Mapping the evidence and gaps of interventions for pediatric chronic pain to inform policy, research, and practice: A systematic review and quality assessment of systematic reviews

ABSTRACT Background: Reviews in pediatric chronic pain often focus on only one intervention or population, making it difficult for policymakers and decision makers to quickly synthesize knowledge to inform larger-scale policy and funding priorities. Aims: The aims of this study were to (1) create an evidence and gap map of interventions for pediatric chronic pain and (2) identify gaps between existing evidence and recently identified patient-oriented research priorities. Methods: We performed a systematic review of English-language peer-reviewed systematic reviews or clinical practice guidelines of pediatric chronic pain intervention published in the past 20 years. Database searches of Medline, Embase, PsycINFO, Web of Science, CINAHL, and SCOPUS were conducted inclusive to June 3, 2019. Review quality was assessed using the AMSTAR-2. Results: Of 4168 unique abstracts, 50 systematic reviews (including 2 clinical practice guidelines) crossing diverse pediatric chronic pain populations and intervention settings were included. One third were rated high quality, with half rated low to critically low quality. The largest proportion of reviews addressed psychological and pharmacological interventions, followed by interdisciplinary, other (e.g., dietary), and physical interventions. Most common outcomes included pain, physical, emotional, and role functioning and quality of life. Treatment satisfaction and adverse events were less common, with minimal report of sleep or economic factors. Most patient-oriented research priorities had not been investigated. Conclusions: Sufficient quality evidence is available to guide evidence-informed policies in pediatric chronic pain, most notably regarding psychological and pharmacological interventions. Numerous evidence gaps in patient-oriented research priorities and treatment outcomes should guide prioritization of research funds, as well as study aims and design.

Chronic pain is a leading cause of disability and morbidity for children and adults. 1 Despite this, chronic pain was only recently recognized as its own disease through the inclusion of new chronic pain diagnostic codes in the World Health Organization's International Classification of Diseases, 11th revision, in 2018. 2 The classification of chronic primary pain as a disease in its own right facilitates the progress of large-scale national policies to improve chronic pain management across the life span, many of which are underway in countries around the world. [3][4][5] Furthermore, an evidencebased policy focus on improved chronic pain management is critical alongside policy efforts to address the opioid epidemic. 6 The development of effective health policies is informed by both scientific evidence and stakeholder experience to ensure relevance and tailored implementation to the local context. Our group recently completed a national prioritysetting partnership that engaged people with lived experience with pediatric chronic pain, family members, and treating health care providers across Canada to identify the top priorities for pediatric chronic pain research and care. 7 The final top ten identified patient-oriented priorities direct the need for more evidence on prevention and treatment, as well as an improved understanding of the impact of pediatric chronic pain, delivery, access to care, and coordination of care. On its own, this priority-setting work provides a guided call to action for policymakers, decision makers, and researchers-from basic science to clinical research to health systems design-to address identified patient-oriented priorities; however, the uptake of these priorities may be limited by a lack of information about what research already exists in these areas. Current systematic reviews in pediatric chronic pain are often very niche and focus on one type of intervention. [8][9][10] This makes it difficult for policymakers and decision makers to quickly synthesize knowledge across a variety of intervention modalities to inform clinical practice policy and research funding priorities. This is problematic given the current recommendation for multimodal care to thoroughly address biopsychosocial contributors to pediatric chronic pain. 11 Although pediatric pain research is growing rapidly, 12 there remains a disconnect between existing scientific evidence and current clinical practice, a further challenge to developing pediatric chronic pain policy. 13 Estimates suggest that it can take up to 17 years for research to impact patient care, 14 and many children and adolescents with chronic pain struggle to access evidence-based treatment. [15][16][17] There is an identified need for more effectual and efficient knowledge mobilization in pediatric pain. 13 The availability of high-quality evidence synthesis is a key step in the process of moving generated scientific knowledge into sustainable action, as outlined in the knowledge-toaction framework. 18 Evidence and gap maps have emerged as an effective knowledge translation evidence synthesis tool to inform evidence-informed policymaking and the development of strategic research agendas. 19,20 Like other evidence synthesis methods, such as a Cochrane reviews, 21 evidence and gap maps are rigorous in their search for and assessment of research evidence 19,22 ; however, they differ in their primary goal, which is to review the breadth and quality of available evidence compared to determining the efficacy of single specific interventions. This shift in focus facilitates the strategic identification of key gaps where little or no evidence exists or areas currently with only poor quality research. 19,22 The use of schematic visual representation of findings in evidence and gap maps also makes research evidence more easily accessible and usable to researchers and decision makers. 19,22 Our primary goal was to create a contemporary evidence and gap map of systematic reviews of all interventions for pediatric chronic pain. Our secondary aim was to identify gaps between existing evidence and recently identified patient-oriented research priorities for pediatric chronic pain. 7 Given that many pediatric chronic pain interventions have limited evidence, 9,23 we expected many priority areas to be lacking high-quality research evidence.

Protocol and Registration
This review adheres to PRISMA reporting guidelines for systematic reviews. 24 A protocol was registered for this  review  in  February  2018 on PROSPERO: CRD42018086817. The current review presents a minor modification from our original review protocol that outlines our initial intent to conduct a traditional overview of systematic reviews. 25 The decision to modify the current review to an evidence and gap map was made following consultation with an international expert in evidence-informed health policy (Dr. John Lavis, personal communication, April 17, 2019) and in response to emerging national chronic pain policy efforts through the development of the Government of Canada's Canadian Pain Task Force. 3 It was felt that an evidence and gap map would better achieve our primary goal of uptake of evidence and patient priorities by policymakers and decision makers and identify clear gaps to guide research efforts in key areas identified by patients and clinicians as priorities.
Evidence and gap maps provide an overview of the availability and quality of evidence of a sector, in this case interventions for pediatric chronic pain. 19,20,22,26 Recommended evidence and gap map methodology includes completion of six primary steps: development of scope, inclusion criteria, systematic review of the literature, data extraction, analysis, and visualization. 19,22,27 Evidence and gap maps are underpinned by a rigor similar to that of other systematic review methodology. 28 As such, reporting of the evidence and gap map methods in this article adhere to the PRISMA statement for reporting of systematic reviews and meta-analyses. 24 The current review adheres to our original protocol with regards to the stated review question, search strategy, type of study, participants/population, interventions, risk of bias/quality assessment, narrative synthesis, and report by type of intervention modality. The current review diverges only from that outlined in our original protocol in that the current review now is restricted to publications within the past 20 years (since 1999), no longer extracts specific efficacy findings for intervention outcomes, and does not conduct subgroup analyses by type of chronic pain condition; additionally, the review now includes an evidence and gap map.
A completed evidence and gap map provides a simple and accessible visual summary of existing systematic review evidence for various types of interventions in pediatric chronic pain across selected outcome domains. 19,20,22,26 The rows of the evidence and gap map list the types of interventions and the columns list the outcome domains. Each cell shows the number and quality of systematic reviews that contain evidence on that combination of intervention and outcome domain. In doing so, evidence and gap maps identify areas where little or no evidence exists ("absolute gaps") and areas where there is systematic review evidence is available but is either out of date and/or of poor quality ("synthesis gaps"). 19,20,22,26 Evidence and gap maps can be used to inform strategic research investment by highlighting intervention and outcome areas where new primary studies and/or systematic reviews can add value. They can also be used to inform decision making by capturing best available evidence that can then be compared against existing policy or programming to inform discussions about areas of prioritizing future research, policy, or investment. 19,20,22,26

Eligibility Criteria
Papers were eligible for inclusion if they (1) were peer-reviewed published systematic review or clinical practice guidelines; (2) were published in English; (3) included at least 50% or more reviewed studies focused on children or adolescents ≤18 years old or reported findings from pediatric studies separately; (4) included randomized and nonrandomized studies focused on any intervention for any type of chronic pain (defined as pain lasting at least 3 months or longer and/or pain described as "chronic," "recurrent," or "persistent"); and (5) reported on at least one primary or secondary outcome included in PedIMMPACT recommended for clinical trials in pediatric chronic pain (that is, pain intensity, physical functioning, emotional functioning, role functioning, quality of life, sleep, global treatment satisfaction, economic factors, and/or adverse events). 29 Systematic reviews were excluded if they focused exclusively on chronic pain diagnosis or assessment and/or only reported prevalence. Prior iterations of eligible reviews were also excluded, as well as reviews/clinical practice guidelines published >20 years ago, given the availability of more current up-to-date evidence.
Reviews including any type of intervention study design were included given recognized difficulty in conducting randomized controlled trials (RCTs) for some intervention modalities in pediatric populations (e.g., pharmacological) and given that interventions needed to address identified patient-oriented research priorities may not lend themselves easily to randomized study designs (e.g., school-based interventions). Given variability in evidence synthesis methodology, requirements for being defined as a systematic review and/or clinical practice guideline were drawn from those used by the James Lind Alliance. 30 Thus, a systematic review was defined as a review that attempts to identify, appraise, and synthesize all of the empirical evidence that meets prespecified eligibility criteria to answer a given research question. Therefore, a systematic review typically states/identifies a research question, provides search terms, searches multiple scientific databases, and reviews titles, abstracts, and full-text publications against some identified inclusion criteria. Clinical practice guidelines are clearly defined as such and include a systematic review to inform development of the guidelines. If multiple iterations or updates of the same systematic review or clinical practice guideline were found and identified as such, only the most recently published version of the systematic review or clinical practice guideline meeting the eligibility criteria was reviewed to reflect the most up-to-date evidence.

Search Strategy and Conduct
Searches were conducted in Medline, Embase, PsycINFO, Web of Science, CINAHL, and SCOPUS from database inception to June 3, 2019. Database search strategies were developed in collaboration with a pediatric medical librarian and experts in pediatric chronic pain care and research. A sample comprehensive search strategy for Medline is available in Supplementary Online Material 1.

Study Selection
Database search results were imported into Covidence 31 for study selection. Initial abstract screening was conducted independently by two review authors (K.A. B. and T.D.A.), and full-text screening was independently performed by two review authors (C.O. and T.D.A.), with conflicts resolved by a third author (K.A.B.).

Data Extraction and Quality Ratings
Data were independently extracted by two review authors (K.A.B. and T.D.A.). Extracted data items included review sponsorship, country, author, primary review objective, inclusion/exclusion criteria, date of literature search, inclusion of meta-analysis, types of reviewed studies (RCT or nonrandomized study [NRS]), total number of reviewed studies, number of reviewed studies focused on pediatric chronic pain intervention, population of reviewed studies (type of chronic pain/disease), setting of reviewed studies (e.g., outpatient, inpatient, emergency, etc.), type of intervention (pharmacological, psychological, physical, interdisciplinary, other), comparator groups, inclusion of quality of evidence rating, inclusion of PedIMMPACT 29 recommended outcomes (pain intensity, physical functioning [e.g., mobility, disability], emotional functioning [e.g., anxiety, depression], role functioning [e.g., school attendance], quality of life, sleep, global treatment satisfaction, economic factors [e.g., cost, health care utilization, parent missed workdays], and/or adverse events), and time of outcome assessments.
When eligible systematic reviews included nonrelevant data (that is, pertaining to adults and/or nonchronic pain pediatric samples), only data relevant to reviewed studies focused on pediatric chronic pain were extracted. Supplementary material was accessed to inform data extraction and quality assessment if cited in published eligible systematic reviews. Separately reported systematic reviews that informed eligible clinical practice guidelines were accessed online (published and unpublished) and informed data extraction and quality assessment.
Risk of bias/quality of assessment of all eligible systematic reviews was conducted using the AMSTAR-2. 32 The AMSTAR-2 critical appraisal tool includes 16 items that are rated to assess the quality of systematic reviews that include randomized or nonrandomized studies of health care interventions or both. Items address the review's reporting of review criteria including elements of PICO (Population, Intervention, Comparator group, and Outcome), a priori review protocol registration, justification of study design selection, adequacy of literature search, study selection and data extraction in duplicate, justification for excluding individual studies, adequate description of included studies, risk of bias from individual studies included in the review, report of funding of included studies, appropriateness of meta-analytical methods (if applicable), consideration of risk of bias when interpreting the review results, and assessment and likely impact of publication bias (italics denote critical domains). Quality assessments for all eligible systematic reviews were rated independently by two authors (K.A.B. and C.O.), with disagreements resolved by consensus. Each systematic review was summarized by an single overall quality rating reflecting confidence in the results of review. 32 Overall quality ratings are described as follows: • High: No or one noncritical weakness; the systematic review provides an accurate and comprehensive summary of the results of the available studies that address the question of interest.
• Moderate: More than one noncritical weakness; the systematic review has more than one weakness but no critical flaws. It may provide an accurate summary of the results of the available studies that were included in the review. • Low: One critical flaw with or without noncritical weaknesses; the systematic review has a critical flaw and may not provide an accurate and comprehensive summary of the available studies that address the question of interest. • Critically Low: More than one critical flaw with or without noncritical weaknesses; the systematic review has more than one critical flaw and should not be relied on to provide an accurate and comprehensive summary of the available studies.
Eligible systematic reviews and clinical practice guidelines were also independently coded by two authors (K.A. B. and C.O.) for relevance to each of the top ten patientoriented research priorities for pediatric chronic pain identified in the Partnering For Pain priority-setting partnership. 7 In brief, Partnering For Pain engaged hundreds of diverse Canadians with lived experience with pediatric chronic pain, family members, and multidisciplinary health care providers across four priority setting phases using the James Lind Alliance Priority Setting Partnership methodology. The James Lind Alliance methodology is recognized as being robust, strategic, objectively based and inclusive, and promoting equity in patient voices. 33

Study Selection
Database searches identified 5077 records. After duplicates were removed, 4168 unique abstracts remained for review. Of these, 3897 were deemed not eligible. A total of 261 full texts were reviewed and 211 were excluded. Fifty full texts met inclusion criteria. See Figure 1 for the PRISMA review flowchart, including reasons for full-text exclusion.

Study Characteristics
Of the 50 full texts meeting review inclusion criteria, 2 reported a related systematic review and clinical practice guideline for pediatric chronic abdominal pain 34,35 and 2 reported a related systematic review and clinical practice guideline for pediatric chronic widespread pain. 36,37 Data extraction and quality assessment were combined for each pair of related systematic reviews and clinical practice guidelines. One additional paper 38 was a summary of 3 other included systematic reviews. 10,39,40 Data extraction and quality ratings were not conducted for the summary review because information was obtained from the original included systematic reviews. Thus, data and quality ratings are reported for 47 unique reviews/clinical practice guidelines. Of these, 24 (51.6%) included meta-analyses. Almost half of the reviews reported no funding or sponsorship (n = 22; 46.8%). See Tables 1 and 2 for characteristics and outcomes for each included review.

Types of Studies Included
The majority of reviews exclusively included RCTs or reviews of RCTs (n = 26; 55.3%). The remaining reviews included a variety of study designs, including nonrandomized intervention studies, cohort or observational studies, retrospective chart reviews, and case studies or case series (n = 21; 44.6%). Most reviews included at least one study with a comparator group (n = 41; 87.2%). Comparator groups included usual/standard medical care, waitlist controls, placebo or sham interventions, or other active interventions.

Types of Outcomes
Three reviews of pharmacological interventions found no eligible studies for inclusion 8,72,73 ; as such, extraction of assessed outcomes was not possible for those reviews.

Quality of Systematic Reviews
See Figure 2 for a summary of the AMSTAR-2 quality ratings for the included reviews. Of the 47 reviews, the greatest number were rated as high quality (n = 16; 34.0%), followed by critically low quality (n = 13; 27.7%) and low quality (n = 11; 23.4%), with the fewest rated as moderate quality (n = 7; 14.9%). Reviews were primarily downgraded in quality for failing to register a review protocol or demonstrate clear evidence of review methods established a priori or failing to provide a list of excluded studies with justification, with fewer studies failing to use a comprehensive literature strategy, failing to include a satisfactory technique for assessing risk of bias, or failing to account for risk of bias in the interpretation of review results.

Synthesis of Results
See Figure 3 for the evidence and gap map summarizing the quality and number of included reviews relevant to each extracted treatment outcome of interest.

Additional Analyses: Mapping to the Top Ten Patient-Oriented Research Priorities
See Figure 4 for a summary of the quality and number of included reviews relevant to each of the top ten patient-oriented research priorities for pediatric chronic pain. All but two priorities had at least one relevant review and/or clinical practice guideline. Priority 3 (physical and psychological interventions) had the greatest number of relevant reviews (n = 9; 19.1% and n = 24; 51.1%, respectively), albeit primarily from reviews of low and critically low quality. Priority 1 (prevention of chronic pain) and priority 4 (improved access and delivery) were addressed by four reviews each (8.5%), and priority 2 (impact on education and vocational planning), priority 8 (managing acute pain flares), and priority 9 (treatment of co-occurring mental health symptoms) were addressed by only two to three reviews each (4.3-6.4%). Priority 5 (increase health care providers' knowledge) and priority 10 (timing of interventions) had only one relevant review each (2.1%), and priority 6 (increase government and organization financial support) and priority 7 (educating school personnel) had no relevant reviews. Almost one third of included reviews and clinical practice guidelines did not address any of the patient-oriented research priorities (n = 15; 31.9%).

Summary of Evidence
This systematic review offers a rigorous synthesis of available systematic reviews and clinical practice guidelines of interventions of any modality for pediatric chronic pain. The resulting evidence and gap map offers a succinct but thorough data visualization to effectively convey the current state of the evidence for use by key stakeholders, including members of the public, policymakers and decision makers, health care providers, and researchers alike. The broad scope of this review across intervention modalities and pediatric chronic pain populations, as well as its evidence and gap map methodology, uniquely positions its findings to be quickly and easily utilized. This review reveals much about the contemporary state of synthesized evidence of interventions for pediatric chronic pain. It is promising for policymakers that many high-quality reviews exist to guide decisions (most of which were Cochrane reviews); however, more than half (55%) of included reviews were rated to be of low or critically low quality. It was surprising that only two clinical practice guidelines were identified. Most systematic reviews examine psychological interventions only, followed closely by pharmacological interventions. The sizable study of psychological interventions for pediatric chronic pain is promising given its prioritization among patients, family members, and treating health care providers 7 but stands in stark contrast to the generally poor access to specialized multidisciplinary pediatric chronic pain intervention 17 or mental health treatment. 82 Three reviews focused on the remote or computerized delivery of psychological interventions. 47,56,75 Far fewer systematic reviews examined interdisciplinary interventions despite this being the recommended approach to chronic pain management, 83 followed by reviews of other interventions such as alternative diets, herbal supplements, and surgeries. The fewest reviews examined physical interventions, which highlights this as a key area for further research given its prioritization by patients and families, 7 as well as the evidence for multimodal interventions, of which physical interventions are included. Possible contributing factors for less evidence in these areas could be their greater difficulty in studying with traditional clinical trial methodologies and fewer professionals in areas outside of medicine and psychology with advanced training to conduct research.
The largest proportion of reviews included diverse pediatric chronic pain populations. This suggests the applicability of many interventions across types of chronic pain and aligns with an all-encompassing primary chronic pain diagnosis. 2 Reviews with medically  complex children and adolescents were largely absent, with the exception of cerebral palsy. 80 No reviews obviously addressed interventions for children with cognitive or intellectual disabilities or those who are nonverbal, which is of concern given their greater risk for undertreated and poorly recognized pain. 84 When reviews focused on single patient groups, headaches and migraines or abdominal pain were the most common, possibly reflecting their higher prevalence rates. 85 Reviews of interventions for pediatric migraines and headaches offered unique contributions and alignment with patient-oriented priorities not well addressed by other evidence, including a focus on prevention (prophylaxis) and management of acute pain flares. Only one review focused on interventions in the emergency department. 63 This is of great relevance given the high frequency with which children with chronic pain seek care in the emergency setting, 63 its high economic cost, the use of opioids to treat acute pain, and the potential for interdisciplinary care to reduce utilization of emergency care. 86,87 Other reviews largely addressed interventions in outpatient or community clinics or within tertiary care centers.
With regards to intervention impact, all reviews addressed the PedIMMPACT 29 recommended outcome of pain intensity, with fewer reporting on outcomes related to physical (disability, mobility), emotional (anxiety, depression), and role functioning (school attendance) or quality of life. Fewer still reported outcomes of treatment satisfaction or adverse events, with very little about sleep or economic factors. This reflects a neglect of outcomes identified as relevant by patients, family members, and treating health care providers, such as self-efficacy, participation in meaningful activities, social roles and relationships, vocational planning, concentration, acceptance, and resilience. 7,88 Although almost half of reviews addressed emotional functioning, many excluded children with cooccurring primary mental health disorders. Thus, these reviews effectively omitted a large proportion of children with chronic pain with mental health concerns 89 and decreased the relevance of available evidence to the identified patient-oriented priority about how co-occurring chronic pain and mental health can be effectively addressed. 7 Given that the estimated annual incremental costs of treating an individual with chronic pain are CA $1742 per person, costing billions to society overall, 86 there is a clear need to better demonstrate the economic benefit of evidence-based interventions to guide policymakers and decision makers. Though this review focused on previously recommended key outcome categories for clinical trials of interventions for pediatric chronic pain, 29 we note that this approach is likely to miss all outcomes included in the systematic reviews, clinical practice guidelines, or the original studies they include. Other than physical and psychological interventions, less than 10% of included reviews addressed any of the other top ten patient-oriented priorities. The movement toward patient engagement and partnership in health research offers a great opportunity to lessen the divide between existing intervention studies and outcomes and that of patient priorities. 13  Effectiveness-implementation hybrid research designs are gaining traction to enhance public health impact through efficient, feasible, sustainable, and widespread adoption of studied treatments. 13,92,93 Limitations Several limitations warrant mention in considering the above presented evidence. First, this review and evidence and gap map included published systematic reviews and clinical practice guidelines only. A comprehensive review of all original intervention studies in pediatric chronic pain would be a phenomenal undertaking and beyond the scope and resources available. However, it is possible, if not likely, that additional original studies exist with relevance to identified patient-oriented research priorities that are not captured here (see interventions to educate teachers 94 and health care providers 95 about pediatric chronic pain, for example). This suggests that the current review overlooks areas or priorities where systematic reviews have not yet been conducted and/or in research areas less likely to rely on randomized controlled trials or other traditional treatment study designs. The patient-oriented priorities with minimal systematic review evidence shown here would likely benefit from quality systematic reviews of original studies.

Conclusions
This systematic review reveals the great amount of contemporary evidence synthesis that has been conducted to identify effective multimodal interventions for pediatric chronic pain to date. Creation of an evidence and gap map identifies the availability of sufficient quality evidence to guide the development of evidence-informed policies and additional practice guidelines, most notably regarding psychological and pharmacological interventions to improve children's pain and quality of life and across physical, emotional, and role functioning domains. Despite this success, the numerous obvious evidence gaps in the top patient-oriented research priorities and treatment outcomes in pediatric chronic pain should be noted by health research funders and researchers to guide prioritization of funds, as well as study aims and design.