients. All time-domain parameters reflected slightly decreased HRV in early OA patients and significantly reduced HRV in late OA patients. Moreover, frequency-domain analysis revealed decreased HF and LF power in all OA patients, reflecting diminished parasympathetic and sympathetic activities. However, LF/HF ratio was significantly higher in early OA patients compared to late OA patients and implied a clear sympathetic dominance. Furthermore, OA patients perceived significantly higher chronic stress and WOMAC pain levels compared to healthy controls. Serum cortisol and cortisol/DHEA-S ratio significantly increased with GoD and positively correlated with WOMAC pain. In contrast, serum catecholamines only trended to increase with GoD and pain level. CONCLUSIONS: This prospective study provides compelling evidence of an autonomic dysfunction with indirect sympathetic dominance in early and late knee OA patients for the first time based on HRV analyses and further confirmed by serum stress hormone measurements. Increased sympathetic activity and chronic low-grade inflammation in OA as well as in its major comorbidities reinforce each other and might therefore create a vicious cycle. The observed autonomic alterations coupled with increased stress and pain levels highlight the potential of HRV as a prognostic marker. In addition, modulation of autonomic activity represents an attractive future therapeutic option.

Lower plasma melatonin levels in non-hypoxic premature newborns associated with neonatal pain.

We analyzed plasma melatonin levels in different groups of preterm newborns without hypoxia and their relationship with several perinatal variables like gestational age or neonatal pain. Prospective cohort study of preterm newborns (PTNB) without perinatal hypoxia, Apgar > 6 at 5 min, and oxygen needs on the third day of life. We compared melatonin levels at day 3 of life in different groups of non-hypoxic preterm infants (Student's t-tests, Mann-Whitney U, and chi2) and analyzed the relationship of melatonin with GA, birth weight, neonatal pain (Premature Infant Pain Profile (PIPP) scale), caffeine treatment, parenteral nutrition, or the development of free radical diseases (correlation study, linear regression) and factors associated with moderate/intense pain and free radical diseases (logistic regression analysis). Sixty-one preterm infants with gestational age (GA) of 30.7 ± 2.0 weeks with no oxygen requirements at day 3 of life were studied with plasma melatonin levels of 33.8 ± 12.01 pg/ml. Preterm infants weighing < 1250 g at birth had lower plasma melatonin levels (p = 0.05). Preterm infants with moderate or severe pain (PPIPP > 5) have lower melatonin levels (p = 0.01), and being preterm with PIPP > 5 is associated with lower plasma melatonin levels (p = 0.03). Being very preterm (GA < 32 GS), having low weight for gestational age (LWGA), receiving caffeine treatment, or requiring parenteral nutrition did not modify melatonin levels in non-hypoxic preterm infants (p = NS). Melatonin on day 3 of life in non-hypoxic preterm infants is not associated with later development of free radical diseases (BPD, sepsis, ROP, HIV, NEC). CONCLUSION: We observed that preterm infants with moderate to severe pain have lower melatonin levels. These findings are relevant because they reinforce the findings of other authors that melatonin supplementation decreases pain and oxidative stress in painful procedures in premature infants. Further studies are needed to evaluate whether melatonin could be used as an analgesic in painful procedures in preterm infants. TRIAL REGISTRATION: Trial registration was not required since this was an observational study. WHAT IS KNOWN: • Melatonin is a potent antioxidant and free radical scavenger in newborns under stress conditions: hypoxia, acidosis, hypotension, painful procedures, or parenteral nutrition. • Pain stimulates the production of melatonin. • Various studies conclude that melatonin administration decreases pain during the neonatal period. WHAT IS NEW: • Non-hypoxic preterm infants with moderate to severe pain (PIPP>5) have lower levels of melatonin. • Administration of caffeine and treatment with parenteral nutrition do not modify melatonin levels in non-hypoxic preterm infants.

Data-driven dynamic profiles of tonic heat pain perception in pain-free volunteers are associated with differences in anandamide levels.

Our laboratory previously developed a method for assessing experimentally induced pain perception through a 2-min constant heat pain stimulation. However, the traditional analysis relying on group means struggles to interpret the considerable inter-individual variability due to the dynamic nature of the response. Recently, trajectory analysis techniques based on extended mixed models have emerged, providing insights into distinct response profiles. Notably, these methods have never been applied to pain paradigms before. Furthermore, various socio-demographic and neurobiological factors, including endocannabinoids, may account for these inter-individual differences. This study aims to apply the novel analysis to dynamic pain responses and investigate variations in response profiles concerning socio-demographic, psychological, and blood endocannabinoid concentrations. 346 pain-free participants were enrolled in a psychophysical test involving a continuous painful heat stimulation lasting for 2 min at a moderate intensity. Pain perception was continuously recorded using a computerized visual scale. Dynamic pain response analyses were conducted using the innovative extended mixed model approach. In contrast to the traditional group-mean analysis, the extended mixed model revealed three pain response trajectories. Trajectory 1 is characterized by a delay peak pain. Trajectory 2 is equivalent to the classic approach (peak pain follow by a constant and moderate increase of pain perception). Trajectory 3 is characterized by extreme responses (steep peak pain, decrease, and increase of pain perception), Furthermore, age and blood anandamide levels exhibited significant variations among these three trajectories. Using an innovative statistical approach, we found that a large proportion of our sample had a response significantly different from the average expected response. Endocannabinoid system seems to play a role in pain response profile.

Different pain phenotypes are associated with anti-Caspr2 autoantibodies.

Autoantibodies against contactin-associated protein 2 (Caspr2) not only induce limbic autoimmune encephalitis but are also associated with pain conditions. Here, we analyzed clinical data on pain in a large cohort of patients included into the German Network for Research in Autoimmune Encephalitis. Out of 102 patients in our cohort, pain was a frequent symptom (36% of all patients), often severe (63.6% of the patients with pain) and/or even the major symptom (55.6% of the patients with pain). Pain phenotypes differed between patients. Cluster analysis revealed two major phenotypes including mostly distal-symmetric burning pain and widespread pain with myalgia and cramps. Almost all patients had IgG4 autoantibodies and some additional IgG1, 2, and/or 3 autoantibodies, but IgG subclasses, titers, and presence or absence of intrathecal synthesis were not associated with the occurrence of pain. However, certain pre-existing risk factors for chronic pain like diabetes mellitus, peripheral neuropathy, or preexisting chronic back pain tended to occur more frequently in patients with anti-Caspr2 autoantibodies and pain. Our data show that pain is a relevant symptom in patients with anti-Caspr2 autoantibodies and support the idea of decreased algesic thresholds leading to pain. Testing for anti-Caspr2 autoantibodies needs to be considered in patients with various pain phenotypes.

Plasmatic adipocyte biomarkers and foot pain associated with flatfoot in schoolchildren with obesity

SUMMARY OBJECTIVE The aim of this study was to determine the potential association of foot pain and plasmatic adipocytes as physiological biomarkers of childhood obesity with the incidence of flatfoot in a cohort of Egyptian school children aged 6 -12 years. METHODS A total of 550 Egyptian schoolchildren (220 boys and 330 girls) aged 6-12 years were randomly invited to participate in this descriptive survey analysis. For all children, we assessed the diagnosis and severity of flatfoot as well as plasma adipocytes, as well as adiponectin, leptin, resistin, IL-6, and TNF-α, using the Dennis method and immunoassay techniques respectively. Foot pain was assessed by using a standard VAS of 100 mm and Faces Pain Scale, respectively. RESULTS Flat foot was predicted in 30.4% of school-age children, most of them showed a higher frequency of overweight (33.3%) and obesity (62.5%). Boys showed higher ranges of flat foot than girls. Foot pain significantly correlated with flat foot and obesity among the studied populations. In overweight-obese children, plasmatic adipocyte variables, as well as adiponectin, leptin, resistin, IL-6, TNF-α.; showed significant correlations with foot stance, especially in boys. Also, the studied adipocyte variables along with BMI, age, gender explained about~65% of the variance of flatfoot with pain among our school-age students. CONCLUSION Foot pain showed an association with flat foot and childhood obesity in 30.4% of school-age students (6-12 years). Foot pain was shown to correlate positively with the incidence of flat foot and changes in adiposity markers, as well as adiponectin, leptin, resistin, Il-6, TNF-α

RESUMO OBJETIVO O objetivo deste estudo foi determinar a potencial associação de dor no pé e adipócitos plasmáticos como biomarcadores fisiológicos da obesidade infantil com incidência de pé plano em uma coorte de escolares egípcios de 6 a 12 anos. MÉTODOS Um total de 550 escolares egípcios (220 meninos e 330 meninas) com idades entre 6 e 12 anos foram convidados aleatoriamente para participar desta análise descritiva. Para todas as crianças, diagnóstico e gravidade do flatfoot, bem como adipócitos plasmáticos; adiponectina, leptina, resistina, IL-6 e TNF-α; foram avaliados pelo método de Dennis e técnicas de imunoensaio, respectivamente. A dor no pé foi avaliada usando uma EVA padrão de 100 mm e a Faces Pain Scale, respectivamente. RESULTADOS O pé plano foi predito em 30,4% das crianças em idade escolar; a maioria apresentou maior frequência de sobrepeso (33,3%) e obesidade (62,5%). Os meninos apresentaram maiores faixas de pé plano do que as meninas. A dor no pé correlacionou-se significativamente com pé plano e obesidade entre as populações estudadas. Em crianças obesas com sobrepeso, variáveis adipocitárias plasmáticas; adiponectina, leptina, resistina, IL-6 e TNF-α; apresentaram correlação significativa com a postura do pé, em meninos e meninas. Além disso, as variáveis estudadas dos adipócitos, juntamente com o IMC, idade e sexo, explicaram cerca de 65% da variância do pé plano com a dor entre os nossos alunos em idade escolar. CONCLUSÃO A dor no pé mostrou associação com pé plano e obesidade infantil em 30,4% dos estudantes em idade escolar (6-12 anos). A dor no pé se correlacionou positivamente com a incidência de pé plano e a mudança nos marcadores de adiposidade; adiponectina, leptina, resistina, IL-6, TNF-α.

Método óptimo para la obtención de plasma rico en plaquetas en el Servicio de Clínica del Dolor del CMN 20 de noviembre ISSSTE / Optimal method to obtain platelet-rich plasma at the Pain Management Clinic of the NMC 20 de noviembre ISSSTE

Objetivos: Describir el método óptimo para obtener plasma rico en plaquetas (PRP). Material y métodos: Previo consentimiento informado, se obtuvieron de 36 pacientes sanos una muestra sanguínea de 15 ml distribuidos en 5 tubos estériles: uno para obtención de biometría hemática y el resto se sometieron a alguno de los 3 protocolos para obtención de plasma rico en plaquetas. Protocolo 1 (n = 21): 1200 rpm/2 ciclos/8 minutos (cada ciclo); protocolo 2 (n = 8): 1200 rpm/1 ciclo de centrifugado/8 minutos. Protocolo 3 (n = 7): 1200 rpm/1 ciclo de centrifugado/10 minutos. De las muestras obtenidas, se analizó 1 ml de plasma mediante citómetro de flujo automatizado (BD FACSCanto II) y se determinó el rendimiento plaquetario mediante la fórmula: recuento de plaquetas PRP (100)/recuento de plaquetas de sangre total. El método estadístico empleado fue medidas de tendencia central, Chi cuadrado, t de Student, análisis de varianza, prueba de Wilcoxon y probabilidad de Kruskal-Wallis. Resultados: El promedio de concentración basal plaquetaria fue de 261.2 miles/mcl para los 3 métodos (p = 0.906). Después del proceso de centrifugado para protocolo 1 fue 662.3 ± 243.3 (p = 0.001); protocolo 2, 377.9 ± 101.4 (p = 0.008) y 30.9 ± 18.8 (p = 0.016) para el 3. El rendimiento fue: 255.2 ± 57.6 %; 149.3 ± 24.6 %; 13.3 ± 11.6 %, respectivamente. Conclusión: Se logró obtener PRP aplicando el primer protocolo (1200 rpm/2 ciclos/8 minutos cada ciclo). El estudio se realizó en pacientes adultos sanos, sin embargo, se tendrán que realizar estudios posteriores con una mayor población para comprobar la efectividad de este método. En caso de que la obtención plaquetaria en estudios con mayor población sea la adecuada, deberá validarse su utilidad clínica en paciente con enfermedades crónico degenerativas y se tomen en cuenta las enfermedades concomitantes (AU)

Objective: To determine the optimal method to collect platelet- rich plasma (PRP). Material and methods: We collected 15 ml of blood from 36 healthy adults to determine platelet count and to test which of the following three protocols were the best to collect PRP. We used 3 ml of blood for each method: protocol 1: (n = 21) the blood tube was tested at 1200 revolutions per minute (RPM) in 2 centrifuge cycles of 8 minutes each; protocol 2 (n = 8): 1200 RPM/1 cycle/8 minutes, and protocol 3: (n = 7): 1200 RPM/1 cycle/10 minutes. From the blood samples that we collected, we also analyzed 1 ml of plasma to determine platelet performance by using an automatic flow cytometer (BD FACSCanto II). Platelet performance was determined by the following formula: platelet PRP count (100)/platelet count from total blood. The statistical method used were measures of central tendency, Chi-square, t-test, analysis of variance and the Wilcoxon and Kruskal-Wallis tests. Results: The basal overall count of platelet was 261.2 miles/ mcl for the three methods (p = 0.906), 662.3 ± 243.3 (p = 0.001) for protocol 1; 377.9 ± 101.4 (p = 0.008) for protocol 2 and 30.9 ± 18.8 (p = 0.016) for protocol 3. Platelet performances were 255.2 ± 57.6 %; 149.3 ± 24.6 %; 13.3 ± 11.6 % respectively. Conclusion: Applying the first protocol we obtain PRP (1200 RPM/2 cycles of 8 minutes each). This study was done in healthy adults; however, future studies with a larger sample size are needed to confirm our findings of this method. In case of collecting platelets in studies with greater population being the adequate, its clinical utility should be validated by including patients with chronic and degenerative diseases and take care of associated diseases (AU)

Effect of high-voltage electrical stimulation on the albumin and histamine serum concentrations, edema, and pain in acute joint inflammation of rats

BACKGROUND: The mechanism by which high-voltage electrical stimulation (HVPC) acts on edema reduction is unknown. OBJECTIVE: To assess the effect of HVPC with negative polarity (-) applied to the ankle of rats with acute joint inflammation. METHOD: Sixty-four rats were divided into four groups (n=16): inflamed+HVPC(-), 0.03 mL application of ι-carrageenan (3%) to the tibiotarsal joint plus HVPC(-); inflamed+HVPC placebo, carrageenan application and HVPC placebo; normal+HVPC(-), HVPC application(-); and normal control, no intervention. The HVPC(-) 100 Hz at a submotor level was applied daily for 45 min on three consecutive days. The variables were pain, hind-foot volume, and serum histamine and albumin assessed before and during the 48 hours following inflammation. The variables were compared using the t test, one-way ANOVA, nested ANOVA for repeated measures, and the post hoc Bonferroni test. Analysis of covariance was applied to adjust the effects of HVPC(-) by measurements of pain, inflammation, albumin, and histamine at 24 h, and the final weight was compared to the other groups. The significance level was set at p<0.05. RESULTS: There were no differences between the inflamed+HVPC(-) and inflamed+HVPC placebo groups in terms of pain or edema (p>0.05). Albumin was reduced in the groups that received the intervention, but there was no differences between them. There was only a 24 hour increase in histamine with the normal+HVPC(-) (p=0.0001) and inflamed+HVPC placebo groups (p=0.01) compared to the normal control group. CONCLUSIONS: The results of the present study suggest that HVPC(-) with the parameters employed did not reduce pain or edema and did not change serum albumin or histamine levels,, which indicates the inability of this resource to have a positive effect when treating treat acute joint inflammation. .

Effects of Seasonal Differences in Testosterone and Cortisol Levels on Pain Responses Under Resting and Anxiety Conditions

PURPOSE: This study investigated whether hormones and pain perception are associated with exam anxiety, and also whether exam anxiety is affected by seasonal differences in testosterone and cortisol levels. MATERIALS AND METHODS: Forty-six healthy males were recruited from a medical college. Anxiety was induced by having participants perform the Objective Structured Clinical Examination. Pressure was applied to the participants to induce pain. Pain thresholds, pain ratings, anxiety ratings, blood pressure, heart rate, salivary testosterone and cortisol levels were measured under resting and anxiety conditions in the spring and summer. Data were collected from 46 participants during the spring (n=25) and summer (n=21). RESULTS: Pain thresholds and testosterone levels were significantly lower under anxiety than at rest for all participants (n=46), while cortisol levels, pain ratings, and anxiety ratings were significantly higher under anxiety than at rest. In the spring (n=25), testosterone levels were significantly higher at rest than under anxiety, while there was no difference in cortisol levels between resting and anxiety conditions. In the summer (n=21), cortisol levels were significantly higher under anxiety than at rest, while there was no difference in testosterone levels between resting and anxiety conditions. There were no significant seasonal differences in pain and anxiety ratings and pain threshold. CONCLUSION: These results indicate that seasonal differences in testosterone and cortisol levels under anxiety and at rest may affect pain responses. These results also suggest that acute clinical pain may be relieved by managing anxiety that is related to a decrease of testosterone in spring and a large increase of cortisol in summer.

Analgesia en la toma sanguínea de talón en los recién nacidos / Analgesia when taking heel-lance blood in the newborn

Objetivo: Determinar el grado de malestar y de dolor causado por la toma sanguínea de talón y comparar diferentes tratamientos analgésicos. Pacientes y método: Se estudiaron 150 recién nacidos procedentes de la maternidad durante un período de 3 meses; se formaron tres grupos aleatorios, previo consentimiento informado. Un primer grupo estaba formado por 50 recién nacidos y no recibió ninguna intervención analgésica específica durante la extracción para el cribado endocrinometabólico, salvo nuestra técnica habitual de contención. Los grupos segundo y tercero (con 50 recién nacidos cada uno), recibieron succión no nutritiva-placebo y succión no nutritiva-sacarosa al 24 %, respectivamente. Resultados: En el grupo control, la puntuación media en la escala de malestar fue de 3,92, con dolor moderado, que provocó un tiempo de llanto de 51,72 s; el grupo que recibió succión no nutritiva-placebo obtuvo una puntuación de 2, 1, dolor leve, con 10,68 s de llanto, mientras que el grupo que recibió succión no nutritiva-sacarosa obtuvo 1,5 puntos, dolor leve, y un tiempo de llanto de 10,70 s. En la comparación de los resultados entre el grupo control y los grupos de succión no nutritiva se observaron diferencias significativas tanto en la puntuación de la escala de molestias como en el tiempo de llanto (p < 0,001). En el análisis comparativo entre los grupos de succión no nutritiva con placeboy sacarosa no se detectaron diferencias significativas. Conclusiones: La toma sanguínea de talón es un procedimiento doloroso de moderada intensidad susceptible de tratamiento analgésico. Un adecuado procedimiento de contención de enfermería, junto con el complemento de succión no nutritiva, disminuye de forma significativa el malestar y el llanto, por lo que no consideramos necesarios otros procedimientos analgésicos (AU)

Objective: To evaluate the pain in healthy newborns requiring blood test by a heel-prick procedure and compare different pain management methods. Patients and method: We studied 150 term infants, in three randomized groups, from the Maternity Unit of our Hospital for a period of three months. The first group of 50 newborns, received no specific analgesic intervention during blood tests, except our usual nursing intervention (“facilitated tucking”). The second and third group (50 newborns), received non-nutritive sucking-placebo and non-nutritivesucking-24% sucrose respectively. Results: In the control group, the average score on the scale of discomfort was 3.92, moderate pain, causing a crying time of 51.72 seconds; the group receiving a non-nutritive sucking-placebo scored 2.1, slight pain, 10.68 seconds crying, while the group receiving non-nutritive sucking-24% sucrose, expressed a level of discomfort of 1.5 points, slight, with an average crying time of 10.70 seconds. The comparative results between the control group and groups of non-nutritive sucking on placebo and 24 % sucrose, both showed significant differences in the scores of the scale of discomfort, as well as in the time crying (p < 0.001). The comparative analysis between groups of non-nutritive sucking sucrose and placebo showed no significant differences. Conclusions: The blood test by heel lance represents a painful procedure of moderate intensity capable of analgesic treatment. A proper nursing method, along with a complement of non-nutritive sucking during extraction, significantly decreases the discomfort and crying, it being unnecessary to consider other analgesics (AU)