RESUMEN
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.
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Ácidos Araquidónicos , Endocannabinoides , Calor , Percepción del Dolor , Alcamidas Poliinsaturadas , Humanos , Endocannabinoides/sangre , Alcamidas Poliinsaturadas/sangre , Ácidos Araquidónicos/sangre , Masculino , Femenino , Adulto , Percepción del Dolor/fisiología , Adulto Joven , Dimensión del Dolor , Persona de Mediana Edad , Dolor/sangre , Dolor/fisiopatología , AdolescenteRESUMEN
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.
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Recien Nacido Prematuro , Melatonina , Dolor , Humanos , Melatonina/sangre , Recién Nacido , Masculino , Recien Nacido Prematuro/sangre , Estudios Prospectivos , Femenino , Dolor/etiología , Dolor/sangre , Dimensión del Dolor , Edad GestacionalRESUMEN
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.
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Frecuencia Cardíaca , Osteoartritis , Sistema Nervioso Simpático , Humanos , Masculino , Femenino , Osteoartritis/fisiopatología , Osteoartritis/sangre , Osteoartritis/complicaciones , Persona de Mediana Edad , Anciano , Sistema Nervioso Simpático/fisiopatología , Hidrocortisona/sangre , Dolor/fisiopatología , Dolor/sangreRESUMEN
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.
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Autoanticuerpos , Proteínas de la Membrana , Proteínas del Tejido Nervioso , Fenotipo , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Estudios de Cohortes , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Proteínas de la Membrana/inmunología , Proteínas del Tejido Nervioso/inmunología , Dolor/inmunología , Dolor/etiología , Dolor/sangreRESUMEN
Importance: Initiation of injection drug use may be more frequent among people dispensed prescription opioid therapy for noncancer pain, potentially increasing the risk of hepatitis C virus (HCV) acquisition. Objective: To assess the association between medically dispensed long-term prescription opioid therapy for noncancer pain and HCV seroconversion among individuals who were initially injection drug use-naive. Design, Setting, and Participants: A population-based, retrospective cohort study of individuals tested for HCV in British Columbia, Canada, with linkage to outpatient pharmacy dispensations, was conducted. Individuals with an initial HCV-negative test result followed by 1 additional test between January 1, 2000, and December 31, 2017, and who had no history of substance use at baseline (first HCV-negative test), were included. Participants were followed up from baseline to the last HCV-negative test or estimated date of seroconversion (midpoint between HCV-positive and the preceding HCV-negative test). Exposures: Episodes of prescription opioid use for noncancer pain were defined as acute (<90 days) or long-term (≥90 days). Prescription opioid exposure status (long-term vs prescription opioid-naive/acute) was treated as time-varying in survival analyses. In secondary analyses, long-term exposure was stratified by intensity of use (chronic vs. episodic) and by average daily dose in morphine equivalents (MEQ). Main Outcomes and Measures: Multivariable Cox regression models were used to assess the association between time-varying prescription opioid status and HCV seroconversion. Results: A total of 382â¯478 individuals who had more than 1 HCV test were included, of whom more than half were female (224â¯373 [58.7%]), born before 1974 (201â¯944 [52.8%]), and younger than 35 years at baseline (196â¯298 [53.9%]). Participants were followed up for 2â¯057â¯668 person-years and 1947 HCV seroconversions occurred. Of the participants, 41â¯755 people (10.9%) were exposed to long-term prescription opioid therapy at baseline or during follow-up. The HCV seroconversion rate per 1000 person-years was 0.8 among the individuals who were prescription opioid-naive/acute (1489 of 1947 [76.5%] seroconversions; 0.4% seroconverted within 5 years) and 2.1 with long-term prescription opioid therapy (458 of 1947 [23.5%] seroconversions; 1.1% seroconverted within 5 years). In multivariable analysis, exposure to long-term prescription opioid therapy was associated with a 3.2-fold (95% CI, 2.9-3.6) higher risk of HCV seroconversion (vs prescription opioid-naive/acute). In separate Cox models, long-term chronic use was associated with a 4.7-fold higher risk of HCV seroconversion (vs naive/acute use 95% CI, 3.9-5.8), and long-term higher-dose use (≥90 MEQ) was associated with a 5.1-fold higher risk (vs naive/acute use 95% CI, 3.7-7.1). Conclusions and Relevance: In this cohort study of people with more than 1 HCV test, long-term prescription opioid therapy for noncancer pain was associated with a higher risk of HCV seroconversion among individuals who were injection drug use-naive at baseline or at prescription opioid initiation. These results suggest injection drug use initiation risk is higher among people dispensed long-term therapy and may be useful for informing approaches to identify and prevent HCV infection. These findings should not be used to justify abrupt discontinuation of long-term therapy, which could increase risk of harms.
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Analgésicos Opioides/uso terapéutico , Hepacivirus , Trastornos Relacionados con Opioides/virología , Dolor/tratamiento farmacológico , Abuso de Sustancias por Vía Intravenosa/virología , Adulto , Colombia Británica , Prescripciones de Medicamentos/estadística & datos numéricos , Femenino , Hepatitis C/complicaciones , Humanos , Masculino , Dolor/sangre , Dolor/virología , Farmacias/estadística & datos numéricos , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , SeroconversiónRESUMEN
The fundamental aim of this study is to establish the role of antioxidant supplementation in alleviating acute amitriptyline induced oxidative stress. The effect of supplementation was compared on treatment of acute amitriptyline intoxication cases for pain management, with alpha lipoic acid (ALA) alone or with vitamin C, with that of healthy individuals (group I), and those receiving only routine standard treatment (RST) as control (group II). A total of 132 human subjects divided into 5 groups were supplemented with either placebo, RST, RST with vitamin C, RST with ALA, or RST with vitamin C, and ALA. Results of this study revealed that the decrease in the level of oxidative stress and enzyme activity was observed among those supplemented with either alpha lipoic acid alone or along with vitamin C, with a slightly more decrease in the latter group. P value of < 0.001 was considered statistically significant. The percentage of benefit of treatment on supplementation with vitamin C and alpha lipoic acid showed a marked increase in group V cases after supplementation with both in combination. The results provided that the oxidative stress induced by acute amitriptyline poisoning is comparatively decreased by supplementation with antioxidants like alpha lipoic acid and vitamin C, than those only on routine standard treatment.
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Amitriptilina/efectos adversos , Antioxidantes/administración & dosificación , Ácido Ascórbico/administración & dosificación , Suplementos Dietéticos , Dolor/tratamiento farmacológico , Trastornos Relacionados con Sustancias/tratamiento farmacológico , Ácido Tióctico/administración & dosificación , Enfermedad Aguda , Adulto , Amitriptilina/administración & dosificación , Femenino , Humanos , Masculino , Estrés Oxidativo/efectos de los fármacos , Dolor/sangre , Trastornos Relacionados con Sustancias/sangreRESUMEN
INTRODUCTION: Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease affecting the synovial joints and causing severe disability. Environmental and lifestyle factors, including diet, have been proposed to play a role in the onset and severity of RA. Dietary manipulation may help to manage the symptoms of RA by lowering inflammation and potentially decreasing pain. METHODS: In 40 patients with long-standing RA with stable symptoms and treated with conventional (c-) and biological (b-) disease modifying anti-rheumatic drugs (DMARDs), the effect of a 3-month diet avoiding meat, gluten, and lactose (and all dairy products; privative diet) was evaluated in comparison with a control balanced diet including those foods. Both diets were designed to reduce weight since all patients were overweight or obese. Patients were randomly assigned to one of the diets, and RA was clinically assessed at Time 0 (T0), through the Visual Analogue Scale (VAS), for pain, and the Disease Activity Score of 28 joints (DAS 28) for RA activity. Patients were also administered the Short Form Health survey (SF-36) and the Health Assessment Questionnaire (HAQ). At T0, a blood sample was collected for laboratory tests and adipokines measurements, and anthropometric measurements were compared. These evaluations were repeated at the end of the 3 months' dietary regimens. RESULTS: A significant decrease in VAS and the improvement of the overall state of physical and mental health, assessed through SF-36, was observed in patients assigned to the privative diet. Both dietary regimens resulted in the improvement of quality of life compared to baseline values; however, the change was significant only for the privative diet. With either diet, patients showed significant decreases in body weight and body mass index, with a reduction in waist and hips circumference and lower basal glucose and circulating leptin levels. A privative diet was also able to significantly reduce systolic (p = 0.003) and diastolic (p = 0.025) arterial pressure. The number of circulating leukocytes and neutrophils, and the level of hs-C-Reactive Protein also decreased after 3 months of the meat-, lactose-, and gluten-free diet. CONCLUSIONS: Our results suggest that a privative diet can result in a better control of inflammation in RA patients under stable optimized drug treatment.
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Artritis Reumatoide/complicaciones , Artritis Reumatoide/dietoterapia , Inflamación/dietoterapia , Inflamación/etiología , Dolor/dietoterapia , Dolor/etiología , Adipoquinas/sangre , Adulto , Anciano , Artritis Reumatoide/sangre , Citocinas/sangre , Femenino , Humanos , Inflamación/sangre , Persona de Mediana Edad , Dolor/sangre , Cooperación del Paciente , Encuestas y Cuestionarios , Escala Visual AnalógicaRESUMEN
Although Janus kinase inhibitors (JAKi) could reduce patient-reported pain in rheumatoid arthritis (RA), their mechanism remains unclear. Therefore, we examined lipid metabolites change in JAKi-treated patients and evaluate their association with pain reduction. We used 1H-NMR-based lipid/metabolomics to determine serum levels of lipid metabolites at baseline and week 24 of treatment. Serum levels of significant lipid metabolites were replicated by ELISA in 24 JAKi-treated and 12 tocilizumab-treated patients. Pain was evaluated with patients' assessment on a 0-100 mm VAS, and disease activity assessed using DAS28. JAKi or tocilizumab therapy significantly reduced disease activity. Acceptable pain (VAS pain ≤20) at week 24 was observed in 66.7% of JAKi-treated patients, and pain decrement was greater than tocilizumab-treated patients (ΔVAS pain 70.0 vs. 52.5, p = 0.0595). Levels of omega-3 fatty acids and docosahexaenoic acid (DHA) were increased in JAKi-treated patients (median 0.55 mmol/L versus 0.71 mmol/L, p = 0.0005; 0.29 mmol/L versus 0.35 mmol/L, p = 0.0004; respectively), which were not observed in tocilizumab-treated patients. ELISA results showed increased DHA levels in JAKi-treated patients with acceptable pain (44.30 µg/mL versus 45.61 µg/mL, p = 0.028). A significant association of pain decrement with DHA change, not with DAS28 change, was seen in JAKi-treated patients. The pain reduction effect of JAKi probably links to increased levels of omega-3 fatty acids and DHA.
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Artritis Reumatoide/sangre , Artritis Reumatoide/complicaciones , Ácidos Docosahexaenoicos/sangre , Ácidos Grasos Omega-3/sangre , Inhibidores de las Cinasas Janus/uso terapéutico , Dolor/tratamiento farmacológico , Adulto , Antirreumáticos/sangre , Antirreumáticos/uso terapéutico , Humanos , Inhibidores de las Cinasas Janus/sangre , Masculino , Persona de Mediana Edad , Dolor/sangre , Dolor/etiología , Proyectos Piloto , Estudios ProspectivosRESUMEN
To investigate the association between markers of synovial inflammation and matrix turnover (MRI-based and serum biomarkers) and knee symptoms in established knee osteoarthritis (KOA). This cross-sectional study utilised data from a randomised, multicentre placebo-controlled trial (UK-VIDEO) of vitamin D therapy in symptomatic KOA. Data on serum biomarkers, type III collagen degradation (C3M), metabolite of C-reactive protein (CRPM) and cartilage oligomeric matrix protein (COMP), were available at baseline whilst contrast-enhanced (CE) MRI data were acquired in a subsample at baseline and annually. Knee symptoms were assessed using WOMAC at all visits. We examined the cross-sectional association between knee symptoms and three MRI-based and three serum markers of synovitis and matrix turnover, respectively. A total of 447 participants were included in the serum and 136 participants in the MRI analyses. MRI-defined medial perimeniscal synovitis was positively associated with knee pain and, suprapatellar and medial perimeniscal synovitis with knee function in multivariate analysis. We observed a statistically significant, negative association between a higher concentration of serum C3M and CRPM and knee pain, respectively. Furthermore, the highest CRPM quartile was negatively associated with knee function. Our findings suggest that, in established painful radiographic KOA, MRI-defined medial perimeniscal and suprapatellar synovitis were positively associated with knee symptoms. Serum-based C3M and CRPM markers were negatively associated with knee symptoms. Pain fluctuations are common in KOA and a better understanding of the relationship between markers of synovitis and matrix turnover and knee symptoms would facilitate a more accurate assessment of temporal changes in disease progression.
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Proteína C-Reactiva/metabolismo , Proteína de la Matriz Oligomérica del Cartílago/sangre , Colágeno Tipo III/sangre , Osteoartritis de la Rodilla/sangre , Dolor/sangre , Sinovitis/sangre , Anciano , Biomarcadores/sangre , Estudios Transversales , Progresión de la Enfermedad , Femenino , Humanos , Articulación de la Rodilla/diagnóstico por imagen , Articulación de la Rodilla/metabolismo , Articulación de la Rodilla/patología , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Osteoartritis de la Rodilla/diagnóstico por imagen , Osteoartritis de la Rodilla/patología , Dolor/diagnóstico por imagen , Dolor/patología , Índice de Severidad de la Enfermedad , Sinovitis/diagnóstico por imagen , Sinovitis/patologíaRESUMEN
Even though it has been well documented that stress can lead to the development of sleep disorders and the intensification of pain, their relationships have not been fully understood. The present study was aimed at investigating the effects of predictable chronic mild stress (PCMS) on sleep-wake states and pain threshold, using the PCMS rearing conditions of mesh wire (MW) and water (W) for 21 days. Exposure to PCMS decreased the amount of non-rapid eye movement (NREM) sleep during the dark phase. Moreover, the chronicity of PCMS decreased slow-wave activity (SWA) during NREM sleep in the MW and W groups in both the light and dark phases. Mechanical and aversively hot thermal hyperalgesia were more intensified in the PCMS groups than the control. Higher plasma corticosterone levels were seen in mice subjected to PCMS, whereas TNF-α expression was found higher in the hypothalamus in the W and the trigeminal ganglion in the MW group. The W group had higher expression levels of IL-6 in the thalamus as well. The PCMS paradigm decreased SWA and may have intensified mechanical and thermal hyperalgesia. The current study also suggests that rearing under PCMS may cause impaired sleep quality and heightened pain sensation to painful mechanical and aversively hot thermal stimuli.
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Dolor Facial/fisiopatología , Locomoción/fisiología , Trastornos del Sueño-Vigilia/fisiopatología , Animales , Corticosterona/sangre , Electroencefalografía , Dolor Facial/sangre , Masculino , Ratones , Ratones Endogámicos C57BL , Dolor/sangre , Dolor/fisiopatología , Umbral del Dolor , Reacción en Cadena en Tiempo Real de la Polimerasa , Privación de Sueño/sangre , Privación de Sueño/fisiopatología , Trastornos del Sueño-Vigilia/sangre , Sueño REM/fisiología , Vigilia/fisiologíaRESUMEN
BACKGROUND: Pain may undergo modulation in the central nervous system prior to reaching the primary somatosensory cortex and being perceived as pain. Faulty pain modulation mechanisms have been linked to various chronic pain conditions. Cytokines such as IL-10 and IL-1beta, are known to be involved in initiation and maintenance of neuropathic pain. In this study, we investigated the association between pain modulation profile, pain intensity and cytokines (IL-10 and IL-1beta) levels in a rat model of neuropathic pain. METHODS: Exercise-Induced Hypoalgesia (EIH) was assessed by evaluating the percentage of responses to a train of 60g mechanical stimuli before and after 180 seconds of exercise on a rotating rod. The differences in the response rates before and after the exercise were used to divide the rats into low and high EIH responders. Rats from low and high EIH groups underwent constriction injury of the left sciatic nerve. Pain behavior (allodynia and hyperalgesia) were assessed by measuring responses to mechanical and thermal stimuli applied to the plantar surface of the foot. Serum, sciatic nerve and the related Dorsal Root Ganglia (DRG) levels of IL-10 and IL-1beta were determined by ELISA. The DRG mRNA levels of IL-10 and IL-1beta measured with PCR. A comparison between the low and high EIH rats of all measured parameters was made. RESULTS: The low EIH rats developed significantly more severe allodynia and hyperalgesia in the affected paw and allodynia in the contralateral paw compared to the high EIH rats, 7 days following the injury. The low EIH rats had higher IL-1beta protein levels in serum prior to and following injury, higher affected and contralateral sciatic nerve IL-1beta levels following injury and higher IL-1beta levels in the contralateral DRG (protein and mRNA) following injury when compared to high EIH rats. The high EIH rats had higher affected sciatic nerve IL-10 levels following nerve injury and higher IL-10 levels of both protein and mRNA in the affected and contralateral DRG at baseline and following injury. CONCLUSION: EIH profile was found to be predictive of pain behavior following nerve injury, low EIH rats developed more severe allodynia and hyperalgesia. IL-1beta may be associated with painful neuropathy developed in rats with low EIH while the anti-inflammatory cytokine IL-10 may have a protective role, inhibiting the development of painful.
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Interleucina-10/sangre , Interleucina-1beta/sangre , Tejido Nervioso/lesiones , Dolor/sangre , Dolor/patología , Condicionamiento Físico Animal , Animales , Hiperalgesia/sangre , Hiperalgesia/complicaciones , Masculino , Tejido Nervioso/patología , Dolor/complicaciones , Dimensión del Dolor , Ratas Sprague-Dawley , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND: Insulin resistance (IR) is a pathological condition in which cells fail to respond normally to insulin. IR has been associated with multiple conditions, including chronic pain. Fibromyalgia (FM) is one of the common generalized chronic painful conditions with an incidence rate affecting 3% to 6% of the population. Substantial interest and investigation into FM continue to generate many hypotheses.The relationship between IR and FM has not been explored. IR is known to cause abnormalities in the cerebral microvasculature, leading to focal hypoperfusion. IR also has been shown to cause cognitive impairment in FM patients, as in parkinsonism. As demonstrated by advanced imaging methods, similar brain perfusion abnormalities occur in the brain of patients with FM as with IR. OBJECTIVES: To determine the potential association between FM and IR. SETTING: Subspecialty pain medicine clinics. STUDY DESIGN: Observational cross-sectional study. METHODS: Laboratory data was extracted through a retrospective review of medical records from patients who had met the American College of Rheumatology (ACR) criteria for FM. The Hemoglobin A1c (HbA1c) values from 33 patients with FM were compared with the means of the glycated HbA1c levels of 2 control populations. In addition, established indices of IR [Quantitative Insulin Sensitivity Check Index (QUICKI) and the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR)] were calculated in a subgroup of patients in whom the analytes necessary for these calculations were available. To assess for confounding factors, the associations between HbA1c, QUICKI, HOMA-IR, fasting insulin levels, and glucose, after controlling for age, were explored by multiple analyses of variance with relation to gender and ethnicity. RESULTS: We found an association between IR and FM that was independent of age, gender, and ethnicity. We found that patients with FM belong to a distinct population that can be segregated from the control groups by their HbA1c levels, a surrogate marker of IR. This was demonstrated by analyzing the data after introducing an age correction into a linear regression model. This strategy showed significant differences between patients with FM and control subjects (P < 0.0001 and P = 0.0002, for 2 separate control populations, respectively). A subgroup analysis using the QUICKI and HOMA-IR showed that all patients with FM in this subgroup (100%) exhibited laboratory abnormalities pointing to IR. LIMITATIONS: Small observational cross-sectional study. There are also intrinsic limitations that are attributed to cross-sectional studies. CONCLUSION: The association demonstrated in this study warrant further investigation, including the pursuit of randomized, double-blind clinical trials to determine the effect of improving insulin sensitivity in FM related pain scores. Such studies could unveil a potential pathogenetic relationship between FM, central pain, and IR. Based on these initial findings, we present the hypothesis that IR may underlie pathological mechanisms leading to central pain. If confirmed, this may lead to a paradigm shift in the management of central pain.
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Fibromialgia/sangre , Fibromialgia/epidemiología , Resistencia a la Insulina/fisiología , Dolor/sangre , Dolor/epidemiología , Adulto , Anciano , Biomarcadores/sangre , Estudios Transversales , Método Doble Ciego , Ayuno/sangre , Femenino , Fibromialgia/diagnóstico , Hemoglobina Glucada/metabolismo , Humanos , Insulina/administración & dosificación , Masculino , Persona de Mediana Edad , Dolor/diagnóstico , Estudios RetrospectivosRESUMEN
BACKGROUND: Fibromyalgia (FM) is a complex syndrome of uncertain etiology, characterized by the presence of widespread pain. Both nitric oxide and enkephalinases modulate pain perception. OBJECTIVES: The aim of this study was to evaluate the relationships among serum nitric oxide levels, oxytocinase activity, and enkephalin-degrading aminopeptidase (EDA) activity with pain-related clinical manifestations in women with FM. METHODS: We performed an observational case study in a population of 58 women diagnosed with FM. Serum nitric oxide levels were analyzed by an ozone chemiluminescence-based assay. Both serum oxytocinase and EDA activities were fluorometrically determined. Pain threshold and pain magnitude were evaluated using the PainMatcher. The pressure pain thresholds were measured using a digital pressure algometer. We used a visual analog scale, the Central Sensitization Inventory, the Revised Fibromyalgia Impact Questionnaire, and the Beck Anxiety Inventory to assess the global level of pain, the symptoms associated with the central sensitization syndrome, the severity of FM, and the anxiety level, respectively. RESULTS: Multiple linear regression analysis adjusted by age, body mass index, and menopause status revealed significant associations between nitric oxide levels and dominant occiput pressure pain thresholds, nondominant occiput pressure pain thresholds, and FM effects. Significant associations of oxytocinase activity with the visual analog scale and dominant knee pressure pain thresholds were also found. Moreover, results showed a significant association between high EDA activity levels and dominant second-rib pressure pain thresholds. DISCUSSION: Our data have shown significant relationships of serum nitric oxide levels and oxytocinase and EDA activities with some body pressure pain thresholds, the daily activity level, and the global intensity of pain in women with FM. These results suggest that pain, which is the main symptom of this syndrome, may be related to alterations in nitric oxide levels and in oxytocinase and EDA activities in patients with FM.
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Aminopeptidasas/sangre , Fibromialgia/sangre , Óxido Nítrico/sangre , Dolor/diagnóstico , Adulto , Femenino , Fibromialgia/complicaciones , Fibromialgia/fisiopatología , Humanos , Persona de Mediana Edad , Dolor/sangre , Dolor/etiología , Dimensión del Dolor , Umbral del Dolor , Índice de Severidad de la EnfermedadRESUMEN
Selection of a personalized dose for an individual patient can be informed by the patient's preferences, translated as weights on each of the clinically relevant safety and efficacy drug attributes, based on results from a brief patient preference elicitation questionnaire. In this analysis, the weighted attributes were simulated to represent various endometriosis patient profiles. Exposure-response simulations were performed for elagolix, a drug approved for management of moderate to severe pain associated with endometriosis, across a range of plasma exposures corresponding to a range of doses. The results were combined to calculate a personalized clinical utility index. An interactive user-friendly online application was developed and envisioned as a physician's desk tool to personalize the dose selection process based on individual patient preferences. This demonstration should serve as an example of how patient/physician conversation can be facilitated with quantitative tools for personalizing the dose.
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Analgésicos/administración & dosificación , Endometriosis/tratamiento farmacológico , Hidrocarburos Fluorados/administración & dosificación , Modelos Biológicos , Dolor/tratamiento farmacológico , Prioridad del Paciente , Pirimidinas/administración & dosificación , Adolescente , Adulto , Analgésicos/sangre , Analgésicos/farmacocinética , Ensayos Clínicos Fase I como Asunto , Ensayos Clínicos Fase III como Asunto , Simulación por Computador , Relación Dosis-Respuesta a Droga , Endometriosis/complicaciones , Endometriosis/metabolismo , Femenino , Humanos , Hidrocarburos Fluorados/sangre , Hidrocarburos Fluorados/farmacocinética , Transportador 1 de Anión Orgánico Específico del Hígado/genética , Persona de Mediana Edad , Dolor/sangre , Dolor/etiología , Medicina de Precisión , Pirimidinas/sangre , Pirimidinas/farmacocinética , Encuestas y Cuestionarios , Adulto JovenRESUMEN
OBJECTIVES: We have a weak understanding of how aerobic training may influence migraine, and the optimal parameters for exercise regimens as migraine therapy are not clear. The objectives of this study were to assess, first, effects of two different intensities of aerobic exercise on migraine headache indices; second, serum neuro-biomarker in women migraineurs. METHODS: A total of 45 non-athlete female migraine patients were selected by a neurologist and randomly divided into three groups: control (CON), moderate-intensity aerobic training (MOD T), and high-intensity aerobic training (HIGH T). Before and after the training protocol, body composition factors, migraine pain indices, VO2max, and serum Adenylate-Cyclase Activating Polypeptide (PACAP) and Substance P (SP) were measured. Exercise training protocol includes two different intensities of aerobic exercise: Moderate (13-15 Borg Scale, 60-80% HRmax) and High (15-17 Borg Scale, 65-95% HRmax). RESULTS: Moderate-intensity aerobic training (MOD T) reduced headache intensity, frequency, and duration in women with migraine (p < 0.001, for all). Also, high-intensity aerobic training (HIGH T) reduced headache intensity, frequency, and duration (p < 0.001, for all). However, for headache intensity and duration, MOD T was effective rather than HIGH T (p < 0.001; p ≤ 0.05, respectively). In addition, neither MOD T nor HIGH T could not alter PACAP and SP contents (p = 0.712; p = 0.249, respectively). CONCLUSIONS: Our results demonstrated that either MOD T or HIGH T could modify migraine pain indices but neither MOD T nor HIGH T could not alter the PACAP and SP contents in women with migraine.
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Biomarcadores/sangre , Ejercicio Físico/fisiología , Trastornos Migrañosos/sangre , Trastornos Migrañosos/fisiopatología , Dolor/fisiopatología , Adulto , Femenino , Humanos , Oxígeno/sangre , Dolor/sangre , Polipéptido Hipofisario Activador de la Adenilato-Ciclasa/sangreRESUMEN
In a recent clinical trial, the metabolite l-glutamine was shown to reduce painful crises in sickle cell disease (SCD) patients. To support this observation and identify other metabolites implicated in SCD clinical heterogeneity, we profiled 129 metabolites in the plasma of 705 SCD patients. We tested correlations between metabolite levels and six SCD-related complications (painful crises, cholecystectomy, retinopathy, leg ulcer, priapism, aseptic necrosis) or estimated glomerular filtration rate (eGFR), and used Mendelian randomization (MR) to assess causality. We found a potential causal relationship between l-glutamine levels and painful crises (N = 1278, odds ratio (OR) [95% confidence interval] = 0.68 [0.52-0.89], P = 0.0048). In two smaller SCD cohorts (N = 299 and 406), the protective effect of l-glutamine was observed (OR = 0.82 [0.50-1.34]), although the MR result was not significant (P = 0.44). We identified 66 significant correlations between the levels of other metabolites and SCD-related complications or eGFR. We tested these correlations for causality using MR analyses and found no significant causal relationship. The baseline levels of quinolinic acid were associated with prospectively ascertained survival in SCD patients, and this effect was dependent on eGFR. Metabolomics provide a promising approach to prioritize small molecules that may serve as biomarkers or drug targets in SCD.
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Anemia de Células Falciformes/sangre , Anemia de Células Falciformes/complicaciones , Glutamina/sangre , Dolor/etiología , Adolescente , Adulto , Niño , Preescolar , Femenino , Humanos , Masculino , Análisis de la Aleatorización Mendeliana , Persona de Mediana Edad , Dolor/sangre , Adulto JovenRESUMEN
Previously, we showed that serum soluble interleukin-2 receptor (sIL-2R) levels, a marker for T-cell activation, were higher in complex regional pain syndrome (CRPS) patients than in healthy controls, suggesting pathogenic T-cell activation in CRPS. Additionally, sIL-2R levels discriminated well between CRPS and healthy controls with a high sensitivity (90%) and specificity (89.5%), suggesting a possible role for sIL-2R in the diagnosis of CRPS. In order to further validate this marker in the diagnostic workup of CRPS, we conducted this prospective cohort study in which we determined sIL-2R levels in patients that were referred to our tertiary referral center with a suspicion of CRPS in a limb, and subsequently compared sIL-2R levels between the patients that were diagnosed with CRPS (CRPS group) and those who were not (no CRPS group). A group of anonymous blood bank donors were used as a healthy control group. Furthermore, we explored the relationship between sIL-2R and CRPS disease severity using the CRPS severity score. Median sIL-2R levels of both the CRPS group (2809.0 pg/ml; Q3-Q1: 3913.0-1589.0) and no CRPS group (3654.0 pg/ml; Q3-Q1: 4429.0-2095.5) were significantly higher than that of the control group (1515.0 pg/ml; Q3-Q1: 1880.0-1150.0): CRPS vs. controls, p < .001; no CRPS vs. controls, p < 0.001. Serum sIL-2R levels did not differ significantly between the CRPS and no CRPS group. A statistically significant negative correlation was observed between sIL-2R levels and the CRPS severity score (r s = -0.468, p = 0.024). Our results confirm our previous findings of higher sIL-2R levels in CRPS patients than in healthy controls. We further showed that serum sIL-2R cannot differentiate between CRPS and other pain conditions of a limb in a tertiary referral setting. Interestingly, a negative correlation was found between sIL-2R and CRPS disease severity; this finding warrants further research into the relationship between sIL-2R and CRPS disease severity.
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Biomarcadores/sangre , Síndromes de Dolor Regional Complejo/sangre , Dolor/sangre , Receptores de Interleucina-2/sangre , Adulto , Síndromes de Dolor Regional Complejo/diagnóstico , Femenino , Humanos , Activación de Linfocitos/fisiología , Masculino , Persona de Mediana Edad , Dolor/diagnóstico , Estudios ProspectivosRESUMEN
To clarify the relevance of prolactin (PRL) to clinical parameters in patients who visited our general medicine department, medical records of 353 patients in whom serum PRL levels were measured during the period from 2016 to 2018 were retrospectively reviewed. Data for 140 patients (M/F: 42/98) were analyzed after excluding patients lacking detailed records and patients taking dopaminergic agents. Median serum PRL levels were significantly lower in males than females: 6.5 ng/ml (IQR: 4.2-10.3) versus 8.1 ng/ml (5.9-12.9), respectively. Pain and general fatigue were the major symptoms at the first visit, and past histories of hypertension and dyslipidemia were frequent. Male patients with relatively high PRL levels (≥ 10 ng/ml) had significantly lower levels of serum albumin and significantly higher levels of serum LDH than those with low PRL (< 10 ng/ml). There were significant correlations of male PRL level with the erythrocyte sedimentation rate (R=0.62), serum LDH level (R=0.39) and serum albumin level (R=-0.52), while the level of serum CRP (R=0.33) showed an insignificant but weak positive correlation with PRL level. Collectively, these results show that PRL levels had gender-specific relevance to various clinical factors, with PRL levels in males being significantly related to inflammatory status.
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Inflamación/sangre , Prolactina/sangre , Factores Sexuales , Adulto , Anciano , Fatiga/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Dolor/sangre , Estudios RetrospectivosRESUMEN
Pain is the most common symptom in patients with rheumatoid arthritis (RA). Although in recent years, through the implementation of targeted treatment and the introduction of disease-modifying antirheumatic drugs (DMARDs), the treatment of RA patients has made a significant progress, a large proportion of patients still feel pain. Finding appropriate treatment to alleviate the pain is very important for RA patients. Current research showed that, in addition to inflammation, RA pain involves peripheral sensitization and abnormalities in the central nervous system (CNS) pain regulatory mechanisms. This review summarized the literature on pain mechanisms of RA published in recent years. A better understanding of pain mechanisms will help to develop new analgesic targets and deploy new and existing therapies.
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Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Citocinas/sangre , Animales , Artritis Reumatoide/sangre , Sistema Nervioso Central/metabolismo , Sensibilización del Sistema Nervioso Central/fisiología , Humanos , Dolor/sangre , Dolor/tratamiento farmacológicoRESUMEN
BACKGROUND/AIM: The simultaneous increase of antioxidant CAT (catalase) enzyme and plasma MDA (malonidialdehyde) concentrations versus the numeric rating scale (NRS) pain score following surgery is unknown. Patients and Methods: The study included 114 patients with gallstone disease and 29 patients in the cancer group. RESULTS: Following surgery, the plasma CAT concentrations increased and plasma MDA concentrations decreased in all patients and especially in cancer patients. The linear mixed model time-effect was statistically significant in CAT and MDA (p<0.001 and p=0.02, respectively). In addition, a significant correlation between NRS pain score values and plasma MDA median concentrations in cancer patients was identified (r=0.430, p<0.001). CONCLUSION: The plasma MDA concentrations decreased and CAT concentrations increased significantly in all patients and especially in cancer patients following surgery. The simultaneous increase of antioxidant CAT enzyme with the decrease of plasma MDA may be an important ROS inhibiting mechanism to help patients return to normal antioxidant-oxidant status.