A rapid systematic review of breakthrough pain definitions and descriptions.

Background: Breakthrough pain is common in life-limiting conditions and at end-of-life. Despite over 30 years of study, there is little consensus regarding the definition and characteristics of breakthrough pain. Objective: This study aims to update and expand a 2010 systematic review by Haugen and colleagues to identify (1) all definitions of breakthrough pain and (2) all descriptions and classifications of breakthrough pain reported by patients, caregivers, clinicians, and experts. Design: This rapid systematic review followed the Cochrane Rapid Review Methods Group guidelines. A protocol is published on PROSPERO (CRD42019155583). Data sources: CINAHL, MEDLINE, PsycINFO, and the Web of Science were searched for breakthrough pain terms from the inception dates of each database to 26th August 2022. Results: We identified 65 studies that included data on breakthrough pain definitions, descriptions, or classifications from patients (n = 30), clinicians (n = 6), and experts (n = 29), but none with data from caregivers. Most experts proposed that breakthrough pain was a sudden, severe, brief pain occurring in patients with adequately controlled mild-moderate background pain. However, definitions varied and there was no consensus. Pain characteristics were broadly similar across studies though temporal factors varied widely. Experts classified breakthrough pain into nociceptive, neuropathic, visceral, somatic, or mixed types. Patients with breakthrough pain commonly experienced depression, anxiety, and interference with daily life. Conclusions: Despite ongoing efforts, there is still no consensus on the definition of breakthrough pain. A compromise is needed on breakthrough pain nomenclature to collect reliable incidence and prevalence data and to inform further refinement of the construct.

Definition and Assessment of Paediatric Breakthrough Pain: A Qualitative Interview Study.

Infants, children and young people with life-limiting or life-threatening conditions often experience acute, transient pain episodes known as breakthrough pain. There is currently no established way to assess breakthrough pain in paediatric palliative care. Anecdotal evidence suggests that it is frequently underdiagnosed and undertreated, resulting in reduced quality of life. The development of a standardised paediatric breakthrough pain assessment, based on healthcare professionals' insights, could improve patient outcomes. This study aimed to explore how healthcare professionals define and assess breakthrough pain in paediatric palliative care and their attitudes towards a validated paediatric breakthrough pain assessment. This was a descriptive qualitative interview study. Semi-structured interviews were conducted with 29 healthcare professionals working in paediatric palliative care across the UK. An inductive thematic analysis was conducted on the data. Five themes were generated: 'the elusive nature of breakthrough pain', 'breakthrough pain assessment', 'positive attitudes towards', 'reservations towards' and 'features to include in' a paediatric breakthrough pain assessment. The definition and assessment of breakthrough pain is inconsistent in paediatric palliative care. There is a clear need for a validated assessment questionnaire to improve assessment, diagnosis and management of breakthrough pain followed by increased healthcare professional education on the concept.

Oral morphine versus transmucosal diamorphine for breakthrough pain in children: methods and outcomes: UK (DIPPER study) consensus.

OBJECTIVES: No randomised controlled trials have been conducted for breakthrough pain in paediatric palliative care and there are currently no standardised outcome measures. The DIPPER study aims to establish the feasibility of conducting a prospective randomised controlled trial comparing oral and transmucosal administration of opioids for breakthrough pain. The aim of the current study was to achieve consensus on design aspects for a small-scale prospective study to inform a future randomised controlled trial of oral morphine, the current first-line treatment, versus transmucosal diamorphine. METHODS: The nominal group technique was used to achieve consensus on best practice for mode of administration, dose regimen and a range of suitable pain intensity outcome measures for transmucosal diamorphine in children and young people with breakthrough pain. An expert panel of ten clinicians in paediatric palliative care and three parent representatives participated. Consensus was achieved when agreement was reached and no further comments from participants were forthcoming. RESULTS: The panel favoured the buccal route of administration, with dosing according to the recommendations in the Association for Paediatric Palliative Medicine formulary (fifth Edition, 2020). The verbal Numerical Rating Scale was selected to measure pain in children 8 years old and older, the Faces Pain Scale-Revised for children between 4 and 8 years old, and Face, Legs, Activity, Cry and Consolability (FLACC)/FLACC-Revised as the observational tools. CONCLUSIONS: The nominal group technique allowed consensus to be reached for a small-scale, prospective, cohort study and provided information to inform the design of a randomised controlled trial.

A Systematic Review of Measures of Breakthrough Pain and Their Psychometric Properties.

CONTEXT: Breakthrough pain (BTP) is common in cancer and other conditions yet there is a lack of validated BTP measurement tools. OBJECTIVES: We aimed to identify all tools assessing or characterising BTP in patients of any age with any condition, and to critically appraise their psychometric properties. METHODS: The Cochrane Library, PROSPERO, Embase, CINAHL, Medline, PsycINFO, Web of Science, Google Scholar, ProQuest, Evidence Search and OpenGrey were searched to identify all available tools used to assess BTP. A second search identified studies that had evaluated psychometric properties of tools identified in Search 1. Databases were searched from inception to November 2020. Studies were assessed using COSMIN criteria and GRADE guidelines. RESULTS: Search 1 found 51 tools used to assess BTP. Search 2 found six tools that had a development study and/or a study evaluating a tool psychometric property. No tool had more than one study evaluating psychometric properties so a meta-analysis could not be conducted. Studies were of inadequate to very good quality. Only the Breakthrough Pain Assessment Tool (BAT) had sufficient content validity and at least low-quality evidence for sufficient internal consistency. CONCLUSION: The BAT is recommended to characterise BTP in adults with cancer; its applicability to other conditions is unknown. The remaining tools need further evaluation. Only the Breakthrough Pain Questionnaire for Children was designed for children with cancer, but no psychometric properties were evaluated. There is a need for a tool to assess and characterise BTP in children with non-cancer diagnoses and those who cannot self-report.

Artificial nutrition and hydration for children and young people towards end of life: consensus guidelines across four specialist paediatric palliative care centres.

There is a paucity of evidence on the role, use, benefit and challenges of artificial nutrition and hydration (ANH) in children at end of life. Parents express the difficulty they face with making the decision to withdraw ANH. Decision-making on the role of ANH in an individual child requires careful multidisciplinary team deliberation and clear goals of care with children and families. Four paediatric palliative care specialist centres reviewed the current literature and developed consensus guidelines on ANH at end of life. These guidelines seek to provide a practical approach to clinical decision-making on the role of ANH in a child or young person entering the end-of-life phase.

Managing childhood cancer pain into survivorship: recognition and emerging principles.

PURPOSE OF REVIEW: Continual refinement and further stratification of childhood cancer treatment has led to increased survivorship with recognized improvements in many long-term health outcomes. Despite this progress, persisting pain prevalence in childhood cancer survivors is increasing and emerging as a significant long-term health concern. RECENT FINDINGS: Currently, there is no guidance on how to approach and manage persisting pain in survivors of childhood cancer. SUMMARY: Clinicians should work with children and young people to optimize the management of pain and other symptoms on treatment. Focusing on an early post treatment screening for pain and other symptoms (including sleep and fatigue), and the role of on-going analgesic use. Follow-up should offer a multidisciplinary approach, aimed at lessening reliance on pharmacological approaches to pain management, addressing psychological concerns and promoting increased physical activity. The onus is on clinicians to mitigate the long-term risk of pharmacological reliance, particularly opioid dependency, in patients leaving their care and heading into adulthood. In this article, we highlight the emerging evidence of persisting pain in survivors of childhood cancer as a significant long-term health outcome and consider some initial principles of management.

A protocol for a systematic review and meta-analysis to identify measures of breakthrough pain and evaluate their psychometric properties.

INTRODUCTION: Breakthrough pain is common in children and adults with cancer and other conditions, including those approaching end-of-life, although it is often poorly managed, possibly partly due to a lack of validated assessment tools. This review aims to (1) identify all available instruments measuring breakthrough pain in infants, children, adolescents or adults and (2) critically appraise, compare and summarise the quality of the psychometric properties of the identified instruments using COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) criteria. METHODS AND ANALYSIS: Two searches will be carried out between October 2019 and January 2020, one for each aim of the review. The Cochrane Library, International Prospective Register of Systematic Reviews, Embase, Cumulative Index of Nursing and Allied Health Literature, Medical Literature Analysis and Retrieval System Online (MEDLINE), PsycINFO, Web of Science Core Collection, Google Scholar, the ProQuest Dissertations & Theses Database, Evidence Search and OpenGrey databases will be searched from database inception until the date the search is conducted. Reference lists of eligible articles will be screened and authors in the field contacted. For search 1, articles will be screened by two reviewers by abstract, and full-text where necessary, to identify if a breakthrough pain assessment was used. Search 2 will then be conducted to identify studies evaluating measurement properties of these assessments. Two reviewers will screen articles from search 2 by title and abstract. All potentially relevant studies will be screened by full text by both reviewers. For search 2, data will be extracted in parallel with the quality assessment process, as recommended by COSMIN. Two reviewers will assess methodological quality using the COSMIN Risk of Bias checklist and the COSMIN updated criteria for good measurement properties. Findings will be summarised and, if possible, data will be pooled using meta-analysis. The quality of the evidence will be graded and summarised using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) guidelines. ETHICS AND DISSEMINATION: Results of this review will be submitted for publication in a peer review journal and presented at conferences. PROSPERO REGISTRATION NUMBER: CRD42019155583.

Inter-Rater Reliability of the Phase of Illness Tool in Pediatric Palliative Care.

BACKGROUND: Phase of Illness is used to describe the stages of a patient's illness in the palliative care setting. Categorization is based on individual needs, family circumstances, and the adequacy of a care plan. Substantial (κ = .67) and moderate (κ = .52) inter-rater reliability is demonstrated when categorizing adults; however, there is a lack of similar studies in pediatrics. OBJECTIVE: To test the inter-rater reliability of health-care professionals when assigning pediatric palliative care patients to a Phase of Illness. Furthermore, to obtain user views on phase definitions, ease of assignment, feasibility and acceptability of use. METHOD: A prospective cohort study in which up to 9 health-care professionals' independently allocated 80 pediatric patients to a Phase of Illness and reported on their experiences. This study took place between June and November 2017. RESULTS: Professionals achieved a moderate level of agreement (κ = 0.50). Kappa values per phase were as follows: stable = 0.63 (substantial), unstable = 0.26 (fair), deteriorating = 0.45 (moderate), and dying = 0.43 (moderate). For the majority of allocations, professionals report that the phase definitions described patients very well (76.1%), and they found it easy to assign patients (73.5%). However, the unstable phase caused the most uncertainty. CONCLUSION: The results of this study suggest Phase of Illness is a moderately reliable, acceptable, and feasible tool for use in pediatric palliative care. Current results are similar to those found in some adult studies. However, in a quarter of cases, users report some uncertainty in the application of the tool, and further study is warranted to explore whether suggested refinements improve its psychometric properties.

Pharmacological interventions for chronic pain in children: an overview of systematic reviews.

We know little about the safety or efficacy of pharmacological medicines for children and adolescents with chronic pain, despite their common use. Our aim was to conduct an overview review of systematic reviews of pharmacological interventions that purport to reduce pain in children with chronic noncancer pain (CNCP) or chronic cancer-related pain (CCRP). We searched the Cochrane Database of Systematic Reviews, Medline, EMBASE, and DARE for systematic reviews from inception to March 2018. We conducted reference and citation searches of included reviews. We included children (0-18 years of age) with CNCP or CCRP. We extracted the review characteristics and primary outcomes of ≥30% participant-reported pain relief and patient global impression of change. We sifted 704 abstracts and included 23 systematic reviews investigating children with CNCP or CCRP. Seven of those 23 reviews included 6 trials that involved children with CNCP. There were no randomised controlled trials in reviews relating to reducing pain in CCRP. We were unable to combine data in a meta-analysis. Overall, the quality of evidence was very low, and we have very little confidence in the effect estimates. The state of evidence of randomized controlled trials in this field is poor; we have no evidence from randomised controlled trials for pharmacological interventions in children with cancer-related pain, yet cannot deny individual children access to potential pain relief. Prospero ID: CRD42018086900.

The 'surprise' question in paediatric palliative care: A prospective cohort study.

BACKGROUND: The question 'would you be surprised if this patient died in the next 12-months' is widely used for identifying adult patients in the last year of life. However, this has not yet been studied in children. AIM: To assess the prognostic accuracy of the surprise question when used by a multidisciplinary team to predict survival outcomes of children with life-limiting conditions over a 3 and 12 month period. DESIGN: A prospective cohort study. SETTING/PARTICIPANTS: Six multidisciplinary team members working in a children's hospice answered a 3 and 12 month surprise question about 327 children who were either newly referred or receiving care at the hospice between 2011 and 2013. RESULTS: The prognostic accuracy of the multidisciplinary team for the 3 (and 12)month surprise question were: sensitivity 83.3% (83.3%), specificity 93.2% (70.7%), positive predictive value 41.7% (23.6%), negative predictive value 99% (97.5%) and accuracy 92.6% (71.9%). Patients with a 'no' response had an increased risk of death at 3 (hazard ratio, 22.94, p ⩽ 0.001) and 12 months (hazard ratio, 6.53, p ⩽ 0.001). CONCLUSION: The surprise question is a highly sensitive prognostic tool for identifying children receiving palliative care who are in the last 3 and 12 months of life. The tool is accurate at recognising children during stable periods demonstrated through a high negative predictive value. In practice, this tool could help identify children who would benefit from specialist end of life care, act as a marker to facilitate communications on advance care planning and assist in resource allocation.

The use of rapid onset fentanyl in children and young people for breakthrough cancer pain.

BACKGROUND AND AIMS: No published studies have looked at the dosing and use of rapid onset fentanyl preparations in children. The primary aim of this study was to assess whether there is a correlation between effective dose of rapid onset fentanyl and background oral morphine equivalent analgesia in children less than 18 years old. Secondary objectives included establishing whether there is a correlation between effective dose of rapid onset fentanyl and age and weight. Reported side effects were also reviewed. METHODS: This study is a retrospective case note review of all children less than 18 years old who received rapid onset fentanyl products in a tertiary paediatric oncology centre in England between 2010 and 2015. Correlations were analysed using Spearman's correlation coefficient as data was non-parametric. RESULTS: Data on 26 children (5-17 yrs; 13-100kg) was analysed. The most common diagnosis in children being given rapid onset fentanyl products was a solid tumour (84.6%). Eleven children used sublingual tablets, 17 used lozenges and one used a fentanyl nasal spray (three patients used two different preparations). The only significant correlation found was between dose of fentanyl lozenge and weight (rs=0.81, p<0.001). Very few side effects were reported with the most frequent being nausea (8%) and sleepiness (8%). CONCLUSIONS: Fentanyl lozenges seem to be safe and well tolerated in children as young as five years old, weighing as little as 13kg. Results suggest that children should always be started on the lowest available dose of chosen preparation and that this dose should be titrated according to response. This study demonstrates that there is no correlation between background opioid dose and effective dose of rapid onset fentanyl in children. This mirrors findings of similar studies in adults. There was a strong correlation between effective dose of fentanyl lozenge and weight. This may be in part due to clinicians being more inclined to increase fentanyl lozenge doses as the child is in control of when they have had enough medication. In contrast, buccal tablets are absorbed quickly and the child always receives the full dose, making clinicians more reluctant to titrate the dose. IMPLICATIONS: This article presents initial evidence for feasibility and tolerability of fentanyl lozenges in children as young as five years old, who are on relatively low doses of background opioids. This could be of interest to clinicians who are looking for alternatives to oral opioids to manage breakthrough pain in children with cancer.

Opioids for cancer-related pain in children and adolescents.

BACKGROUND: Pain is a common feature of childhood and adolescence around the world, and for many young people, that pain is chronic. The World Health Organization (WHO) guidelines for pharmacological treatments for children's persisting pain acknowledge that pain in children is a major public health concern of high significance in most parts of the world. Views on children's pain have changed over time and relief of pain is now seen as important. In the past, pain was largely dismissed and was frequently left untreated, and it was assumed that children quickly forgot about painful experiences.We designed a suite of seven reviews in chronic non-cancer pain and cancer pain (looking at antidepressants, antiepileptic drugs, non-steroidal anti-inflammatory drugs, opioids, and paracetamol) to review the evidence for children's pain using pharmacological interventions.As one of the leading causes of mortality and morbidity for children and adolescents in the world today, childhood cancer (and its associated pain) is a major health concern. Cancer pain in infants, children, and adolescents is primarily nociceptive pain with negative long term effects. Cancer-related pain is generally caused directly by the tumour itself such as compressing on the nerve or inflammation of the organs. Cancer-related pain generally occurs as a result of perioperative procedures, nerve damage caused by radiation or chemotherapy treatments, or mucositis. However, this review focused on pain caused directly by the tumour itself such as nerve infiltration, external nerve compression, and other inflammatory events.Opioids are used worldwide for the treatment of pain. Currently available opioids include: buprenorphine, codeine, fentanyl, hydromorphone, methadone, morphine, oxycodone, and tramadol. Opioids are generally available in healthcare settings across most developed countries but access may be restricted in developing countries. To achieve adequate pain relief in children using opioids, with an acceptable grade of adverse effects, the recommended method is to start with a low dose gradually titrated to effect or unacceptable adverse effect in the child. OBJECTIVES: To assess the analgesic efficacy, and adverse events, of opioids used to treat cancer-related pain in children and adolescents aged between birth and 17 years, in any setting. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online, MEDLINE via Ovid and Embase via Ovid from inception to 22 February 2017. We also searched the reference lists of retrieved studies and reviews, and searched online clinical trial registries. SELECTION CRITERIA: Randomised controlled trials (RCTs), with or without blinding, of any dose, and any route, treating cancer-related pain in children and adolescents, comparing opioids with placebo or an active comparator. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for eligibility. We planned to use dichotomous data to calculate risk ratio and number needed to treat for one additional event, using standard methods. We assessed GRADE (Grading of Recommendations Assessment, Development and Evaluation) and planned to create a 'Summary of findings' table. MAIN RESULTS: No studies were identified that were eligible for inclusion in this review (very low quality evidence). Several studies tested opioids on adults with cancer-related pain, but none in participants aged from birth to 17 years.We rated the quality of evidence as very low, downgraded due to a lack of available data; no analyses could be undertaken. AUTHORS' CONCLUSIONS: No conclusions can be drawn about efficacy or harm in the use of opioids to treat cancer-related pain in children and adolescents. As a result, there is no RCT evidence to support or refute the use of opioids to treat cancer-related pain in children and adolescents.

Development of research priorities in paediatric pain and palliative care.

Priority setting for healthcare research is as important as conducting the research itself because rigorous and systematic processes of priority setting can make an important contribution to the quality of research. This project aimed to prioritise clinical therapeutic uncertainties in paediatric pain and palliative care in order to encourage and inform the future research agenda and raise the profile of paediatric pain and palliative care in the United Kingdom. Clinical therapeutic uncertainties were identified and transformed into patient, intervention, comparison and outcome (PICO) format and prioritised using a modified Nominal Group Technique. Members of the Clinical Studies Group in Pain and Palliative Care within National Institute for Health Research (NIHR) Clinical Research Network (CRN)-Children took part in the prioritisation exercise. There were 11 clinically active professionals spanning across a wide range of paediatric disciplines and one parent representative. The top three research priorities related to establishing the safety and efficacy of (1) gabapentin in the management of chronic pain with neuropathic characteristics, (2) intravenous non-steroidal anti-inflammatory drugs in the management of post-operative pain in pre-schoolers and (3) different opioid formulations in the management of acute pain in children while at home. Questions about the long-term effect of psychological interventions in the management of chronic pain and various pharmacological interventions to improve pain and symptom management in palliative care were among the 'top 10' priorities. The results of prioritisation were included in the UK Database of Uncertainties about the Effects of Treatments (DUETS) database. Increased awareness of priorities and priority-setting processes should encourage clinicians and other stakeholders to engage in such exercises in the future.

Palliative and end-of-life care for children with diffuse intrinsic pontine glioma: results from a London cohort study and international survey.

BACKGROUND: More than 90% of patients with diffuse intrinsic pontine glioma (DIPG) will die within 2 years of diagnosis. Patients deteriorate rapidly during the disease course, which severely impairs their quality of life. To date, no specific research on this clinically important subject has been conducted. This study aimed to compile an inventory of symptoms experienced, interventions applied, and current service provision in end-of-life care for DIPG. METHODS: We performed a retrospective cohort study of children with DIPG, aged 0-18 years, who received treatment under the care of 2 London hospitals. Symptoms, interventions, and services applied during the 12 weeks before death were analyzed. In addition, we conducted a global questionnaire-study among health care professionals. RESULTS: In more than 78% of DIPG patients, problems concerning mobility, swallowing, communication, consciousness, and breathing arose during end-stage disease. Supportive drugs were widely prescribed. The use of medical aids was only documented in <15% of patients. Palliative and end-of-life care was mostly based on the health care professional's experience; only 21% of the questionnaire respondents reported to have a disease-specific palliative care guideline available. CONCLUSIONS: This research assessed the current state of palliative and end-of-life care for children with DIPG. Our results show the variability and complexity of symptoms at end-stage disease and the current lack of disease-specific guidelines for this vulnerable group of patients. This first descriptive paper is intended to act as a solid basis for developing an international clinical trial and subsequent guideline to support high-quality palliative and end-of-life care.