Exploring the analgesic potential of isorhamnetin: insights from formalin-induced pain and diabetic neuropathy models.

OBJECTIVE: Isorhamnetin, a naturally occurring flavonoid compound, holds paramount importance as a primary constituent within several medicinal plants, exhibiting profound pharmacological significance. The aim of this study is to investigate the pain-relieving attributes of isorhamnetin in murine models through both formalin-induced pain and diabetic neuropathy scenarios. MATERIALS AND METHODS: To achieve our objective, isorhamnetin was orally administered to mice at varying dosage levels (10 to 100 mg/kg). Pain-related behaviors were assessed using the formalin test during its secondary phase. Additionally, the potential pain-alleviating effect of isorhamnetin was evaluated in a diabetic neuropathy model induced by streptozotocin. Additionally, we carried out advanced interventions using naloxone, which is a well-known antagonist of opioid receptors, yohimbine, which blocks α2-adrenergic receptors, and methysergide, which inhibits serotonergic receptors, during the formalin test. RESULTS: The oral intake of isorhamnetin showed a decrease in behaviors associated with pain that was proportional to the dose observed during the second phase of the formalin test when induced by formalin. In the diabetic neuropathy model, isorhamnetin administration effectively reversed the reduced pain threshold observed. Notably, naloxone, the opioid receptor antagonist, effectively counteracted the pain-relieving effect produced by isorhamnetin in the formalin test, whereas yohimbine and methysergide did not yield similar outcomes. Isorhamnetin also led to a reduction in elevated spinal cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) levels triggered by formalin, with this effect reversed by pre-treatment with naloxone. The compound also suppressed heightened spinal phosphorylated CREB (p-CREB) levels caused by diabetic neuropathy. CONCLUSIONS: This research determined that isorhamnetin has notable abilities to relieve pain in models of formalin-induced pain and diabetic neuropathy. The pain-relieving mechanism of isorhamnetin in the formalin-induced pain model seems to be connected to the activation of spinal opioid receptors and the adjustment of CREB protein amounts. This insight improves our knowledge of how isorhamnetin could be used therapeutically to treat pain conditions stemming from formalin-induced pain and diabetic neuropathy.

Obesity aggravates the role of C-reactive protein on knee pain: A cross-sectional analysis with NHANES data.

OBJECTIVE: To examine the relationship between C-reactive protein (CRP) and knee pain, and further explore whether this association is mediated by obesity. METHODS: The population was derived from 1999 to 2004 National Health and Nutrition Examination Survey. Logistic regression was used to analyze the relationship between CRP and knee pain in three different models, and the linear trend was analyzed. A restricted cubic spline model to assess the nonlinear dose-response relationship between CRP and knee pain. Mediation analyses were used to assess the potential mediating role of obesity. Subgroup analyses and sensitivity analyses were performed to ensure robustness. RESULTS: Compared with adults with lower CRP (first quartile), those with higher CRP had higher risks of knee pain (odds ratio 1.39, 95% confidence interval 1.12-1.72 in third quartile; 1.56, 1.25-1.95 in fourth quartile) after adjusting for covariates (except body mass index [BMI]), and the proportion mediated by BMI was 76.10% (p < .001). BMI and CRP were linear dose-response correlated with knee pain. The odds ratio for those with obesity compared with normal to knee pain was 2.27 (1.42-3.65) in the first quartile of CRP, 1.99 (1.38-2.86) in the second, 2.15 (1.38-3.33) in the third, and 2.92 (1.72-4.97) in the fourth. CONCLUSION: Obesity mediated the systemic inflammation results in knee pain in US adults. Moreover, higher BMI was associated with higher knee pain risk in different degree CRP subgroups, supporting an important role of weight loss in reducing knee pain caused by systemic inflammation.

[Systematic evaluation of the painful hip]. / Evaluación sistemática de la cadera dolorosa.

The painful hip has been a topic of study that has evolved from the beginning of the last century to the present. The clinical approach is complex, and requires a systematization process associated with good questioning, clinical maneuvers with their corresponding interpretation, and complementary imaging studies. The understanding of hip pathology, especially in young adults, is highly simplified and sometimes underdiagnosed, therefore, not treated in a timely manner. The prevalence of painful hip is more common in males (49 to 55%) than in females (25 to 28%), and the causes may vary according to demographic characteristics and the history of each patient. Bryan Kelly, made a topographic and anatomical description of the approach to the painful hip according to the theory or system of the layers: I. Osteochondral layer; II. Inert layer; III. Contractile layer; and IV. Neuro-mechanical layer. This system helps us understand the anatomical site of pain and its clinicopathological correlation. The semiological approach to hip pain is the fundamental pillar for differential diagnosis. We can divide it according to its topography into anterior, lateral and posterior, as well as according to its chronology and characteristics. The physical examination should be carried out systematically, starting from a generalized inspection of gait and posture to the evaluation of specific signs for alterations in each layer, which evoke pain with specific postures and ranges of mobility, or weakness and alterations in the arc of mobility of the joint. Image evaluation is initially recommended with radiographic projections that evaluate different planes, both coronal, sagittal and axial, complemented with panoramic views, and eventually dynamic sagittal ones if necessary. Requesting specific studies such as tomography to evaluate bone structure and reserve, or simple MRI when there is suspicion of soft tissue affection, or failing that, arthroresonance for joint pathology, will depend on the clinical symptoms and radiographic findings.

La cadera dolorosa ha sido un tema de estudio que ha evolucionado desde principios del siglo pasado hasta la actualidad. El abordaje clínico es complejo y exige un proceso de sistematización asociado a un buen interrogatorio, maniobras clínicas con su interpretación correspondiente y estudios de imagen complementarios. El entendimiento de la patología de cadera, sobre todo en adulto joven, es altamente simplificado y en ocasiones infradiagnosticado, por lo tanto, no tratado en tiempo y forma. La prevalencia de cadera dolorosa es más frecuente en el sexo masculino (49 a 55%) que en el femenino (25 a 28%), y las causas pueden variar de acuerdo a características demográficas y a los antecedentes de cada paciente. Bryan Kelly realizó una descripción topográfica y anatómica del abordaje de la cadera dolorosa de acuerdo con la teoría o sistema de las capas: I. Capa osteocondral; II. Capa inerte; III. Capa contráctil; y IV. Capa neuromecánica. Este sistema nos ayuda a entender el sitio anatómico del dolor y su correlación clínico-patológica. El abordaje semiológico del dolor de cadera es el pilar fundamental para el diagnóstico diferencial. Podemos dividirlo de acuerdo con su topografía en anterior, lateral y posterior, así como de acuerdo a su cronología y características. La exploración física debe realizarse de manera sistemática, iniciando desde inspección generalizada, de la marcha y postura hasta la evaluación de signos específicos para alteraciones en cada capa, los cuales evocan dolor con posturas y arcos de movilidad específicos, o bien debilidad y alteraciones en el arco de movilidad de la articulación. La evaluación por imagen se recomienda inicialmente con proyecciones radiográficas que evaluen diferentes planos, tanto coronal, sagital y axial, complementado con panorámicas, y eventualmente sagitales dinámicas de ser necesarios. Solicitar estudios específicos como tomografía para evaluar estructura y reserva ósea, o bien, resonancia simple cuando hay sospecha de afección a tejidos blandos, o en su defecto, artrorresonancia para patología articular, dependerá de la clínica y los hallazgos radiográficos.

The effects of aromatherapy and music on pain, anxiety, and stress levels in palliative care patients.

AIM: Pain and anxiety levels in palliative care patients negatively impact their quality of life, highlighting the need for research on non-pharmacological methods. This study aimed to evaluate the effects of music and aromatherapy interventions on pain, anxiety, and stress levels in these patients. MATERIAL AND METHODS: The research was designed as a single-blind, four-group, randomized controlled trial. The sample consisted of 88 patients hospitalized in a palliative care center (receiving palliative care services with terminal or advanced diseases). Patients were randomly assigned to four groups (n = 22, music, aromatherapy, music and aromatherapy, and control group). Patients in the experimental groups received the intervention to which they were assigned for 20 min each day for three consecutive days: music, aromatherapy, or music accompanied by aromatherapy. No intervention was applied to the control group. The patients' levels of pain, anxiety, and stress were assessed before and after the intervention using the Visual Analog Scale (VAS), the Facial Anxiety Scale (FAS), and the Distress Thermometer. RESULTS: No significant differences were found in the demographic characteristics of the groups (p > 0.05). The Wilcoxon Signed-Rank and Kruskal-Wallis tests indicated statistically significant differences in pre- and post-intervention scores for VAS, FAS, and Distress across all experimental groups on all follow-up days (p < 0.05). CONCLUSION: Implementing music, aromatherapy, and their combination effectively reduced pain, anxiety, and stress levels in palliative care patients, suggesting these non-pharmacological interventions can improve their quality of life. TRIAL REGISTRATION: ClinicalTrails.gov (Registration number: NCT06024954) at 05-SEP-2024.

Investigation of Spatiotemporal Gait Characteristics, Balance, and Pain in Forefoot and Rearfoot Problems: Preliminary Results.

BACKGROUND: Foot problems are common in the general adult population. Whereas older people experience foot problems because of multiple chronic diseases, younger people often have musculoskeletal foot problems related to overuse. Symptoms and severity may differ depending on the anatomical location of the problem, such as forefoot and rearfoot problems. We aimed to compare the differences in spatiotemporal gait characteristics, balance, and pain in musculoskeletal forefoot and rearfoot problems. METHODS: Twenty-six patients with forefoot (14 participants) and rearfoot (12 participants) problems participated in this prospective study. Spatiotemporal gait characteristics (velocity, cadence, step time, step length, step-extremity ratio, stride length, base support, percentage of swing phase, percentage of stance phase, swing time, and stance time) were evaluated using an electronic walkway, and balance assessment was made using a balance check screener and trainer. The visual analog scale foot and ankle was used to determine patient pain levels. The Mann-Whitney U test was used to determine differences between groups. RESULTS: There were no significant differences between groups regarding spatiotemporal gait characteristics (P > .05). The eyes closed normal stability and eyes open perturbed stability scores were lower in patients with rearfoot problems (P < .05). Pain intensity evaluated with the visual analog scale foot and ankle was higher in patients with rearfoot problems (P < .05). CONCLUSIONS: Pain levels and balance deficits in this study were higher in patients with rearfoot problems. The balance evaluation and possible effects of pain management on balance should be considered, especially in patients with rearfoot problems, in aspects of treatment.

Validity and reliability of the Pain Assessment in Impaired Cognition 15 (PAIC15) observation scale in persons with aphasia.

BACKGROUND: The use of self-report pain scales in persons with aphasia can be challenging due to communication and cognitive problems, while for assessing pain self-report pain is considered the gold standard (Harrison RA, Field TS. Post stroke pain: identification, assessment, and therapy. Cerebrovasc Dis. 2015;39(3-4):190-201.). An observational scale may be used as an alternative. This study examines the validity and reliability of the observational Pain Assessment in Impaired Cognition (PAIC15) scale in persons with aphasia. METHODS: Persons with aphasia were observed during rest and transfer by two observers using the PAIC15. The PAIC15 comprises 15 items covering the three domains of facial expressions, body movements, and vocalizations. When able, the participant completed four self-report pain scales after each observation. The observations were repeated within one week. For criterion validity, correlations between the PAIC15 and self-report pain scales were calculated and for construct validity, three hypotheses were tested. Reliability was determined by assessing internal consistency, and intra- and interobserver agreement. RESULTS: PAIC15 observations were obtained for 71 persons (mean age 75.5 years) with aphasia. Fair positive correlations (rest: 0.35-0.50; transfer: 0.38-0.43) were reported between PAIC15 and almost all self-report pain scales. Results show that significantly more pain was observed in persons with aphasia during transfer than during rest. No differences were found for observed pain between persons with aphasia who use pain medication and those without, or persons who have joint diseases compared to those without. Results showed acceptable internal consistency. Intra- and interobserver agreement was high for most PAIC15 items, particularly for the domains body movements and vocalizations during rest and transfer. CONCLUSIONS: Recognition of pain in persons aphasia using the PAIC15 showed mixed yet promising results.

Can electroencephalography (EEG) identify the different dimensions of pain in fibromyalgia? A pilot study.

BACKGROUND: Electroencephalography (EEG) is a promising tool for identifying the physiological biomarkers of fibromyalgia (FM). Evidence suggests differences in power band and density between individuals with FM and healthy controls. EEG changes appear to be associated with pain intensity; however, their relationship with the quality of pain has not been examined. We aimed to investigate whether abnormal EEG in the frontal and central points of the 10-20 EEG system in individuals with FM is associated with pain's sensory-discriminative and affective-motivational dimensions. The association between EEG and the two dimensions of emotional disorders (depression and anxiety) was also investigated. METHODS: In this cross-sectional pilot study, pain experience (pain rating index [PRI]) and two dimensions of emotional disorders (depression and anxiety) were assessed using the McGill Pain Questionnaire (PRI-sensory and PRI-affective) and Hospital Anxiety and Depression Scale (HADS), respectively. In quantitative EEG analysis, the relative spectral power of each frequency band (delta, theta, alpha, and beta) was identified in the frontal and central points during rest. RESULTS: A negative correlation was found between the relative spectral power for the delta bands in the frontal (r= -0.656; p = 0.028) and central points (r= -0.624; p = 0.040) and the PRI-affective scores. A positive correlation was found between the alpha bands in the frontal (r = 0.642; p = 0.033) and central points (r = 0.642; p = 0.033) and the PRI-affective scores. A negative correlation between the delta bands in the central points and the anxiety subscale of the HADS (r = -0.648; p = 0.031) was detected. CONCLUSION: The affective-motivational dimension of pain and mood disorders may be related to abnormal patterns of electrical activity in patients with FM. TRIAL REGISTRATION: Retrospectively registered on ClinicalTrials.gov (NCT05962658).

Cicely Saunders and the Literary and Cultural Heritage of "Total Pain".

In this article, I present some of the literary and cultural influences behind hospice pioneer Cicely Saunders's idea of "total pain," a term she used from the 1960s onwards to promote the holistic approach which has since become palliative care. Existing studies imply "total pain" emerged from Saunders's own mixed career experiences and her attention to patient narratives. However, I explore how the term originates not only in Saunders's direct encounters with her patients but also in her readings of literary, philosophical, and theological texts from a range of European post-war contexts, from Viktor Frankl and Simone de Beauvoir to Martin Buber and Ladislaus Boros. Examining "total pain" in light of Saunders's reading reveals the particular intellectual milieu-often ignored-from which palliative care emerged.

Quality of life, pain and use of analgesic, anxiolytic and antidepressant medication, in people living in care homes.

BACKGROUND: People living in care homes often have problems with pain, anxiety and depression. Whether being on analgesia, anxiolytics or antidepressants has any bearing on pain severity and quality of life (QoL) in this population, requires further investigation. OBJECTIVES: (i) to examine the relationship between pain, anxiety and depression and medication use in care home residents and (ii) to compare those on medications to treat pain, anxiety and depression, and those who were not, and associations with pain severity and overall QoL. METHODS: This was a secondary analysis of a randomised controlled trial testing a falls prevention intervention in care homes. We recorded pain, anxiety and depression, QoL measurements and prescribed medication use. RESULTS: In 1589 participants, the mean age was 84.7 years (±9.3 SD), 32.2% were male and 67.3% had a diagnosis of dementia. 54.3% and 53.2% of participants had some level of pain and anxiety or depression respectively, regardless of prescribed medication use. There was a direct association between pain severity and being on any analgesia, opioid analgesia, and antidepressants, but no associations between pain severity and use of paracetamol and anxiolytics. QoL was best for residents with no pain and not on any analgesia, anxiolytics or antidepressants and worst for those with moderate-extreme pain and taking at least two of these classes of medications. CONCLUSION: Many care home residents live with pain, anxiety and depression. Addressing residents' pain may also increase their quality of life, but using medication alone to reach this goal may be inadequate.

"Maintaining symbiosis in conflict": the quality of life of disabled elderly individuals in Chinese elderly care institutions - a grounded theory study.

BACKGROUND AND OBJECTIVES: Exploring the quality of life of disabled elderly individuals in eldercare facilities holds significant importance in the improvement of service quality, the allocation of eldercare resources, and the enhancement of the well-being of the elderly. This study, grounded in the subjective perspective of disabled elderly individuals, aims to investigate their quality of life within eldercare institutions. RESEARCH DESIGN AND METHODS: A grounded theory approach was employed, involving semi-structured interviews with 35 participants. RESULTS: Data analysis revealed that the quality of life of disabled elderly individuals in Chinese elderly care institutions is characterized by "maintaining symbiosis in conflict" and encompasses four dimensions: complex adaptation process, complexities in social interactions, physical pain and the lonely soul. DISCUSSION AND IMPLICATIONS: Spending late years in elderly care institutions poses a trial and challenge for disabled elderly individuals, especially within a cultural environment that traditionally revolves around the "family" unit. In these institutions, disabled elderly individuals not only endure physical pain but also grapple with feelings of loneliness. They maintain the facade of family dignity by concealing true emotions, ensuring the harmonious and stable operation of the elderly care institution.Enhancing the quality of life for disabled elderly individuals requires not only an improvement in the service capabilities of elderly care institution staff but also collaborative efforts from policymakers and family members.

Human heat sensation: A randomized crossover trial.

Sensing of noxious heat has been reported to be mediated by TRPV1, TRPA1, TRPM3, and ANO1 in mice, and this is redundant so that the loss of one receptor is at least partially compensated for by others. We have established an infusion-based human heat pain model. Heat-induced pain probed with antagonists for the four receptors did not match the redundancy found in mice. In healthy participants, only TRPV1 contributes to the detection of noxious heat; none of the other three receptors are involved. TRPV1 inhibition reduced the pain at all noxious temperatures, which can also be seen as an increase in the temperature that causes a particular level of pain. However, even if the TRPV1-dependent shift in heat detection is about 1°C, at the end of the temperature ramp to 52°C, most heat-induced pain remains unexplained. This difference between species reopens the quest for the molecular safety net for the detection of noxious heat in humans.

Understanding invisible pain in the older adult: a content analysis of social media's representation of herpes zoster vaccine.

Herpes zoster (HZ), a common disease in older adults, affects their quality of life. Therefore, this study aimed to examine the blog posts of HZ-related information on social media platforms to analyze the attitudes and behaviors of residents toward the dissemination of health information. This research used content analysis to focus on Weibo, a representative social media in China, to analyze the content of 1866 blog posts related to herpes zoster (HZ) and herpes zoster vaccine (HZV). According to the consistency test by Cohen's Kappa, four themes were identified: (a) sources, (b) tones, (c) epidemiological information, and (d) extended parallel process model elements. The findings showed that most information on Weibo came from non-professionals, with a neutral tone, and showed the invisible pain of HZ and the effectiveness of HZV through the two largest aspects of prevention and aged protection in epidemiological information. However, current blog posts treat the older adult as invisible individuals, failing to acknowledge them as recipients of the information. Additionally, the cost of the vaccine acts as an invisible economic barrier, contributing to the dissemination of incorrect information about folk remedies. This impacts the older adult's acceptance of health information related to HZV. Thus, the way to share health information with the older adult needs to be improved in the future, and attention should be paid to the transmission of incorrect information to improve their vaccination rates and awareness of health management.

The mode of action of IL-23 in experimental inflammatory arthritic pain and disease.

OBJECTIVES: We have previously reported using gene-deficient mice that the interleukin (IL)-23p19 subunit is required for the development of innate immune-driven arthritic pain and disease. We aimed to explore here, using a number of in vivo approaches, how the IL-23p19 subunit can mechanistically control arthritic pain and disease in a T- and B- lymphocyte-independent manner. METHODS: We used the zymosan-induced arthritis (ZIA) model in wild-type and Il23p19-/- mice, by a radiation chimera approach, and by single cell RNAseq and qPCR analyses, to identify the IL23p19-expressing and IL-23-responding cell type(s) in the inflamed joints. This model was also utilized to investigate the efficacy of IL-23p19 subunit blockade with a neutralizing monoclonal antibody (mAb). A novel IL-23-driven arthritis model was established, allowing the identification of putative downstream mediators of IL-23 in the control of pain and disease. Pain and arthritis were assessed by relative static weight distribution and histology, respectively. RESULTS: We present evidence that (i) IL-23p19+ non-bone marrow-derived macrophages are required for the development of ZIA pain and disease, (ii) prophylactic and therapeutic blockade of the IL-23p19 subunit ameliorate ZIA pain and disease and (iii) systemically administered IL-23 can induce arthritic pain and disease in a manner dependent on TNF, GM-CSF, CCL17 and cyclooxygenase activity, but independently of lymphocytes, CGRP, NGF and substance P. CONCLUSIONS: The data presented should aid IL-23 targeting both in the choice of inflammatory disease to be treated and the design of clinical trials.

Comparison of Thermal and Mechanical Pain Testing Modalities in Sprague Dawley and Fischer 344 Rats (Rattus norvegicus).

While rodents are used extensively for studying pain, there is a lack of reported direct comparisons of thermal and mechanical pain testing methods in rats of different genetic backgrounds. Understanding the range of interindividual variability of withdrawal thresholds and thermal latencies based on these testing methods and/or genetic background is important for appropriate experimental design. Testing was performed in two common rat genetic backgrounds: outbred Sprague-Dawley (SD) and inbred Fischer 344 (F344). Male and female, 10- to 14-wk-old F344 and SD rats were used to assess withdrawal thresholds in 3 different modalities: the Randall-Selitto test (RST), Hargreaves test (HT), and tail flick test (TFT). The RST was performed by using an operator-controlled handheld instrument to generate a noxious pressure stimulus to the left hind paw. The HT and the TFT used an electronically controlled light source to deliver a noxious thermal stimulus to the left hind paw or tail tip, respectively. Rats of each sex and genetic background underwent one type of test on day 0 and day 7. Withdrawal thresholds and thermal latencies were compared among tests. No significant differences were observed. Our findings can serve as a guide for researchers considering these nociceptive tests for their experiments.

How can the pain sensitivity to be affected by maximal progressive exercise test during pregnancy?

The multidimensional etiology of pain may explain the beneficial effects of regular physical activity, as evidenced by increased pain tolerance. Physically active people find it easier to exert themselves, which enables them to increase their physical activity, which in turn leads to a reduction in pain. However, no study investigated the physical activity and exercise tests as modulators of pain sensitivity in pregnant women. Therefore, this study aimed to investigate the changes in pain perception in pregnant women during pregnancy, with a particular interest in the effects of maximal progressive exercise test (CPET) and self-performed physical activity (PA). Thirty-one women with an uncomplicated singleton pregnancy (aged 23-41 years; M = 31.29, SD = 4.18) were invited to participate in pain sensitivity measurements before and after CPET twice during pregnancy (with an 8-week break). We found that pregnant women had a significantly lower pain threshold after a maximal exercise test than before, regardless of whether the test was performed in the second or third trimester of pregnancy. This effect was most pronounced in women with low levels of physical activity. Second, women with high physical activity had higher pain tolerance than women with moderate and low physical activity. In addition, physical activity levels predicted changes in pain tolerance over the course of pregnancy, with negative changes in women with low physical activity and positive changes in women with moderate physical activity. Finally, these associations were not reflected in differences in the subjective pain experience.