Dalhousie University

We are pleased to introduce the collection Frontiers in Pain Research – Highlights in Pediatric Pain 2021/22. This collection will welcome and showcase a selection of high impact articles authored by leaders in the field. The work presented here highlights the broad diversity of research performed across the Pediatric Pain section, and aims to put a spotlight on the main areas of interest. This collection aims to further support Frontiers’ strong community by shining a spotlight on our authors' highly impactful research.

College of Medicine, University of Nigeria

University of Malaga

University of Bath

Frontiers in Pain Research

Pediatric Pain

Highlights in Pediatric Pain 2021/22

Editorial on the Research Topic <a href="https://www.frontiersin.org/research-topics/32706/highlights-in-pediatric-pain-202122">Highlights in pediatric pain 2021/22</a>Chronic pain affects one in four children and adolescents (<a href="#B1">1</a>–<a href="#B3">3</a>) and has been declared a global health priority (<a href="#B4">4</a>) because of its economic burden to society (<a href="#B5">5</a>) and substantial impact on child and family (<a href="#B6">6</a>). Psychological treatments have been found to be effective in reducing pain intensity and disability (<a href="#B7">7</a>, <a href="#B8">8</a>), however, there is considerable variability in treatment response, such that some children and adolescents benefit while others do not and more research has been called for in this area. This editorial highlights the broad diversity of research performed across the Pediatric Pain section, including a summary of pediatric chronic pain management modalities, from bench to bedside, and an intersect of the biopsychosocial aspects of pain. It includes five manuscripts: three original studies, one brief research report and one mini review.The review article by <a href="https://doi.org/10.3389/fpain.2022.1022699">Jotwani et al.</a> highlights the importance of behavioural treatments in pediatric chronic pain, the latter being widespread and of complex nature as a result of the progressive growth of the nervous system (<a href="#B9">9</a>). The authors found mixed efficacy of psychological interventions for pain outcomes, proposing interactions between psychosocial factors such as pain catastrophizing and biobehavioral mechanisms like inflammatory biomarkers, and the relevance of such interactions to patient treatment outcomes, the authors posit that in order to further expand this vital research area, conducting mechanistic clinical trials (which are studies involving human participants to have a better understanding of biologic or behavioral mechanisms) (<a href="#B10">10</a>) utilizing mixed methods may help explain the mixed results. They suggest that neuroimaging techniques (especially fNIRs imaging) to observe for neurologic pain processes and artificial intelligence to detect pain predictors are new frontiers in mechanistic pediatric pain research.In line with the suggestions of the review by <a href="https://doi.org/10.3389/fpain.2022.1022699">Jotwani et al.</a> <a href="https://doi.org/10.3389/fpain.2022.962037">Lalouni et al.</a> explored the role of parental factors on psychological treatment effects. They conducted a secondary data from a study that randomized 90 children (8- to 12-year-olds) to receive either exposure-based online cognitive behavioral therapy (ICBT) or usual care, to look at the influence of parental protective behaviours (such as allowing child stay at home on a school day), parental catastrophizing and monitoring behaviours on children with functional abdominal pain disorder (FAPD). Parental catastrophizing only was associated less change in pediatric quality of life after treatment. Findings from this study encourage parent-child co-treatment and the necessity of parental catastrophizing treatments for the benefit of children with FAPD.The research by <a href="https://doi.org/10.3389/fmed.2022.897533">Semkovych and Dmytriiev</a> focuses on an under-researched area: the use of biomarkers to track pain progression in clinical practice (<a href="#B11">11</a>). They investigate the role of biomarkers of the innate immune system to address this issue. Their 3-arm randomized controlled trial (RCT) conducted in children who underwent inguinal herniotomy, examined the relationship between postoperative Toll-like receptor 4 (TLR4) levels, a pro-inflammatory biomarker implicated in the development of neuropathic pain, different perioperative analgesic regimens and their effect on pain chronification. Acute pain was found to be significantly higher in the general anesthesia (GA) group than the Quadratus Lumborum Block (QLB) group and the Transversalis Fascia Plane Block (TFPB) group. Chronic pain was found to be prevalent in the GA group when compared with the QLB and TFPB groups. They conclude by summarizing the benefits of regional anaesthesia for children to include ease of use, adequate perioperative pain relief, reduction in opioid requirements and reduced TLR4 levels, reducing the possibility of pain chronicity.Regarding risk factors for paediatric pain, the brief research report by <a href="https://doi.org/10.3389/fpain.2021.720236">Borschneck et al.</a> sheds some light on risk factors for anterior knee pain (AKP) in adolescents, a condition considered to be responsible for up to 40% of visits to the physiotherapist (<a href="#B12">12</a>). They elucidate the intrinsic and extrinsic risk factors that have been found to increase the risk of AKP including participation in sports but highlight the observation that there is a lack of information regarding the association between participation in specific sports and increased risk of AKP. They found that previous AKP and previously treated knee injuries seem to be risk factors especially in females. In addition, participation in basketball, baseball, cross-country, riding, and volleyball, are associated with increases the risk of AKP.Finally, <a href="https://doi.org/10.3389/fpain.2021.713430">Kaczynskyi et al.</a> conducted a peri-pandemic assessment of pain and other psychosocial outcomes among children and adolescents diagnosed with chronic pain disorders and their families. In comparing functioning of participants during two periods and in two situations: outside the home pre-pandemic and inside the home during the COVID-19 pandemic, the authors found significant decreases in pain intensity, pain catastrophizing (including rumination and helplessness) and significant decreases in psychological stress and anxiety during the first few months of the lockdown. The authors surmise that although reduction in pain was experienced when participants were removed from the traditional school setting, teaching children effective coping strategies and self-advocacy skills will help them adapt to any environment they find themselves in.The articles composing this collection provide key insights for pediatric pain assessment and psychological treatment and a path forward to advance the field, focusing on identifying biomarkers, moderators and mediators of treatment efficacy and using mixed methods to better-understand mechanisms of change. They identify the need to take a more directed approach to many aspects of pediatric pain care, and to seek an understanding of specific biological and cognitive mechanisms in the diagnosis, assessment, and management of pain in children. We look forward to other innovative and exciting submissions on pediatric pain research.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication. All authors contributed to the article and approved the submitted version.We would like to thank all the authors who agreed to participate in this Research Topic with their original contributions, and to all the reviewers who promoted the quality of research and manuscripts with their comments.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Editorial: Highlights in pediatric pain 2021/22

Pediatric chronic pain is a significant global issue, with biopsychosocial factors contributing to the complexity of the condition. Studies have explored behavioral treatments for pediatric chronic pain, but these treatments have mixed efficacy for improving functional and psychological outcomes. Furthermore, the literature lacks an understanding of the biobehavioral mechanisms contributing to pediatric chronic pain treatment response. In this mini review, we focus on how neuroimaging has been used to identify biobehavioral mechanisms of different conditions and how this modality can be used in mechanistic clinical trials to identify markers of treatment response for pediatric chronic pain. We propose that mechanistic clinical trials, utilizing neuroimaging, are warranted to investigate how to optimize the efficacy of behavioral treatments for pediatric chronic pain patients across pain types and ages.

Pediatric chronic pain is a significant global issue, with biopsychosocial factors contributing to the complexity of the condition. Studies have explored behavioral treatments for pediatric chronic pain, but these treatments have mixed efficacy for improving functional and psychological outcomes. Furthermore, the literature lacks an understanding of the biobehavioral mechanisms contributing to pediatric chronic pain treatment response. In this mini review, we focus on how neuroimaging has been used to identify biobehavioral mechanisms of different conditions and how this modality can be used in mechanistic clinical trials to identify markers of treatment response for pediatric chronic pain. We propose that mechanistic clinical trials, utilizing neuroimaging, are warranted to investigate how to optimize the efficacy of behavioral treatments for pediatric chronic pain patients across pain types and ages.

The missing mechanistic link: Improving behavioral treatment efficacy for pediatric chronic pain

ObjectiveTo test if decreased parental protective behaviors, monitoring behaviors, and parental catastrophizing mediate relief of gastrointestinal symptoms in children 8–12 years with functional abdominal pain disorders (FAPDs). The study uses secondary data analyses of a randomized controlled trial in which exposure-based online cognitive behavioral therapy (ICBT) was found superior to treatment as usual in decreasing gastrointestinal symptoms.</sec>MethodsThe ICBT included 10 weekly modules for children and 10 weekly modules for parents. Treatment as usual consisted of any medication, dietary adjustments, and healthcare visits that the participants engaged in during 10 weeks. All measures were self-assessed online by parents. Biweekly assessments of the Adult Responses to Children's Symptoms (ARCS), Protect and Monitor subscales, and the Pain Catastrophizing Scale, parental version (PCS-P) were included in univariate and multivariate growth models to test their mediating effect on the child's gastrointestinal symptoms assessed with the Pediatric Quality of Life Gastrointestinal Symptoms Scale (PedsQL).</sec>ResultsA total of 90 dyads of children with FAPDs and their parents were included in the study, of which 46 were randomized to ICBT and 44 to treatment as usual. The PCS-P was found to mediate change in the PedsQL ab = 0.639 (95% CI 0.020–2.331), while the ARCS Monitor ab = 0.472 (95% CI −1.002 to 2.547), and Protect ab = −0.151 (95% CI −1.455 to 0.674) were not mediators of change.</sec>ConclusionsTo target parental catastrophizing in ICBT for pediatric FAPDs is potentially important to reduce abdominal symptoms in children.</sec>

Objective: To test if decreased parental protective behaviors, monitoring behaviors, and parental catastrophizing mediate relief of gastrointestinal symptoms in children 8–12 years with functional abdominal pain disorders (FAPDs). The study uses secondary data analyses of a randomized controlled trial in which exposure-based online cognitive behavioral therapy (ICBT) was found superior to treatment as usual in decreasing gastrointestinal symptoms.Methods: The ICBT included 10 weekly modules for children and 10 weekly modules for parents. Treatment as usual consisted of any medication, dietary adjustments, and healthcare visits that the participants engaged in during 10 weeks. All measures were self-assessed online by parents. Biweekly assessments of the Adult Responses to Children's Symptoms (ARCS), Protect and Monitor subscales, and the Pain Catastrophizing Scale, parental version (PCS-P) were included in univariate and multivariate growth models to test their mediating effect on the child's gastrointestinal symptoms assessed with the Pediatric Quality of Life Gastrointestinal Symptoms Scale (PedsQL).Results: A total of 90 dyads of children with FAPDs and their parents were included in the study, of which 46 were randomized to ICBT and 44 to treatment as usual. The PCS-P was found to mediate change in the PedsQL ab = 0.639 (95% CI 0.020–2.331), while the ARCS Monitor ab = 0.472 (95% CI −1.002 to 2.547), and Protect ab = −0.151 (95% CI −1.455 to 0.674) were not mediators of change.Conclusions: To target parental catastrophizing in ICBT for pediatric FAPDs is potentially important to reduce abdominal symptoms in children.

Parental responses and catastrophizing in online cognitive behavioral therapy for pediatric functional abdominal pain: A mediation analysis of a randomized controlled trial

IntroductionThe perioperative period of any surgery is accompanied by immune suppression. The level of Toll-like receptor 4 (TLR4) is known to increase in inflammation and after nerve injury and contributes to the development of neuropathic pain. The interaction of TLRs in response to the effect of opioids results in paradoxical hyperalgesia. Regional anesthesia techniques are the standard of care for perioperative pain management in children.</sec>AimThe aim of the study was to determine and evaluate the indicators of TLR4 for different methods of pain relief in anesthetic management of hernia repair in children and their effect on pain chronification.</sec>Materials and methodsThere were examined 60 children with inguinal hernia during 2020–2022. Children were divided into 3 groups: Group I included 20 children who underwent surgery under general anesthesia using the block of the anterior abdominal wall—transversalis fascia plane block (TFPB), combined with the quadratus lumborum block (QLB-4) via a single intramuscular injection; Group II included 20 children who underwent surgery under general anesthesia using the TFPB; Group III comprised 20 children who underwent surgery under general anesthesia using opioid analgesics. The levels of TLR4 were evaluated at a discharge from the hospital, 3 and 6 months after surgery.</sec>ResultsThere was no difference in age and body weight among all groups. In Group II, boys prevailed. In Group III, the length of hospital stay was the longest (3.28 ± 0.24 days, p < 0.05, t = 4.09) as compared to children of Group II and Group I (3.0 ± 0.30 (p < 0.05, t = 2.647) and 2.1 ± 0.16 days, respectively). While staying in the surgical department, children of Group III demonstrated significantly higher FLACC and VAS scores. The prevalence of chronic pain was the highest among children of Group III (35%) as compared to those in Group II and Group I (20 and 15%, respectively). The highest increase in the level of TLR4 was found in the group of opioid analgesia on the third and sixth months after surgery (68.86 + 10.31 pg/ml and 143.15 + 18.77 pg/ml (p < 0.05, t = 6.33), respectively) as compared to patients who received regional anesthesia.</sec>ConclusionsThere were confirmed the following advantages of the transversalis fascia plane block combined with the quadratus lumborum block (QLB + TFPB) via a single intramuscular injection: ease of use; adequate perioperative pain control as evidenced by the FLACC and VAS pain assessment scales; reduced perioperative use of opioid analgesics; shortening the length of hospital stay.</sec>

Introduction: The perioperative period of any surgery is accompanied by immune suppression. The level of Toll-like receptor 4 (TLR4) is known to increase in inflammation and after nerve injury and contributes to the development of neuropathic pain. The interaction of TLRs in response to the effect of opioids results in paradoxical hyperalgesia. Regional anesthesia techniques are the standard of care for perioperative pain management in children.Aim: The aim of the study was to determine and evaluate the indicators of TLR4 for different methods of pain relief in anesthetic management of hernia repair in children and their effect on pain chronification.Materials and methods: There were examined 60 children with inguinal hernia during 2020–2022. Children were divided into 3 groups: Group I included 20 children who underwent surgery under general anesthesia using the block of the anterior abdominal wall—transversalis fascia plane block (TFPB), combined with the quadratus lumborum block (QLB-4) via a single intramuscular injection; Group II included 20 children who underwent surgery under general anesthesia using the TFPB; Group III comprised 20 children who underwent surgery under general anesthesia using opioid analgesics. The levels of TLR4 were evaluated at a discharge from the hospital, 3 and 6 months after surgery.Results: There was no difference in age and body weight among all groups. In Group II, boys prevailed. In Group III, the length of hospital stay was the longest (3.28 ± 0.24 days, p &lt; 0.05, t = 4.09) as compared to children of Group II and Group I (3.0 ± 0.30 (p &lt; 0.05, t = 2.647) and 2.1 ± 0.16 days, respectively). While staying in the surgical department, children of Group III demonstrated significantly higher FLACC and VAS scores. The prevalence of chronic pain was the highest among children of Group III (35%) as compared to those in Group II and Group I (20 and 15%, respectively). The highest increase in the level of TLR4 was found in the group of opioid analgesia on the third and sixth months after surgery (68.86 + 10.31 pg/ml and 143.15 + 18.77 pg/ml (p &lt; 0.05, t = 6.33), respectively) as compared to patients who received regional anesthesia.Conclusions: There were confirmed the following advantages of the transversalis fascia plane block combined with the quadratus lumborum block (QLB + TFPB) via a single intramuscular injection: ease of use; adequate perioperative pain control as evidenced by the FLACC and VAS pain assessment scales; reduced perioperative use of opioid analgesics; shortening the length of hospital stay.

Elevated serum TLR4 level as a potential marker for postsurgical chronic pain in pediatric patients with different approaches to analgesia

Background: Anterior knee pain is a common complaint amongst adolescents, which can both be persistent, and in some cases, disabling. This study investigated a series of potential risk factors potentially linked to the onset of anterior knee pain.Methods: Questionnaires were distributed amongst 367 10–15 years-olds enrolled in the local school board. These surveys included questions on sex, age, sport participation, and history of anterior knee pain verified by a physician. Bivariate correlations and a binomial logistic regression were conducted. Overall rate of AKP in the population studied was 7.4%. The results indicated that past history of knee pain, age, and increased sports participation significantly correlated with increased risk of AKP. AKP was significantly more common in females than males. While sex, height, age, overall sport participation, participation in specific sports, and history of knee injury all contributed to the binomial model.

Background: Anterior knee pain is a common complaint amongst adolescents, which can both be persistent, and in some cases, disabling. This study investigated a series of potential risk factors potentially linked to the onset of anterior knee pain.Methods: Questionnaires were distributed amongst 367 10–15 years-olds enrolled in the local school board. These surveys included questions on sex, age, sport participation, and history of anterior knee pain verified by a physician. Bivariate correlations and a binomial logistic regression were conducted. Overall rate of AKP in the population studied was 7.4%. The results indicated that past history of knee pain, age, and increased sports participation significantly correlated with increased risk of AKP. AKP was significantly more common in females than males. While sex, height, age, overall sport participation, participation in specific sports, and history of knee injury all contributed to the binomial model.

Cross-Sectional Risk Factors of Anterior Knee Pain in Adolescents

Objectives: Youth with chronic pain often struggle to function in multiple domains due to pain and associated psychosocial distress. In 2020, schools and businesses shut down and people were encouraged to remain at home due to the COVID-19 pandemic, eliminating or reducing stress due to functional difficulties. This study assessed whether pain and associated psychosocial outcomes improved in youth with chronic pain during the shutdown, compared with before the pandemic.Methods: Patients who completed clinical outcome measures during a multidisciplinary evaluation before the pandemic were readministered the same measures (PROMIS Anxiety, Depression, Sleep Disturbance, PCS, PedsQL) during the shutdown. At follow-up, patients also completed measures of adjustment to COVID-19 and their parents completed a measure of pandemic effects.Results: Participants included 47 patients ages 8–18 and a parent/guardian. The pandemic impacted families in both positive (e.g., more quality time with family) and negative ways (e.g., social isolation, disruption in care). Pain intensity and pain catastrophizing significantly decreased during the shutdown (ps <0.01). Change in pain catastrophizing was correlated positively with change in psychological stress (p = 0.004) and anxiety (p = 0.005) and negatively with change in quality of life (p = 0.024).Discussion: Pain and pain catastrophizing decreased initially during the shutdown related to the COVID-19 pandemic. Change in catastrophizing was associated with change in stress and anxiety. It may be that the reduction in functional demands contributed to this change. Functional difficulties should be addressed in treatment, including pain coping and also environmental modification to support optimal functioning in youth with chronic pain.

Objectives: Youth with chronic pain often struggle to function in multiple domains due to pain and associated psychosocial distress. In 2020, schools and businesses shut down and people were encouraged to remain at home due to the COVID-19 pandemic, eliminating or reducing stress due to functional difficulties. This study assessed whether pain and associated psychosocial outcomes improved in youth with chronic pain during the shutdown, compared with before the pandemic.Methods: Patients who completed clinical outcome measures during a multidisciplinary evaluation before the pandemic were readministered the same measures (PROMIS Anxiety, Depression, Sleep Disturbance, PCS, PedsQL) during the shutdown. At follow-up, patients also completed measures of adjustment to COVID-19 and their parents completed a measure of pandemic effects.Results: Participants included 47 patients ages 8–18 and a parent/guardian. The pandemic impacted families in both positive (e.g., more quality time with family) and negative ways (e.g., social isolation, disruption in care). Pain intensity and pain catastrophizing significantly decreased during the shutdown (ps &lt;0.01). Change in pain catastrophizing was correlated positively with change in psychological stress (p = 0.004) and anxiety (p = 0.005) and negatively with change in quality of life (p = 0.024).Discussion: Pain and pain catastrophizing decreased initially during the shutdown related to the COVID-19 pandemic. Change in catastrophizing was associated with change in stress and anxiety. It may be that the reduction in functional demands contributed to this change. Functional difficulties should be addressed in treatment, including pain coping and also environmental modification to support optimal functioning in youth with chronic pain.