Markers of Tissue Deterioration and Pain on Earth and in Space.

Purpose: Pain is an understudied physiological effect of spaceflight. Changes in inflammatory and tissue degradation markers are often associated with painful conditions. Our aim was to evaluate the changes in markers associated with tissue deterioration after a short-term spaceflight. Patients and Methods: Plasma levels of markers for systemic inflammation and tissue degeneration markers were assessed in two astronauts before and within 24 h after the 17-day Axiom Space AX-1 mission. Results: After the spaceflight, C-reactive protein (CRP) was reduced in both astronauts, while INFγ, GM-CSF, TNFα, BDNF, and all measured interleukins were consistently increased. Chemokines demonstrated variable changes, with consistent positive changes in CCL3, 4, 8, 22 and CXCL8, 9, 10, and consistent negative change in CCL8. Markers associated with tissue degradation and bone turnover demonstrated consistent increases in MMP1, MMP13, NTX and OPG, and consistent decreases in MMP3 and MMP9. Conclusion: Spaceflight induced changes in the markers of systemic inflammation, tissue deterioration, and bone resorption in two astronauts after a short, 17-day, which were often consistent with those observed in painful conditions on Earth. However, some differences, such as a consistent decrease in CRP, were noted. All records for the effect of space travel on human health are critical for improving our understanding of the effect of this unique environment on humans.

Pain Experience and Sensory Changes in Astronauts During and After Short-Lasting Commercial Spaceflight: A Proof-of-Concept Study.

Space travel has been associated with musculoskeletal pain, yet little is known about the nociceptive changes and pain experience during spaceflight. This preliminary study aims to investigate the pain experience and sensory alterations in astronauts following a 17-day mission to the International Space Station (ISS) on Axiom Space's AX-1 commercial space flight. Two participants were enrolled, and data were collected pre-flight, in-flight, post-flight, and three-month post-flight. Validated pain questionnaires assessed anxiety, catastrophizing, impact on physical and mental health, disability, and overall pain experience. Qualitative interviews were conducted post-landing and conditioned pain modulation (CPM) and quantitative sensory testing (QST) were performed. Both astronauts reported musculoskeletal pain during and after the flight, which was managed with anti-inflammatories and stretching techniques. Pain levels returned to baseline after three months. Pain questionnaires revealed heightened pain experiences in-flight and immediately post-flight, although their adequacy in assessing pain in space is uncertain. Qualitative interviews allowed astronauts to describe their pain experiences during the flight. Sensory changes included increased mechanical touch detection thresholds, temporal pain summation, heat pain thresholds, and differences in conditioned pain modulation post-flight. This preliminary study suggested that spaceflight may affect various aspects of sensory perception and regulation in astronauts, albeit in a variable manner. More data are needed to gain insight of on gain and loss of sensory functions during space missions. Further investigation into the multifactorial stressors affecting the somatosensory system during space travel could contribute to advancements in space and pain medicine.

The Psychosocial Characteristics and Somatosensory Function of Children and Adolescents Who Meet the Criteria for Chronic Nociplastic Pain.

Purpose: Nociplastic pain distinguishes individuals with pain and hypersensitivity in body regions with apparently normal tissues, without any signs of neuropathy, but with contribution of central and/or peripheral sensitization. There is a lack of literature describing nociplastic pain in the pediatric population. The objective of this study was to investigate the differences between pediatric patients with nociplastic pain compared with patients with non-nociplastic pain. Patients and Methods: This study included 414 pediatric patients followed at an interdisciplinary centre for complex pain. All patients underwent an exhaustive pain assessment consisting of face-to-face interviews, validated self-report questionnaires and quantitative sensory testing. Recently established criteria for chronic nociplastic pain, and quantitative sensory testing was used to describe and stratify our cohort. Results: One hundred and sixty-five patients (40%) were stratified as having possible nociplastic pain and two hundred and forty-nine (60%) patients, as non-nociplastic pain. Patients with nociplastic pain displayed pain hypersensitivity in the region of pain, more symptoms of panic and social phobia, and worse sleep quality than patients with non-nociplastic pain. The proportion of patients achieving a meaningful clinical outcome after completion of their treatment (medications, physiotherapy, psychology, nursing, social worker, and/or interventional procedures) was lower in patients with nociplastic pain (62%) than those without nociplastic pain (86%). Conclusion: Our results suggest that patients who meet the criteria for nociplastic pain can be identified in a population of children and adolescents being treated in a center for complex pain. Combining screening with validated questionnaires and quantitative sensory testing facilitates the phenotyping and graded severity of patients with nociplastic pain in daily clinical practice.

Evaluation of Nociception during Pediatric Surgery: A Topical Review.

The association between intraoperative nociception and increased patient's morbidity is well established. However, hemodynamic parameters, such as heart rate and blood pressure, may result in an inadequate monitor of nociception during surgery. Over the last two decades, different devices have been marketed to "reliably" detect intraoperative nociception. Since the direct measure of nociception is impractical during surgery, these monitors measures nociception surrogates such as sympathetic and parasympathetic nervous systems responses (heart rate variability, pupillometry, skin conductance), electroencephalographic changes, and muscular reflex arc. Each monitor carries its own advantages and disadvantages. The manuscript aims to give an overview of the most up-to-date information available in the literature on current nociceptor monitors available in clinical practice, with particular focus on their applications in pediatrics.

Experience and Management of the Adverse Effects of Analgesics After Surgery: A Pediatric Patient Perspective.

After surgery, the adverse effects (AEs) of analgesics are common and critical factors influencing the postoperative experience of pediatric patients. Inadequate management of AEs has been found to prolong hospital stay, increase readmission rates and decrease satisfaction with care. The aim of this qualitative descriptive study was to better understand the AEs of analgesics from the perspective of adolescent patients with idiopathic scoliosis after spinal surgery. A total of 7 patients participated in the study. Semistructured interviews were conducted at discharge and 1 week after discharge. Transcribed data were analyzed using qualitative content analysis and themes were identified. Overall, participants most frequently reported gastrointestinal and cognitive AEs, with constipation being the most persistent and bothersome. The pediatric participants used a combination of 3 strategies to mitigate analgesic AEs, namely pharmacologic, nonpharmacologic, and reduction of analgesic intake. Participants demonstrated a lack of understanding of AEs and involvement in their own care. Future studies should be conducted to evaluate the efficacy of nonpharmacological strategies in managing analgesic AEs for pediatric patients after surgery.

Phenotyping Chronic Musculoskeletal Pain in Male and Female Adolescents: Psychosocial Profiles, Somatosensory Profiles and Pain Modulatory Profiles.

PURPOSE: A major limitation in treatment outcomes for chronic pain is the heterogeneity of the population. Therefore, a personalized approach to the assessment and treatment of children and adolescents with chronic pain conditions is needed. The objective of the study was to subgroup pediatric patients with chronic MSK pain that will be phenotypically different from each other based on their psychosocial profile, somatosensory function, and pain modulation. PATIENTS AND METHODS: This observational cohort study recruited 302 adolescents (10-18 years) with chronic musculoskeletal pain and 80 age-matched controls. After validated self-report questionnaires on psychosocial factors were completed, quantitative sensory tests (QST) and conditioned pain modulation (CPM) were performed. RESULTS: Three psychosocial subgroups were identified: adaptive pain (n=125), high pain dysfunctional (n=115), high somatic symptoms (n=62). Based on QST, four somatosensory profiles were observed: normal QST (n=155), thermal hyperalgesia (n=98), mechanical hyperalgesia (n=34) and sensory loss (n=15). Based on CPM and temporal summation of pain (TSP), four distinct groups were formed, dysfunctional central processing group (n=27) had suboptimal CPM and present TSP, dysfunctional inhibition group (n=136) had suboptimal CPM and absent TSP, facilitation group (n=18) had optimal CPM and present TSP, and functional central processing (n=112) had optimal CPM and absent TSP. A significant association between the psychosocial and somatosensory profiles. However, no association was observed between the psychosocial or somatosensory profiles and pain modulatory profiles. CONCLUSION: Our results provide evidence that adolescents with chronic musculoskeletal pain are a heterogenous population comprising subgroups that may reflect distinct mechanisms and may benefit from different treatment approaches. The combination of screening self-reported questionnaires, QST, and CPM facilitate subgrouping of adolescents with chronic MSK pain in the clinical context and may ultimately contribute to personalized therapy.

Canadian surveillance study of complex regional pain syndrome in children.

ABSTRACT: This study describes the minimum incidence of pediatric complex regional pain syndrome (CRPS), clinical features, and treatments recommended by pediatricians and pain clinics in Canada. Participants in the Canadian Paediatric Surveillance Program reported new cases of CRPS aged 2 to 18 years monthly and completed a detailed case reporting questionnaire from September 2017 to August 2019. Descriptive analysis was completed, and the annual incidence of CRPS by sex and age groupings was estimated. A total of 198 cases were reported to the Canadian Paediatric Surveillance Program, and 168 (84.8%) met the case definition. The minimum Canadian incidence of CRPS is estimated at 1.14/100,000 (95% confidence interval 0.93-1.35/100,000) children per year. Incidence was highest among girls 12 years and older (3.10, 95% confidence interval 2.76-3.44/100,000). The mean age of CRPS diagnosis was 12.2 years (SD = 2.4), with the mean time from symptom onset to diagnosis of 5.6 months (SD = 9.9) and no known inciting event for 19.6% of cases. Most cases had lower limb involvement (79.8%). Nonsteroidal anti-inflammatory drugs (82.7%) and acetaminophen (66.0%) were prescribed more commonly than antiepileptic drugs (52.3%) and antidepressants (32.0%). Referrals most commonly included physical therapy (83.3%) and multidisciplinary pain clinics (72.6%); a small number of patients withdrew from treatment because of pain exacerbation (5.3%). Pain education was recommended for only 65.6% of cases. Treatment variability highlights the need for empiric data to support treatment of pediatric CRPS and development of treatment consensus guidelines.

Unbiased immune profiling reveals a natural killer cell-peripheral nerve axis in fibromyalgia.

ABSTRACT: The pathophysiology of fibromyalgia syndrome (FMS) remains elusive, leading to a lack of objective diagnostic criteria and targeted treatment. We globally evaluated immune system changes in FMS by conducting multiparametric flow cytometry analyses of peripheral blood mononuclear cells and identified a natural killer (NK) cell decrease in patients with FMS. Circulating NK cells in FMS were exhausted yet activated, evidenced by lower surface expression of CD16, CD96, and CD226 and more CD107a and TIGIT. These NK cells were hyperresponsive, with increased CCL4 production and expression of CD107a when co-cultured with human leukocyte antigen null target cells. Genetic and transcriptomic pathway analyses identified significant enrichment of cell activation pathways in FMS driven by NK cells. Skin biopsies showed increased expression of NK activation ligand, unique long 16-binding protein, on subepidermal nerves of patients FMS and the presence of NK cells near peripheral nerves. Collectively, our results suggest that chronic activation and redistribution of circulating NK cells to the peripheral nerves contribute to the immunopathology associated with FMS.

The Pittsburgh Sleep Quality Index: Reliability, Factor Structure, and Related Clinical Factors among Children, Adolescents, and Young Adults with Chronic Pain.

This study is aimed at assessing the psychometric properties and the factorial structure of the Pittsburgh Sleep Quality Index (PSQI) in a clinical sample of children, adolescents, and young adults with chronic pain. Data of 482 participants (aged 8-21 years) from two crosssectional studies and a chronic pain services outpatient clinic were analyzed. Exploratory and confirmatory factor analysis and reliability analysis of PSQI component scores were performed. Relationships between the PSQI global score and various clinical measures were investigated to assess external validity. The findings exhibit the reliability and validity of a single-factor model of the PSQI in a clinical sample of youth with chronic pain and support the relationship in this specific population between poor sleep quality and important clinical measures of well-being. These results support an informed decision regarding its use with this specific population and underscore the clinical relevance of assessing sleep quality.

Acute postoperative opioid consumption trajectories and long-term outcomes in pediatric patients after spine surgery.

Background: The days following surgery are a critical period where the use of opioids predicts long-term outcomes in adults. It is currently unknown as to whether opioid consumption throughout the acute postoperative period is associated with long-term outcomes in pediatric patients. The aims of this study were to characterize opioid consumption trajectories in the acute postoperative period, identify predictors of trajectory membership and determine associations between opioid consumption trajectories and long-term patient outcomes. Materials and methods: Medication use, pain and mental health status were assessed at baseline in adolescents with idiopathic scoliosis who were scheduled for spinal fusion surgery. Cumulative 6-hr opioid consumption was recorded for up to 5 days after spinal surgery. At 6 months after surgery, medication use, pain and functional activity were evaluated. Growth mixture modeling was used to identify opioid trajectories. Results: One hundred and six patients were included in the study. Mean cumulative 6-hr opioid consumption in the acute postoperative period was 13.23±5.20 mg/kg. The model with the best fit contained 5 acute postoperative trajectories and a quadratic term (AIC =6703.26, BIC =6767.19). Two types of patient behaviors were identified: high opioid consumers (trajectories 4 and 5) and low opioid consumers (trajectories 1, 2 and 3). Intraoperative intrathecal morphine dose was a predictor of trajectory membership (p=0.0498). Opioid consumption during the acute postoperative period was not significantly associated with pain, functional activity or pain medication use at 6 months after surgery. Conclusion: In pediatric patients, intraoperative intrathecal morphine dose predicts opioid consumption in the acute postoperative period. Importantly, opioid consumption during this period does not affect long-term outcomes in pediatric patients after a spine surgery.

Chronic non-cancer pain in children: we have a problem, but also solutions.

Chronic non-cancer pain in children and adolescents has been described as "a modern public health disaster" that has generated significant medical and economic burdens within society. Seen as a disease in its own right, chronic pain has short and long-term consequences that impact not only the patient's health but also that of friends and families, due to significant parenting stress and disruptions in family life and structure. The evidence supporting pharmacological treatments and interventional procedures is limited, and no single strategy has been shown to be completely effective in children with chronic non-cancer pain. Therefore, considering the multifactorial nature of chronic pain, these patients should be treated with a multidisciplinary, balanced approach that seeks a primary outcome of improved functioning rather than of pain reduction. Using a bio-psycho-social approach, a multidisciplinary team, including a physiotherapist, nurse, social worker, psychologist, and physician, has been effective in achieving this outcome of improved functioning in children and adolescents with chronic pain. In this review, we discuss the impact, associated conditions, and evolution of chronic pain, along with the crucial role of every member of a multidisciplinary chronic pain clinic involved in the care of the children and adolescents with chronic non-cancer pain.

Acute pain management in children: challenges and recent improvements.

PURPOSE OF REVIEW: The evidence regarding the efficacy of analgesics available to guide postoperative pain treatment in pediatric patients is limited. Opioid medications are very often an important component of pediatric postoperative pain treatment but have been associated with perioperative complications. We will focus on initiatives aiming to provide effective treatment minimizing the use of opioids and preventing the long-term consequences of pain. RECENT FINDINGS: Interpatient variability in postoperative pain is currently managed by applying protocols or by trial and error, thus often leading to patients being either undertreated or overtreated. Few evidence-based reports are available to guide the use of opioid medications in children, including the prescription of opioids after hospital discharge. Using combinations of nonopioid analgesics in a multimodal approach may limit the need for opioids, thus decreasing the risk of toxicity and dose-related side effects. There is a lack of adequate research in this field, and more specifically on identifying which patient is at higher risk of poor postoperative pain management. SUMMARY: Treatment options have evolved in recent years, including the combinations of multimodal regimens and regional anesthetic techniques. Using combinations of nonopioid analgesics in a multimodal approach may limit the need for opioids.

Preoperative Norepinephrine Levels in Cerebrospinal Fluid and Plasma Correlate With Pain Intensity After Pediatric Spine Surgery.

PURPOSE: Catecholamines were found to be involved in descending pain modulation and associated with perioperative pain. The purpose of the present study was to investigate the relationship between preoperative concentrations of catecholamines and postoperative pain intensity of pediatric patients. METHODS: Fifty adolescents with idiopathic scoliosis scheduled for elective spinal fusion surgery were enrolled in this prospective cohort study. Preoperative plasma and cerebrospinal fluid (CSF) samples were collected and analyzed by mass spectrometry. Pain intensity was assessed during the acute postoperative period and in the intermediate period. RESULTS: Preoperative plasma concentrations of norepinephrine (NE) and normetanephrine (NME), as well as the CSF concentration of NE, were significantly correlated with the presence of pain six weeks after surgery (r = 0.48, 0.50, and 0.50, respectively; p < .002). We also found that preoperative NE levels in CSF were significantly higher in patients reporting moderate to severe pain intensity than in patients with mild pain during the first day following surgery (0.268 ± 0.29 ng/mL vs. 0.121 ± 0.074 ng/mL, p = .01), as well as between patients reporting pain and painless patients at 6 weeks postsurgery (0.274 ± 0.282 ng/mL vs. 0.103 ± 0.046 ng/mL respectively, U = 69.5, p = .002). CONCLUSIONS: These results support the potential role of catecholamine levels in predicting postoperative pain intensity.

Changes in total plasma and serum N-glycome composition and patient-controlled analgesia after major abdominal surgery.

Systemic inflammation participates to the complex healing process occurring after major surgery, thus directly affecting the surgical outcome and patient recovery. Total plasma N-glycome might be an indicator of inflammation after major surgery, as well as an anti-inflammatory therapy response marker, since protein glycosylation plays an essential role in the inflammatory cascade. Therefore, we assessed the effects of surgery on the total plasma N-glycome and the association with self-administration of postoperative morphine in two cohorts of patients that underwent major abdominal surgery. We found that plasma N-glycome undergoes significant changes one day after surgery and intensifies one day later, thus indicating a systemic physiological response. In particular, we observed the increase of bisialylated biantennary glycan, A2G2S[3,6]2, 12 hours after surgery, which progressively increased until 48 postoperative hours. Most changes occurred 24 hours after surgery with the decrease of most core-fucosylated biantennary structures, as well as the increase in sialylated tetraantennary and FA3G3S[3,3,3]3 structures. Moreover, we observed a progressive increase of sialylated triantennary and tetraantennary structures two days after surgery, with a concomitant decrease of the structures containing bisecting N-acetylglucosamine along with bi- and trisialylated triantennary glycans. We did not find any statistically significant association between morphine consumption and plasma N-glycome.

Human Genetic Variability Contributes to Postoperative Morphine Consumption.

UNLABELLED: High interindividual variability in postoperative opioid consumption is related to genetic and environmental factors. We tested the association between morphine consumption, postoperative pain, and single nucleotide polymorphisms (SNPs) within opioid receptor µ 1 (OPRM1), catechol-O-methyltransferase (COMT), uridine diphosphate glucose-glucuronosyltransferase-2B7, and estrogen receptor (ESR1) gene loci to elucidate genetic prediction of opioid consumption. We analyzed 20 SNPs in 201 unrelated Caucasian patients who underwent abdominal surgery and who were receiving postoperative patient-controlled analgesia-administered morphine. Morphine consumption and pain intensity were dependent variables; age and sex were covariates. A haplotype of 7 SNPs in OPRM1 showed significant additive effects on opioid consumption (P = .007); a linear regression model including age and 9 SNPs in ESR1, OPRM1, and COMT explained the highest proportion of variance of morphine consumption (10.7%; P = .001). The minimal model including 3 SNPs in ESR1, OPRM1, and COMT explained 5% of variance (P = .007). We found a significant interaction between rs4680 in COMT and rs4986936 in ESR1 (P = .007) on opioid consumption. SNPs rs677830 and rs540825 of OPRM1 and rs9340799 of ESR1 were nominally associated with pain Numeric Rating Scale scores. Combinations of genetic variants within OPRM1, COMT, and ESR1 better explain variability in morphine consumption than single genetic variants. Our results contribute to the development of genetic markers and statistical models for future diagnostic tools for opioid consumption/efficacy. PERSPECTIVE: This article presents the efforts dedicated to detect correlations between the genetic polymorphisms and the clinical morphine effect self-administered by patients using a patient-controlled analgesia pump after major surgery. The clinical effect is expressed in terms of morphine consumption and pain scores. REGISTERED ON CLINICALTRIALS.GOV: NCT01233752.

Postoperative Analgesia after Laparoscopic Ovarian Cyst Resection: Double-blind Multicenter Randomized Control Trial Comparing Intraperitoneal Nebulization and Peritoneal Instillation of Ropivacaine.

STUDY OBJECTIVE: To compare the effects of local anesthetic intraperitoneal nebulization with intraperitoneal instillation during laparoscopic ovarian cystectomy on postoperative morphine consumption and pain. DESIGN: Multicenter, randomized, case-control trial. DESIGN CLASSIFICATION: Canadian Task Force Classification I. SETTING: University hospitals in Italy. PATIENTS: One hundred forty patients scheduled for laparoscopic ovarian cystectomy. INTERVENTIONS: Patients were randomized to receive either nebulization of ropivacaine 150 mg before surgery or instillation of ropivacaine 150 mg before surgery. Nebulization was performed using the Aeroneb Pro device (Aerogen, Galway, Ireland). MEASUREMENTS AND MAIN RESULTS: One hundred forty patients were enrolled, and 123 completed the study. There was no difference between the 2 groups in average morphine consumption (7.3 ± 7.5 mg in the nebulization group vs 9.2 ± 7.2 mg in the instillation group; p = .17). Eighty-two percent of patients in the nebulization group required morphine compared with 96% in the instillation group (p < .05). Patients receiving nebulization had a lower dynamic Numeric Ranking Scale compared with those in the instillation group in the postanesthesia care unit postanesthesia care unit and 4 hours after surgery (p < .05). Ten patients (15%) in the nebulization group experienced shivering in the postanesthesia care unit compared with 2 patients (4%) in the instillation group (p = .035). CONCLUSION: Nebulization of ropivacaine prevents the use of morphine in a significant proportion of patients, reduced postoperative pain during the first hours after surgery, and was associated with a higher incidence of postoperative shivering when compared with instillation.