Heeding Pain's Prescription.

Newer definitions of pain remain suggestive of categorization by mainly neurological or psychological bases. All pain recruits cortical interpretation for any sort of directive effects in awareness, attention, and action. That unity of purpose in pain's multi-pathway manifestations can inspire neurophilosophical reflections on the existentiality, subjectivity, and sociality of pain. Pain is neither so subjective as to be relieved of meaning, nor so objective that multi-modal approaches can take turns at targeting its relief. The problem of objectifying the subjective is essential for addressing issues of assessing and treating pain. Integrative plans for pain care make sense if and when all aspects of pain's character are deemed to be integral, and are actually integrated in both theory in practice. A standpoint on the "entity-identity" of pain afflicting the whole person implies that pain is expressed behaviorally and as articulately as circumstances permit. Pain speaks, even for those not able to speak, as their patterns of brain activity may be representative of pain. Heeding pain's prescriptive voice requires collective interpretations before attempting coordinated treatments. Pain's prescription will remain unfilled until its full reality is recognized at a personal level, where comprehensive care is mobilized for the whole patient. Heeding pain looks to the central figure that is never absent from any painful situation, namely the individual person-in-pain. That holistic and humanistic value to mobilizing resources against pain should be reflected in the practice of pain medicine, and the craft of the pain physician.

Uncertainty quantification in neural-network based pain intensity estimation.

Improper pain management leads to severe physical or mental consequences, including suffering, a negative impact on quality of life, and an increased risk of opioid dependency. Assessing the presence and severity of pain is imperative to prevent such outcomes and determine the appropriate intervention. However, the evaluation of pain intensity is a challenging task because different individuals experience pain differently. To overcome this, many researchers in the field have employed machine learning models to evaluate pain intensity objectively using physiological signals. However, these efforts have primarily focused on pain point estimation, disregarding inherent uncertainty and variability in the data and model. A point estimate, which provides only partial information, is not sufficient for sound clinical decision-making. This study proposes a neural network-based method for objective pain interval estimation, and quantification of uncertainty. Our approach, which enables objective pain intensity estimation with desired confidence probabilities, affords clinicians a better understanding of a person's pain intensity. We explored three distinct algorithms: the bootstrap method, lower and upper bound estimation (LossL) optimized by genetic algorithm, and modified lower and upper bound estimation (LossS) optimized by gradient descent algorithm. Our empirical results demonstrate that LossS outperforms the other two by providing narrower prediction intervals. For 50%, 75%, 85%, and 95% prediction interval coverage probability, LossS provides average interval widths that are 22.4%, 7.9%, 16.7%, and 9.1% narrower than those of LossL, and 19.3%, 21.1%, 23.6%, and 26.9% narrower than those of bootstrap. As LossS outperforms, we assessed its performance in three different model-building approaches: (1) a generalized approach using a single model for the entire population, (2) a personalized approach with separate models for each individual, and (3) a hybrid approach with models for clusters of individuals. Results demonstrate that the hybrid model-building approach provides the best performance.

The effect of Camellia sinensis ointment on perineal pain and episiotomy wound healing in primiparous women: A triple-blind randomized clinical trial.

BACKGROUND AND OBJECTIVE: Episiotomy is one of the most commonly performed procedures in obstetrics. complications of episiotomy are pain, bleeding, infection, pain in the sitting position, and difficulty in taking care of the baby. This study aimed to investigate the effect of Camellia sinensis ointment on perineal pain and episiotomy wound healing in primiparous women. METHODS: This triple-blinded randomized clinical trial was conducted on 60 primiparous women who were referred to the maternity ward of Al-Hadi hospital in Shoushtar and Ganjovian hospital in Dezful, Iran, from 2020 to 2021. Participants were randomly assigned into two groups of intervention (Camellia sinensis extract ointment) and control (placebo) with a follow-up of 14 days. REEDA scale (redness, edema, ecchymosis, discharge, and approximation) was used to measure wound healing and the Visual Analog Scale (VAS) was used to measure the pain intensity. RESULTS: There was no significant difference between two groups before intervention in terms of sociodemographic characteristics, pain intensity, and episiotomy wound status. Scores of pain intensity and wound healing reduced on days 7, 10, and 14 post-intervention in the intervention group compared to placebo. There was a significant decrease between the groups of intervention and control in terms of the mean score of pain intensity (VAS scale) on day 10 (1.33 ± 0.71, 1.77 ± 0.93) and day 14 (0.73 ± 0.74, 1.13 ± 0.81) post-intervention (P < 0.05). Also, on day 14 post-intervention, there was a significant decrease between the groups of intervention and control in terms of the mean score of episiotomy wound healing (REEDA index) (0.53 ± 0.77, 1.77 ± 1.46) (P < 0.05). The GLM test was applied for repeated measures. REEDA index and VAS scale changed during different times (time-variable) (p < .001). But, the studied groups (group variable) and the studied groups (interaction effect of group * time) did not affect the changes in the REEDA index (p = .292, p = .306) and VAS scale (p = .47) during different times. CONCLUSION: Our study showed that Camellia sinensis extract ointment has a small effect on the healing process and pain reduction of episiotomy wounds. to confirm its effect, a study with a larger sample size should be conducted. TRIAL REGISTRATION: This trial was registered in the Iranian Registry of Clinical Trials on 04/10/2019 with the IRCT ID: IRCT20190804044428N1. Participants were enrolled between 11 April 2020 and 20 January 2021. URL of registry: https://en.irct.ir/trial/41326.

Ketamine for Pain in Hospice Patients - A Transdermal Gel Applied to the Painful Site.

The author has been using ketamine to treat hospice patients for several years, with varying degrees of success, and reports being most successful with the transdermal-gel form. He has also had success with ketamine administered as a nasal spray. In addition to providing general comments on the use of ketamine in this context, he presents four brief case reports demonstrating the use of ketamine and other medications in treating pain associated with various types of cancer.

Association between pain intensity and depressive status in patients with hip fracture: An observational study.

Identifying depression symptoms in patients with hip fractures and studying the relationship between depression and pain intensity and pain location in hip fracture patients is of great significance for disease recovery in hip fracture patients. This cohort study analyzed 5 wave data from the China Health and Retirement Longitudinal Study in 2011, 2013, 2015, 2018, and 2020, focusing on 1222 patients with hip fractures. The study utilized the CESD-10 Depression Scale to assess depressive symptoms in hip fracture patients and conducted analyses to explore the relationship between depression symptoms, pain, and pain intensity, including binary logistic regression and examination of interaction terms between pain variables and pain intensity in key body parts. Depression symptoms are strongly associated with pain intensity in hip fracture patients, particularly in key body areas. Severe pain significantly increases the risk of depressive symptoms. Moreover, absence of pain in other key body parts is linked to depressive symptoms. Multivariate analysis reveals that higher education levels, marriage, urban residence, and self-rated good health serve as protective factors against depression, while diabetes and heart disease pose significant risks for depressive symptoms in hip fracture patients. Hip fracture pain can induce discomfort and trigger depressive symptoms, showing varied trajectories among patients. Pain intensity predicts the course of depressive symptoms, emphasizing the importance of tailored pain management strategies including medication, physical therapy, and nonpharmacological interventions. Personalized rehabilitation and mental health plans should be designed based on individual patient needs and differences.

Intraplantar aminoglutethimide, a P450scc inhibitor, reduced the induction of mechanical allodynia in a rat model of thrombus-induced ischemic pain.

Neuroactive steroids (NASs) directly affect neuronal excitability. Despite their role in the nervous system is intimately linked to pain control, knowledge is currently limited. This study investigates the peripheral involvement of NASs in chronic ischemic pain by targeting the cytochrome P450 side-chain cleavage enzyme (P450scc). Using a rat model of hind limb thrombus-induced ischemic pain (TIIP), we observed an increase in P450scc expression in the ischemic hind paw skin. Inhibiting P450scc with intraplantar aminoglutethimide (AMG) administration from post-operative day 0 to 3 significantly reduced the development of mechanical allodynia. However, AMG administration from post-operative day 3 to 6 did not affect established mechanical allodynia. In addition, we explored the role of the peripheral sigma-1 receptor (Sig-1R) by co-administering PRE-084 (PRE), a Sig-1R agonist, with AMG. PRE reversed the analgesic effects of AMG during the induction phase. These findings indicate that inhibiting steroidogenesis with AMG alleviates peripheral ischemic pain during the induction phase via Sig-1Rs.

Meningeal lymphatic vessel dysfunction driven by CGRP signaling causes migraine-like pain in mice.

Migraines are a type of headache that occur with other neurological symptoms, but the pathophysiology remains unclear. In this issue of the JCI, Nelson-Maney and authors used constitutive and inducible knockouts of the CGRP receptor components, elegantly demonstrating an essential function of CGRP in modulating meningeal lymphatic vessels (MLVs) in migraine. CGRP was shown to induce rearrangement of membrane-bound gap junction proteins in MLVs, resulting in a reduced CSF flux into cervical lymph nodes. The authors also provided evidence of a primary role for CGRP in modulating neuro-immune function. Finally, by showing that blocking CGRP signaling in MLVs attenuated pain behavior associated with acute migraine in rodents, the authors provided a target for pharmacological blockade of CGRP in relation to primary headache disorders.

[Virtual reality in the outpatient: reducing anxiety and fear in venous puncture]. / Realidad virtual en el paciente ambulatorio: reduciendo la ansiedad y el miedo en la punción de vías venosas.

Up to 80% of children admitted to a hospital experience pain, mainly associated with venipuncture. OBJECTIVE: To analyze whether the use of virtual reality (VR) headsets during venipuncture can modify the perception of pain, anxiety, and fear in pediatrics. PATIENTS AND METHOD: Open label, randomized clinical trial. The presence of intellectual, visual, or hearing impairment were considered exclusion criteria. Two anxiety and fear scales were administered before and after the procedure, and the Wong-Baker face pain scale at the end. The following were recorded: number of venipuncture attempts, duration of the procedure, and side effects. RESULTS: 78 patients were included, 38 males and a mean age of 9.63 years. In the intervention group, the mean pain value was 2.87, with a mean difference (MD) of -0.85 compared with the control one (95% confidence interval (CI) -2.02 to 0.33). There was a significant reduction in the level of anxiety and fear, with MDs of -2.59 (95%CI: -3.92 to -1.26) and -0.85 points (95%CI: -1.45 to -0.24), respectively. CONCLUSIONS: the use of VR headsets in venipuncture in hospital daytime care decreases the level of anxiety and fear in children and seems to reduce pain, without adverse effects. The venipuncture procedure has the same success rate and does not increase its duration.

Using joint probability density to create most informative unidimensional indices: a new method using pain and psychiatric severity as examples.

BACKGROUND: Dimension reduction methods do not always reduce their underlying indicators to a single composite score. Furthermore, such methods are usually based on optimality criteria that require discarding some information. We suggest, under some conditions, to use the joint probability density function (joint pdf or JPD) of p-dimensional random variable (the p indicators), as an index or a composite score. It is proved that this index is more informative than any alternative composite score. In two examples, we compare the JPD index with some alternatives constructed from traditional methods. METHODS: We develop a probabilistic unsupervised dimension reduction method based on the probability density of multivariate data. We show that the conditional distribution of the variables given JPD is uniform, implying that the JPD is the most informative scalar summary under the most common notions of information. B. We show under some widely plausible conditions, JPD can be used as an index. To use JPD as an index, in addition to having a plausible interpretation, all the random variables should have approximately the same direction(unidirectionality) as the density values (codirectionality). We applied these ideas to two data sets: first, on the 7 Brief Pain Inventory Interference scale (BPI-I) items obtained from 8,889 US Veterans with chronic pain and, second, on a novel measure based on administrative data for 912 US Veterans. To estimate the JPD in both examples, among the available JPD estimation methods, we used its conditional specifications, identified a well-fitted parametric model for each factored conditional (regression) specification, and, by maximizing the corresponding likelihoods, estimated their parameters. Due to the non-uniqueness of conditional specification, the average of all estimated conditional specifications was used as the final estimate. Since a prevalent common use of indices is ranking, we used measures of monotone dependence [e.g., Spearman's rank correlation (rho)] to assess the strength of unidirectionality and co-directionality. Finally, we cross-validate the JPD score against variance-covariance-based scores (factor scores in unidimensional models), and the "person's parameter" estimates of (Generalized) Partial Credit and Graded Response IRT models. We used Pearson Divergence as a measure of information and Shannon's entropy to compare uncertainties (informativeness) in these alternative scores. RESULTS: An unsupervised dimension reduction was developed based on the joint probability density (JPD) of the multi-dimensional data. The JPD, under regularity conditions, may be used as an index. For the well-established Brief Pain Interference Inventory (BPI-I (the short form with 7 Items) and for a new mental health severity index (MoPSI) with 6 indicators, we estimated the JPD scoring. We compared, assuming unidimensionality, factor scores, Person's scores of the Partial Credit model, the Generalized Partial Credit model, and the Graded Response model with JPD scoring. As expected, all scores' rankings in both examples were monotonically dependent with various strengths. Shannon entropy was the smallest for JPD scores. Pearson Divergence of the estimated densities of different indices against uniform distribution was maximum for JPD scoring. CONCLUSIONS: An unsupervised probabilistic dimension reduction is possible. When appropriate, the joint probability density function can be used as the most informative index. Model specification and estimation and steps to implement the scoring were demonstrated. As expected, when the required assumption in factor analysis and IRT models are satisfied, JPD scoring agrees with these established scores. However, when these assumptions are violated, JPD scores preserve all the information in the indicators with minimal assumption.

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.

Correlation of Posterior Tibial Tendon Ultrasound with Calcaneal Inclination Angle in Indonesian Professional Athletes with Medial Ankle Pain.

Background: Adult-acquired flatfoot deformity (AAFD) is characterized by partial or complete flattening of the longitudinal medial arch, which develops after maturity. AAFD secondary to posterior tibialis tendon dysfunction (PTTD) is one of professional athletes' most common foot and ankle pathologies. Different modalities and procedures can be used to establish the diagnosis of AAFD and PTTD. However, imaging measurements such as the calcaneal inclination index and ultrasonography (US) of the posterior tibialis tendon (PTT) in professional athletes with medial ankle and focal pain along the PTT have yet to be widely studied. This study investigates the correlation of PTT ultrasound for evaluating PTTD with calcaneal inclination angle (CIA) for evaluating AAFD in professional athletes with medial ankle and focal pain along the PTT. Through this study, clinicians and radiologists may benefit from considering AAFD in athletes with PTTD. Methods: 112 Indonesian professional athletes with medial ankle or foot pain and focal pain along the direction of the PTT underwent foot radiography using the CIA and ankle ultrasound to observe PTT abnormalities. Results: A negative correlation between fluid thickness surrounding the PTT and the CIA (p<0.001; 95% CI - 0.945, - 0.885), as well as a negative correlation between PTT thickness and CIA (p<0.001, 95% CI - 0.926, - 0.845), with a correlation coefficient (r) of - 0.921 and - 0.892, respectively. No significant correlation was found between PTT tear and CIA (p = 0.728; 95% CI -0.223, - 0.159; r - 0.033). Conclusion: This study showed a negative correlation between PTTD and AAFD via ultrasound and CIA in professional athletes with medial ankle and focal pain along the PTT. A better understanding of PTTD and AAFD imaging will lead to more effective management and prompt treatment.

Study of PT1 Peptide Analgesic and Anti-Inflammatory Activity on a Local Inflammation Model in Mice CD-1.

PT1 peptide isolated from the venom of spider Geolycosa sp. is a modulator of P2X3 receptors that play a role in the development of inflammation and the transmission of pain impulses. The anti-inflammatory and analgesic efficacy of the PT1 peptide was studied in a model of complete Freund's adjuvant-induced paw inflammation in CD-1 mice. The analgesic activity of PT1 peptide was maximum after intramuscular injection at a dose of 0.01 mg/kg, which surpassed the analgesic effect of diclofenac at a dose of 1 mg/kg. The anti-inflammatory activity was maximum after intramuscular injection at a dose of 0.0001 mg/kg; a decrease in paw thickness was observed as soon as 2 h after the administration of the PT1 peptide against the background of inflammation development. All tested doses of PT1 peptide showed high anti-inflammatory activity 4 and 24 h after administration. PT1 peptide at a dose of 0.01 mg/kg when injected intramuscularly simultaneously produced high anti-inflammatory and analgesic effects compared to other doses of the peptide. Increasing the dose of PT1 peptide led to a gradual decrease in its analgesic and anti-inflammatory activity; increasing the dose of intramuscular injection to 0.1 and 1 mg/kg is inappropriate.

The Influence of Sex Steroid Hormone Fluctuations on Capsaicin-Induced Pain and TRPV1 Expression.

Sexual dimorphism among mammals includes variations in the pain threshold. These differences are influenced by hormonal fluctuations in females during the estrous and menstrual cycles of rodents and humans, respectively. These physiological conditions display various phases, including proestrus and diestrus in rodents and follicular and luteal phases in humans, distinctly characterized by varying estrogen levels. In this study, we evaluated the capsaicin responses in male and female mice at different estrous cycle phases, using two murine acute pain models. Our findings indicate that the capsaicin-induced pain threshold was lower in the proestrus phase than in the other three phases in both pain assays. We also found that male mice exhibited a higher pain threshold than females in the proestrus phase, although it was similar to females in the other cycle phases. We also assessed the mRNA and protein levels of TRPV1 in the dorsal root and trigeminal ganglia of mice. Our results showed higher TRPV1 protein levels during proestrus compared to diestrus and male mice. Unexpectedly, we observed that the diestrus phase was associated with higher TRPV1 mRNA levels than those in both proestrus and male mice. These results underscore the hormonal influence on TRPV1 expression regulation and highlight the role of sex steroids in capsaicin-induced pain.

Identification of Oxidative Stress-Related Biomarkers for Pain-Depression Comorbidity Based on Bioinformatics.

Oxidative stress has been identified as a major factor in the development and progression of pain and psychiatric disorders, but the underlying biomarkers and molecular signaling pathways remain unclear. This study aims to identify oxidative stress-related biomarkers and signaling pathways in pain-depression comorbidity. Integrated bioinformatics analyses were applied to identify key genes by comparing pain-depression comorbidity-related genes and oxidative stress-related genes. A total of 580 differentially expressed genes and 35 differentially expressed oxidative stress-related genes (DEOSGs) were identified. By using a weighted gene co-expression network analysis and a protein-protein interaction network, 43 key genes and 5 hub genes were screened out, respectively. DEOSGs were enriched in biological processes and signaling pathways related to oxidative stress and inflammation. The five hub genes, RNF24, MGAM, FOS, and TKT, were deemed potential diagnostic and prognostic markers for patients with pain-depression comorbidity. These genes may serve as valuable targets for further research and may aid in the development of early diagnosis, prevention strategies, and pharmacotherapy tools for this particular patient population.

Management and outcomes among patients with hard-to-heal ulcers in Sweden: a national mapping of data from medical records, focusing on diagnoses, ulcer healing, ulcer treatment time, pain and prescription of analgesics and antibiotics.

OBJECTIVE: To investigate whether patients with hard-to-heal ulcers in Sweden were treated according to an aetiological diagnosis and to explore ulcer healing, treatment time, ulcer-related pain and the prescription of analgesics and antibiotics. DESIGN: A national mapping of data from the patients' medical records, between April 2021 and March 2023. SETTING: Data from medical records for patients with hard-to-heal ulcers from a randomised clustered sample of two units per level of care and region. PARTICIPANTS: Patients with hard-to-heal ulcers treated in primary, community and specialist care, public or private, within units covering all 21 regions in Sweden. OUTCOME MEASURES: Descriptive analysis of data from the patients' medical records. RESULTS: A total of 2470 patients from 168 units were included, of which 39% were treated in primary care, 24% in community care and 37% in specialist care. A total of 49% of patients were treated without an aetiological diagnosis. Healing occurred in 37% of patients and ulcer-related pain was experienced by 1224 patients (50%). Antibiotics were given to 56% of the patients. Amputation occurred in 5% and 11% were deceased. CONCLUSION: Only 51% of patients with hard-to-heal ulcers had a documented aetiological ulcer diagnosis, which means that approximately 20 000 patients in Sweden might receive suboptimal treatment. Future research needs to explore why so many patients are undiagnosed and how to improve diagnosis, which could lead to faster healing and shorter treatment times.