Oxford Textbook of Pediatric Pain [2 ed.] 0198818769, 9780198818762

Table of contents :
cover
Oxford Textbook of 
Pediatric Pain
Copyright
Contents
List of abbreviations
Contributors
SECTION 1
Introduction
1. History of pain in children
2. Prevalence and distribution of pain in children
3. Long-​term effects of early pain and injury: animal models
4. Long-​term effects of pain in infants
5. Prevention of the development and maintenance of pediatric chronic pain and disability
SECTION 2 Biological basis of pediatric pain
6. Nociceptive signaling in the periphery and spinal cord
7. Pain and immunity: a lifelong interaction
8. The development of central nociceptive processing and descending modulation of pain
9. Genetics and pain in childhood
SECTION 3 Social and psychological basis of pediatric pain
10. Theoretical basis of pain
11. Pain in the cultural context
12. Families and pain
13. Pain, social relationships, and school
14. The effect of sex and gender on child and adolescent pain
15. Pediatric chronic pain and mental health
16. Sleep and pain in children and adolescents
SECTION 4 Pain in specific populations and diseases
17. Pain in children with intellectual or developmental disabilities
18. Pediatric cancer pain
19. Pain management in major pediatric trauma and burns
20. Needle procedures
21. Procedural sedation
22. Neuropathic pain in children
23. Inflammatory arthritis and arthropathy
24. Chronic pain syndromes in childhood: one trunk, many branches
25. Noninflammatory musculoskeletal pain
26. Pain in sickle cell disease
27. Inflammatory bowel disease, pancreatitis, and gut dysmotility disorders
28. Postoperative pain management
29. Pain treatment and prevention in pediatric palliative care
30. Recurrent abdominal pain
31. Chronic pelvic pain in children and adolescents
32. Headaches
33. Persisting pain in childhood medical illness
34. Common pain problems in the outpatient setting
35. Effective management of children’s pain and anxiety in the Emergency Department
SECTION 5 Measurement of pain
36. Neonatal and infant pain assessment
37. Self-​report: the primary source in assessment after infancy
38. Behavioral measures of pain
39. Biomarkers of pain in infants and children
40. Brain responses in infants
41. Measurement of health-​related quality of life and physical function
SECTION 6 Pharmacological interventions
42. Principles of clinical pharmacology applied to analgesics in children
43. The nonsteroidal anti-​inflammatory drugs and acetaminophen
44. Developmental pharmacology of opioids
45. Opioids in clinical practice
46. Interventional pain-​management techniques for chronic pain
47. Topical anesthetics and analgesics
48. Drugs for neuropathic pain
49. Sucrose and sweet taste
50. Cannabis
SECTION 7 Psychosocial interventions
51. Psychosocial interventions for pediatric pain management
52. Procedural pain distraction
SECTION 8 Physical interventions
53. Occupational and physical therapy for pain in pediatric clients
54. Mother care for procedural pain in infants
SECTION 9 Special topics
55. Complementary drugs: herbs, vitamins, and dietary supplements for pain and symptom management
56. Complementary therapy in pediatric pain
57. Theory-​informed approaches to translating pain evidence into practice
58. Knowledge translation strategies for mobilizing individuals to implement pain evidence to practice
59. Knowledge translation strategies for mobilizing organizations to implement pain evidence to practice
60. Digital health technologies for pediatric pain
61. Ethics of pain management in infants and older children
62. Sociodemographic disparities in pediatric pain management: relationships and predictors
Index

Citation preview

Oxford Textbook of 

Pediatric Pain

Oxford Textbook of 

Pediatric Pain SECOND EDITION

EDITED BY

Bonnie J. Stevens Professor, Lawrence S. Bloomberg Faculty of Nursing and Faculties of Medicine and Dentistry, University of Toronto; and Associate Chief of Nursing Research, Senior Scientist Research Institute, The Hospital for Sick Children, Toronto, ON, Canada

Gareth Hathway Associate Professor of Neuroscience, School of Life Sciences, University of Nottingham, Nottingham, UK

William T. Zempsky The Francine L. and Robert B. Goldfarb-​William T. Zempsky, MD Endowed Chair for Pain and Palliative Medicine, Associate Chair for Research, Connecticut Children's Medical Center; and Professor of Pediatrics and Nursing, University of Connecticut, Farmington, CT, USA

1

3 Great Clarendon Street, Oxford, OX2 6DP, United Kingdom Oxford University Press is a department of the University of Oxford. It furthers the University’s objective of excellence in research, scholarship, and education by publishing worldwide. Oxford is a registered trade mark of Oxford University Press in the UK and in certain other countries © Oxford University Press 2021 The moral rights of the authors have been asserted First Edition published in 2014 Second Edition published in 2021 Impression: 1 All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, without the prior permission in writing of Oxford University Press, or as expressly permitted by law, by licence or under terms agreed with the appropriate reprographics rights organization. Enquiries concerning reproduction outside the scope of the above should be sent to the Rights Department, Oxford University Press, at the address above You must not circulate this work in any other form and you must impose this same condition on any acquirer Published in the United States of America by Oxford University Press 198 Madison Avenue, New York, NY 10016, United States of America British Library Cataloguing in Publication Data Data available Library of Congress Control Number: 2020941564 ISBN 978–​0–​19–​881876–​2 DOI: 10.1093/med/9780198818762.001.0001 Printed in Great Britain by Bell & Bain Ltd., Glasgow Oxford University Press makes no representation, express or implied, that the drug dosages in this book are correct. Readers must therefore always check the product information and clinical procedures with the most up-​to-​date published product information and data sheets provided by the manufacturers and the most recent codes of conduct and safety regulations. The authors and the publishers do not accept responsibility or legal liability for any errors in the text or for the misuse or misapplication of material in this work. Except where otherwise stated, drug dosages and recommendations are for the non-​pregnant adult who is not breast-​feeding Links to third party websites are provided by Oxford in good faith and for information only. Oxford disclaims any responsibility for the materials contained in any third party website referenced in this work.

Preface Pain, and its treatment, continues to be an unsolved mystery for many children and their care providers. However, during the last 6 years we have increased our understanding of how pain in early life differs to that in maturity using a mixture of approaches from basic science, clinical science, and implementation science that is reflected in the 62 chapters of this second edition of the Oxford Textbook of Pediatric Pain. This new knowledge paints an exciting landscape on strategies to prevent and/​or ameliorate pain for the children and families who suffer needless pain, and for healthcare providers, decision-​makers, policymakers, and all those engaged in solving the mysteries of pain. From basic science, we have an increasing appreciation of the role of non-​neuronal cells in mediating pain responses in early life. We have increased our understanding of the role of glia in spinal pain processing in early life and have begun to understand how these macrophage-​ like cells are fundamentally unique—​ undergoing markedly different phenotypic shifts than adult microglia. In early life, these cells mount largely anti-​inflammatory responses rather than the proinflammatory ones seen in later life. Further research is emerging to understand the way in which this response occurs. We are also becoming more aware of the lifelong consequences of pain in early life on the physiological response of individuals. We have known for some time that clinically induced painful injury can alter sensory thresholds in later life and have recently learned that this is also true in laboratory animals, thus allowing for the investigation of the mechanisms that underpin it. We have learned that global hypoalgesia following early life injury results from changes in the maturation of the descending pain control pathways from the brainstem and we have also seen how early life injury can “prime” microglia to alter their response to injury much later in life. Finally, we continue to learn more about the role of the brain in perceiving and modulating pain responses. The last 20 years have seen quantum leaps in our understanding of how the neonatal human brain perceives and processes tactile and painful information. Recently, we have seen how the areas of the brain that process sensory and affective components of pain in early life are very similar to those in the adult (with notable exceptions of the amygdala and orbitofrontal cortex), how brainstem pain control pathways function in early life to modulate pain perception, and how ensembles of neurons in the sensory cortices differentially encode noxious information versus adults. From clinical science, we have seen how hospitalized neonates and infants continue to be exposed to multiple painful procedures daily and how each exposure to a painful event has both immediate and long-​term consequences. Though we witness exponential

expansion in the production and synthesis of evidence supporting the implementation of pharmacological, behavioral, and physical approaches to pain reduction, these strategies continue to be inconsistently applied. There have been reports where assessment is occurring in less than one-​third of Neonatal Intensive Care Unit admissions and daily in only 10% of neonates. In the developing world, there continues to be reports of daily painful procedures such as peripheral cannula insertion and intramuscular injections with almost no infants receiving any analgesia. Of a multitude of validated infant pain assessment tools, and guidelines stipulating their use, consistent pain assessment—​as a basis for treatment—​is still severely lacking. Similarly, pain management for procedural pain, despite rigorous systematic reviews, remains less than optimal, with many effective treatments being omitted from caregiving. Continuous and persistent pain in infants remains poorly defined, assessed, and treated. Hospitalized older children continue to undergo painful procedures for diagnostic and treatment purposes, often without optimal pain assessment or treatment. Studies indicate that up to a third of patients representing all age groups experience pain in the previous 24 hours, with about a quarter reporting moderate-​to-​severe pain. The majority of children in moderate-​to-​severe pain did not have a documented pain assessment, and evidence-​based pharmacological and/​or integrative (“nonpharmacological”) measures were not systematically administered to prevent or treat pain. Also, one in five children suffers from some form of chronic pain without sufficient access to system-​wide resources, resulting in the costs of treatment-​ seeking adolescents with moderate-​ to-​ severe chronic pain upwardof US$20 billion annually in the US alone. The explosion of clinical research that incorporates multiple methodological approaches and patient and family perspectives has continued to expand our knowledge of pain, and pain prevention and treatment, with notable advances in both acute and chronic pain. We are also learning the importance of the influence of culture and diversity in relation to pain assessment and treatment. Our understanding of the factors that may increase risk for the development of chronic pain, including adverse childhood events, gives us new targets for intervention. There has been a growth in research of web-​based e-​health interventions to allow youth to access pain self-​management strategies, pain education, and cognitive behavioral therapies closer to home. There has been notable improvement in the use of multimodal pharmacological therapies in hospitalized children and youth with chronic pain (e.g., regional techniques, and use of adjunctive medications such as ketamine and lidocaine), as well as integrated pain management.

vi

Preface

From implementation science, we now know that immediate uptake of new knowledge is challenging, and poor pain outcomes may be significant owing to implementation and dissemination issues, as compared to the generation of knowledge itself. The theoretical underpinnings of knowledge translation are explored in this edition, and the mobilization of new knowledge is considered at the individual (e.g., child and family) and organizational (e.g., hospital, healthcare system, and societal) levels. We have learned from implementation science that the organizational context in which implementation and dissemination of new knowledge takes place, as well as the effectiveness of the facilitation strategy, is extremely important. Modifiable contextual factors such as leadership support, organizational culture, and communication all play an important role in implementing new knowledge for practice. Over the past six years, the landscape of pain in children, the research that supports it, and prevention and treatment strategies have grown exponentially. The revised 2020 IASP definition of pain states that “verbal description is only one of several behaviors to express pain”, thus making it possible for all humans, including very young

children to experience pain. The scientific basis of pediatric pain is constantly expanding creating escalating excitement, but it is still woefully inadequate. Pediatric pain treatment is more integrated into health care rather than isolated in pain specialists; with the engagement of children, and family and professional caregivers. In this second edition of the book, we will not only update the status of current knowledge from basic and clinical science and practice, but we will also focus on how that knowledge-​to-​practice gap is addressed through individual and organizational implementation and facilitation strategies. This new knowledge is a call to action given that pain in children and youth is common and impacts many dimensions of children’s and families’ lives. It is our role to advocate for improved awareness, increased knowledge, better recognition, effective treatment, and implementation of knowledge regarding pediatric pain. Bonnie J. Stevens Gareth Hathway William T. Zempsky

Acknowledgments As the editorial team for this second edition of the Oxford Textbook of Pediatric Pain, we would like to thank everyone who has given freely of their time and energy to ensure this book represents what we currently know about pain in children and where our efforts should be focused for the future. First, we would like to thank all of the authors of this second edition, as well as those of the first edition, for sharing their expertise and wisdom on the topic of pain in children and providing us with real-​life examples and perspectives. Second, we would like to thank Dr.  Patrick McGrath for his contributions and leadership before stepping down from the Editor responsibility. Dr.  McGrath was an enthusiastic lead co-​editor in the first edition and laid much of the foundation upon which the second edition has been constructed. We are

collectively grateful to him as an editorial team and as a research community. Third, we would like to thank everyone at Oxford University Press who has worked so tirelessly in all aspects of the production of this book. Most importantly, we would like to thank all of the children, families, healthcare providers, researchers, educators, and trainees who inspire us to do the best we can to unravel the mysteries of pain, to prevent and treat pain when it occurs, and to find novel ways of bridging the gaps between the generation of new knowledge and applying that knowledge in practice. Bonnie J. Stevens Gareth Hathway William T. Zempsky

Contents List of abbreviations  xiii Contributors  xvii

8. The development of central nociceptive processing and descending modulation of pain  72 Maria Fitzgerald

SECTION 1 Introduction 

9. Genetics and pain in childhood  79 Jeffrey S. Mogil

1. History of pain in children  3 Anita M. Unruh† and Patrick J. McGrath

2. Prevalence and distribution of pain in children  11 Bonnie J. Stevens and William T. Zempsky

3. Long-​term effects of early pain and injury: animal models  21 Orla Moriarty and Suellen M. Walker

4. Long-​term effects of pain in infants  38 Ruth E. Grunau, Jillian Vinall Miller, and Cecil M. Y. Chau

5. Prevention of the development and maintenance of pediatric chronic pain and disability  47 Brittany N. Rosenbloom, M. Gabrielle Pagé, Anna Huguet, and Joel Katz

SECTION 2 Biological basis of pediatric pain 6. Nociceptive signaling in the periphery and spinal cord  59 Gareth Hathway, Charles M. Greenspon, and Mark L. Baccei

7. Pain and immunity: a lifelong interaction  67 Simon Beggs

SECTION 3 Social and psychological basis of pediatric pain 10. Theoretical basis of pain  89 Liesbet Goubert, Rebecca Pillai Riddell, Laura Simons, and David Borsook

11. Pain in the cultural context  101 Margot Latimer, Amy Bombay, and Rachel VanEvery

12. Families and pain  109 Kristen S. Higgins, Christine T. Chambers, Kathryn A. Birnie, and Katelynn E. Boerner

13. Pain, social relationships, and school  118 Paula Forgeron, Sara King, and Jessica Fales

14. The effect of sex and gender on child and adolescent pain  127 Katelynn E. Boerner and Edmund Keogh

15. Pediatric chronic pain and mental health  136 Maria Pavlova, Jillian Vinall Miller, Patrick J. McGrath, and Melanie Noel

16. Sleep and pain in children and adolescents  146 Rocío de la Vega, Joanne Dudeney, and Tonya M. Palermo

x

Contents

SECTION 4 Pain in specific populations and diseases 17. Pain in children with intellectual or developmental disabilities  157 Andrina MacDonald, Kristi Bennett, Jean C.K. Stansbury, Chantel C. Barney, John Belew, Scott Schwantes, Abraham J. Valkenburg, and Frank J. Symons

18. Pediatric cancer pain  168 Steven J. Weisman

19. Pain management in major pediatric trauma and burns  181 Greta M. Palmer and Franz E. Babl

20. Needle procedures  192 Anna Taddio

21. Procedural sedation  201 Daniel S. Tsze and Joseph P. Cravero

22. Neuropathic pain in children  214 Madeleine A. Verriotis and Suellen M. Walker

23. Inflammatory arthritis and arthropathy  225 Peter Chira and Laura E. Schanberg

24. Chronic pain syndromes in childhood: one trunk, many branches  239 Neil L. Schechter

25. Noninflammatory musculoskeletal pain  250 Jacqui Clinch

26. Pain in sickle cell disease  261 Carlton Dampier and Soumitri Sil

27. Inflammatory bowel disease, pancreatitis, and gut dysmotility disorders  272

32. Headaches  330 Andrew D. Hershey

33. Persisting pain in childhood medical illness  343 Martha Mherekumombe and John J. Collins

34. Common pain problems in the outpatient setting  351 F. Ralph Berberich

35. Effective management of children’s pain and anxiety in the Emergency Department  361 Robert M. (Bo) Kennedy

SECTION 5 Measurement of pain 36. Neonatal and infant pain assessment  375 Mariana Bueno, Mats Eriksson, and Bonnie J. Stevens

37. Self-​report: the primary source in assessment after infancy  391 Carl L. von Baeyer and Mark A. Connelly

38. Behavioral measures of pain  400 Jill M. Chorney and C. Meghan McMurtry

39. Biomarkers of pain in infants and children  413 Naama Rotem-​Kohavi, Susanne Brummelte, Kenneth D. Craig, and Tim F. Oberlander

40. Brain responses in infants  422 Caroline Hartley and Rebeccah Slater

41. Measurement of health-​related quality of life and physical function  430 See Wan Tham, Anna C. Wilson, Lexa K. Murphy, and Tonya M. Palermo

Akshay Batra and R. Mark Beattie

28. Postoperative pain management  282 Glyn Williams and Richard F. Howard

29. Pain treatment and prevention in pediatric palliative care  292 Stefan J. Friedrichsdorf

30. Recurrent abdominal pain  312  Jennifer Verrill Schurman, Amanda Drews Deacy, and Craig A. Friesen

31. Chronic pelvic pain in children and adolescents  321 Susan L. Sager and Marc R. Laufer

SECTION 6 Pharmacological interventions 42. Principles of clinical pharmacology applied to analgesics in children  441 Karel Allegaert, Sinno H.P. Simons, and Dick Tibboel

43. The nonsteroidal anti-​inflammatory drugs and acetaminophen  449 Brian J. Anderson

Contents

44. Developmental pharmacology of opioids  464 Gareth Hathway

45. Opioids in clinical practice  472 Howard Meng, Fiona Campbell, and Scott A. Strassels

46. Interventional pain-​management techniques for chronic pain  483 Navil F. Sethna, Walid Alrayashi, Pradeep Dinakar, and Karen R. Boretsky

47. Topical anesthetics and analgesics  494 William T. Zempsky

48. Drugs for neuropathic pain  501 Sachin Rastogi and Fiona Campbell

49. Sucrose and sweet taste  511 Denise Harrison, Janet Yamada, and Mariana Bueno

50. Cannabis  520 Mark A. Ware, Rebecca Pitt, and Pablo Ingelmo

SECTION 7 Psychosocial interventions 51. Psychosocial interventions for pediatric pain management  531 Kristen Uhl, Laura A. Wright, Rachael M. Coakley, and Deirdre E. Logan

52. Procedural pain distraction  547 Lindsey L. Cohen, Laura A. Wright, Sarah R. Martin, Sharon Shih, and Matthew Donati

SECTION 8 Physical interventions 53. Occupational and physical therapy for pain in pediatric clients  557 Susan M. Tupper, Joyce M. Engel, Mary Swiggum, and Liisa Holsti

54. Mother care for procedural pain in infants  569 Marsha Campbell-​Yeo, Britney Benoit, Brianna Richardson, and Celeste Johnston

SECTION 9 Special topics 55. Complementary drugs: herbs, vitamins, and dietary supplements for pain and symptom management  585 Joy A. Weydert

56. Complementary therapy in pediatric pain  596 Sarah R. Martin and Lonnie K. Zeltzer

57. Theory-​informed approaches to translating pain evidence into practice  607 Janet Yamada, Alison M. Hutchinson, and Shelly-​Anne Li

58. Knowledge translation strategies for mobilizing individuals to implement pain evidence to practice  617 Perri R. Tutelman, Christine T. Chambers, and Melanie Barwick

59. Knowledge translation strategies for mobilizing organizations to implement pain evidence to practice  627 Bonnie J. Stevens, Stefan J. Friedrichsdorf, and Alison Twycross

60. Digital health technologies for pediatric pain  638 Lindsay A. Jibb and Jennifer N. Stinson

61. Ethics of pain management in infants and older children  649 Kenneth D. Craig and Adam Shriver

62. Sociodemographic disparities in pediatric pain management: relationships and predictors  660 Anna Huguet and Miriam O. Ezenwa

Index  671

xi

List of abbreviations 2-​AG 5-​HT/​5-​HT3 5-​HTP A&E AAN AAP AAPD AAT ABR ACC ACEP ACT ADHD AEA AED AFO AIDS ALL AMPA

2-​arachidonoylglycerol 5-​hydroxytryptamine (serotonin) 5-​hydroxytryptophan Accident and Emergency American Academy of Neurology American Academy of Pediatrics American Academy of Pediatric Dentistry animal-​assisted therapy auditory brainstem response anterior cingulate cortex American College of Emergency Physicians acceptance and commitment therapy attention deficit hyperactivity disorder arachidonoyl ethanolamine antiepileptic drug ankle foot orthotic acquired immunodeficiency syndrome acute lymphoblastic leukemia α-​amino-​3-​hydroxy-​5-​methyl-​4-​ isoxazolepropionic acid AMPAR AMPA receptor ANA antinuclear antibody ANS autonomic nervous system AOE acute otitis externa AOM acute otitis media APAP N-​acetyl-​para-​aminophenol ARV antiretroviral ASA American Society of Anesthesiologists ASD autism spectrum disorders ASWS Adolescent Sleep Wake Scale ATP adenosine triphosphate AVN avascular necrosis BAPQ Bath Adolescent Pain Questionnaire BART biofeedback-​assisted relaxation training BBB blood–​brain barrier BDNF brain-​derived neurotrophic factor BDZ benzodiazepine BE beta endorphin BIS Bispectral Index BMA bone marrow aspiration BMI body mass index BMT bone marrow transplant BOLD blood oxygen level-​dependent BPI brachial plexus injury CALI Child Activity Limitations Interview

CAM complementary and alternative medicine CAMPIS Child Adult Medical Procedure Interaction Scale CAMPIS-​R CAMPIS-​Revised CAMPIS-​SF CAMPIS-​Short  Form CAPS Childhood Arthritis Prospective Study CARRA Childhood and Rheumatology Research Alliance CAS Color Analog Scale CAT creative art therapy CBD cannabidiol CBT cognitive behavior therapy CBT-​I cognitive behavior therapy for insomnia CCBT contextual CBT CCK cholecystokinin CCP citrullinated cyclic peptide CD Crohn disease CDH chronic daily headache CDSS clinical decision support system CE cholesterol ester CF cystic fibrosis CFA complete Freund’s adjuvant CFIR Consolidated Framework for Implementation Research CHEOPS Children’s Hospital of Eastern Ontario Pain Scale CI confidence interval C-​IBS constipation-​predominant  IBS CIHR Canadian Institutes of Health Research CINV chemotherapy-​induced nausea and vomiting CIPN chemotherapy-​induced peripheral neuropathy CMT Charcot–​Marie–​Tooth disease CNCP chronic noncancer pain CNS central nervous system CO2 carbon dioxide COMFORT-​B COMFORT Behavioral COMT catecholamine-​O-​methyltransferase CoP community of practice CoQ10 coenzyme Q10 COX cyclooxygenase CP cerebral palsy CPG clinical practice guidelines CPP chronic pelvic pain CPSP chronic postsurgical pain CR conditioned response CRF corticotropin-​releasing  factor CRFR1 corticotropin-​releasing factor receptor 1 CRH corticotropin-​releasing hormone

xiv

List of abbreviations

CRPS complex regional pain syndrome CRU conceptual research use CS conditioned stimulus CSF cerebrospinal fluid CSHQ Children’s Sleep Habits Questionnaire CT computed tomography CVT canine visitation therapy CYP cytochrome P450 CYP2D6 cytochrome P450 2D6 CWP chronic widespread pain DAMGO (D-​Ala2, N-​MePhe4, Gly-​ol)-​enkephalin DD developmental disability DEX dexmedetomidine DH dorsal horn DHE dihydroergotamine DIAPR Development of the Infant Acute Pain Responses Model –​ Revised D-​IBS diarrhea-​predominant  IBS DIP distal interphalangeal predominant DMARD disease-​modifying antirheumatic drug DN4 Douleur Neuropathique en 4 questions DPNB dorsal penile nerve block DRG dorsal root ganglion DZ dizygotic EAL English as an additional language EB epidermolysis bullosa ECG electrocardiogram ECoG electrocorticogram ED Emergency Department EDS Ehlers-​Danlos syndrome EEG electroencephalogram EIH exercise-​induced hypoalgesia EM erythromelalgia EMA European Medicines Agency EMG electromyography EMR electronic medical record ENS enteric nervous system EPIC Evidence-​Based Practice for Improving Quality EPIS Exploration, Preparation, Implementation, Sustainment EPIQ Evidence-​based Practice In Quality EPM elevated-​plus  maze EPOC Effective Practice and Organization of Care EPSC excitatory postsynaptic potential ePRO electronically recorded patient-​reported outcome ERA enthesitis-​related arthritis ERD exacerbated respiratory disease ERLA extended-​release or long-​acting ERRM ecological resilience–​risk model ESES electronic socio-​emotional support ESI epidural steroid injection ESR erythrocyte sedimentation rate FA fractional anisotropy FAAH fatty acid amide hydrolase FAP functional abdominal pain FC free cholesterol FD functional dyspepsia FDA Food and Drugs Administration

FDI Functional Disability Index FGID functional gastrointestinal disorder FLACC Face, Legs, Activity, Cry, Consolability FM fibromyalgia fMRI functional magnetic resonance imaging FODMAP fermentable oligosaccharides, disaccharides, monosaccharides, and polyols FPS Faces Pain Scale FPS-​R Faces Pain Scale-​Revised FST forced swim test GA gestational age GABA   -​aminobutyric  acid GBS Guillain-​Barré syndrome GC glucocorticoid receptor GCS Glasgow Coma Scale GERD gastroesophageal reflux disease GFR glomerular filtration rate GI gastrointestinal GlyR glycine receptor GOF gain of function GRAS Generally Recognized As Safe GVHD graft-​versus-​host disease GWAS genome-​wide association study h2 heritability HCP healthcare provider HIV human immunodeficiency virus HLA human leukocyte antigen HPA hypothalamic–​pituitary–​adrenal HR heart rate HRF hemodynamic response function HRQoL health-​related quality of life HRV heart rate variability IASP International Association for the Study of Pain IB4 isolectin B4 IBD inflammatory bowel disease IBS irritable bowel syndrome IC indeterminate colitis ICC intraclass correlation coefficient ICF International Classification of Functioning, Disability and Health ICF-​CY International Classification Framework of Functioning, Disability and Health for Children and Youth ICHD International Classification of Headache Disorders ICHD-​I International Classification of Headache Disorders, First Edition ICHD-​II International Classification of Headache Disorders, Second Edition ICHD-​3 International Classification of Headache Disorders, Third Edition ICU Intensive Care Unit ID intellectual disability I/​DD intellectual or developmental disabilities IFAM interpersonal fear-​avoidance model IIPT intensive interdisciplinary pain treatment iKT integrated knowledge translation IL interleukin

List of abbreviations

ILAR IM IMg2+ IMMPACT

International League Against Rheumatism intramuscular/​intramuscularly ionized magnesium Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials IN intranasal/​intranasally INF intranasal fentanyl IPC Interprofessional Pain Curriculum IPSC inhibitory postsynaptic current IQ intelligence quotient IR immediate release IRR inter-​rater reliability IRU instrumental research use ISI Insomnia Severity Index IV intravenous JIA juvenile idiopathic arthritis Kd dissociation constant KMC kangaroo mother care KT knowledge translation KTA Knowledge to Action LA local anesthesia LAC acetyl L-​carnitine LANSS Leeds Assessment of Neuropathic Symptoms and Signs LBP low back pain LC locus ceruleus LCT limited attentional capacity theory LET lidocaine–​epinephrine–​tetracaine LFCN lateral femoral cutaneous neuropathy LFP local field potential LOF loss of function LP lumbar puncture LPS lipopolysaccharide LSB lumbar sympathetic blockade LTMR low-​threshold mechanoreceptor LTP long-​term potentiation M3G morphine 3-​glucuronide M6G morphine 6-​glucuronide MAC minimal alveolar concentration MD mean difference mGluR metabotropic glutamate receptor MIDAS Migraine Disability Assessment MOH medication overuse headache mPFC medial prefrontal cortex MR magnetic resonance MRI magnetic resonance imaging mRNA messenger RNA MRT multiple attentional resource theory MS multiple sclerosis MSLT multiple sleep latency test MUA multiunit spiking activity MVA motor vehicle accident myWHI myWireless Headache Intervention MZ monozygotic N2O nitrous oxide NAA N-​acetylaspartate NAM National Academy of Medicine NAPQI N-​acetyl-​p-​benzoquinone  imine

NCA NCCIH

nurse-​controlled analgesia National Center for Complementary and Integrative Health NCCPC Non-​Communicating Children’s Pain Checklist NCCPC-​PV Non-​Communicating Children’s Pain Checklist-​ Postoperative Version NCCPC-​R NCCPC-​Revised NF neurofibromatosis NF1 neurofibromatosis 1 NF2 neurofibromatosis 2 NFCS Neonatal Facial Coding System NFκB nuclear factor kappa B NG nasogastric NGF nerve growth factor NHAMCS National Hospital Ambulatory Medical Care Survey NICU Neonatal Intensive Care Unit NIPS Neonatal Infant Pain Scale NIRS near-​infrared spectroscopy NMDA N-​methyl-​d-​aspartate NMDAR NMDA receptor NNRTI non-​nucleoside analog reverse transcriptase inhibitor NNS non-​nutritive sucking NNT number needed to treat NP neuropathic pain NPO nil per os (nil by mouth) NPY neuropeptide Y NRS numerical rating scale NSAID nonsteroidal anti-​inflammatory drug nsNSAID nonselective nonsteroidal anti-​inflammatory drug OBPI obstetric brachial plexus injury OIC opioid-​induced constipation OIH opioid-​induced hyperalgesia OPPC Online Pediatric Pain Curriculum OR odds ratio OSBD Observational Scale of Behavioral Distress O–​SH–​GA opioids, sedatives, hypnotics, general anesthetics OT occupational therapist OTC over the counter OUCH Opportunities to Understand Childhood Hurt P postnatal day PA pyrrolizidine alkaloid PACU Postanesthesia Care Unit PAG periaqueductal gray PAMORA peripherally acting µ opioid receptor antagonists PARiHS Promoting Action on Research Implementation in Health Services PBCL Procedure Behavior Checklist PBn parabrachial nucleus PBRS Procedure Behavior Rating Scale PCA patient-​controlled analgesia PCRA patient-​controlled regional analgesia PD pharmacodynamics PDSA Plan Do Study Act PE primary erythromelalgia PedsQL Pediatric Quality of Life Inventory PEPD paroxysmal extreme pain disorder

xv

xvi

List of abbreviations

PFC prefrontal cortex PGHS prostagland H2 synthetase P-​gp P-​glycoprotein  1 PGx pharmacogenetics PHN postherpetic neuralgia PI protease inhibitor PICD Pain Interprofessional Curriculum Design PICH Pain in Child Health PICU Pediatric Intensive Care Unit PID pelvic inflammatory disease PIPP Premature Infant Pain Profile PIPP-​R Premature Infant Pain Profile-​Revised PK pharmacokinetics PLP phantom limb pain PNS peripheral nervous system PO orally (per os) POMC preopiomelanocortin PONV postoperative nausea and vomiting POTS postural orthostatic tachycardia syndrome POX peroxidase PPC pediatric palliative care PPI proton pump inhibitor PPP Paediatric Pain Profile PPPM Parent’s Postoperative Pain Measure PPPM-​SF PPPM-​Short  Form PPSP persistent postsurgical pain PROMIS Patient Reported Outcome Measurement Information System PR per rectum PRN pro re nata PSA procedural sedation and analgesia PSG polysomnography PSQ Pediatric Sleep Questionnaire PSST problem-​solving skills training PT physical therapist PTSD post-​traumatic stress disorder PV parvalbumin PVN paraventricular nucleus QI quality improvement QST quantitative sensory testing RA rheumatoid arthritis RAP recurrent abdominal pain RBC red blood cell RCT randomized controlled trial ReACCh-​Out Research in Arthritis in Canadian Children Emphasizing Outcomes REM rapid eye movement RF rheumatoid factor r-​FLACC FLACC-​Revised RNA ribonucleic acid RPC Research Practice Council RTT Rett syndrome RVM rostroventral medulla SC subcutaneous SCD sickle cell disease SCI spinal cord injury

SCS SD SDB SDH SES SG SIB SMS SNI SNP SNRI

spinal cord stimulation standard deviation sleep disordered breathing superficial dorsal horn socioeconomic status substantia gelatinosa self-​injurious behavior short messaging service spared nerve injury single nucleotide polymorphism selective serotonin and noradrenaline reuptake inhibitor SP subplate SSC skin-​to-​skin  care SSRI selective serotonin reuptake inhibitor STT spinothalamic tract SULT sulfotransferase SWS slow wave sleep TAC trigeminal autonomic cephalalgia TB tuberculosis TCA tricyclic antidepressant TCM traditional Chinese medicine TDF Theoretical Domains Framework TENS transcutaneous electrical nerve stimulation Th helper T cell THC tetrahydrocannabinol TLESR transient lower esophageal sphincter relaxation t-​LTP time-​dependent  LTP TMS transcranial magnetic stimulation TN trigeminal neuralgia TNF tumor necrosis factor TrkA tyrosine receptor kinase A TROPIC Translating Research on Pain in Children TRP transient receptor potential TRPA1 transient receptor potential ankyrin 1 TRPV1 transient receptor potential cation channel subfamily V member 1/​transient receptor potential vanilloid 1 TTH tension-​type headache UC ulcerative colitis UCR unconditioned response UCS unconditioned stimulus UGT uridine diphosphate-​glucuronosyltransferase UGT1A6 uridine diphospho-​glucuronosyltransferase 1A6 URI upper respiratory illness URTI upper respiratory tract infection UTCSP University of Toronto Centre for the Study of Pain UTI urinary tract infection VAS visual analog scale VCUG voiding cystourethrogram V/​F volume of distribution VNS verbal numeric scale VR virtual reality VSG videosomnography WHO World Health Organization WMD weighted mean difference

Contributors

Karel Allegaert  Professor, Department of

Development and Regeneration; and Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Flanders, Belgium; and Department of Clinical Pharmacy, Erasmus MC-​Sophia Children’s Hospital, Rotterdam, The Netherlands

Walid Alrayashi  Department of Anesthesiology,

Critical Care, and Pain Medicine, Harvard Medical School and Boston’s Children Hospital, Boston, MA, USA

Brian J. Anderson  Professor, Anaesthesiology,

University of Auckland, Auckland, New Zealand

Franz E. Babl  Professor of Paediatric Emergency

Medicine, Department of Paediatrics, University of Melbourne; Emergency Physician, Emergency Department, Royal Children’s Hospital; and Senior Fellow, Clinical Sciences, Murdoch Children’s Research Institute, Melbourne, VIC, Australia

Mark L. Baccei  Professor, Anesthesiology,

University of Cincinnati, Cincinnati, OH, USA

Chantel C. Barney  Clinical Scientist, Research,

Gillette Children’s Specialty Healthcare, Saint Paul, MN; Faculty Affiliate and Special Education Program, Department of Educational Psychology, University of Minnesota, Minneapolis, MN, USA

Melanie Barwick  Senior Scientist, Research

Institute, The Hospital for Sick Children, Toronto, ON, Canada

Akshay Batra  Consultant, Paediatrics, University

Hospitals Southampton, Southampton, UK

R. Mark Beattie  Consultant, University Hospital

Southampton, Southampton, UK

Simon Beggs  Lecturer in Neurobiology of

Paediatric Pain, Developmental Neurosciences, UCL GOSH Institute of Child Health, London, UK

John Belew  Study Coordinator, Research,

Minneapolis VA Health Care System, Mendota Heights, MN, USA

Kristi Bennett  Gillette Children’s Specialty

Healthcare, Saint Paul, MN, USA

Britney Benoit  Assistant Professor, School

of Nursing, St. Francis Xavier University, Antigonish, NS, Canada

F. Ralph Berberich  Paediatrician, Paediatrics,

Sutter East Bay Medical Group and Pediatric Suggestions, Berkeley, CA, USA

Kathryn A. Birnie  Assistant Professor, Department

Jill M. Chorney  Psychologist, IWK Health

Robert M. (Bo) Kennedy  Professor, Pediatrics,

Jacqui Clinch  Consultant, Paediatric

of Anesthesiology, Perioperative and Pain Medicine, University of Calgary, Calgary, AB, Canada Washington University in St. Louis School of Medicine, St Louis, MO, USA

Katelynn E. Boerner  Postdoctoral Fellow,

Paediatrics, University of British Columbia and BC Children’s Hospital, Vancouver, BC, Canada

Amy Bombay  Associate Professor, School

of Nursing and Department of Psychiatry, Dalhousie University, Halifax, NS, Canada

Centre and Department of Anesthesia, Pain Management, and Perioperative Medicine, Dalhousie University, Halifax, NS, Canada Rheumatology, Bristol Royal Hospital for Children, Bristol, UK; and Adolescent/​Young Adult Pain Management Service, Bath Centre Pain Services, Bath, UK

Rachael M. Coakley  Director, Clinical Innovation

and Outreach in Pain Medicine, Department of Anesthesia, Critical Care and Pain Medicine, Boston Children's Hospital, Boston, MA, USA

Karen R. Boretsky  Senior Associate in Anesthesia,

Lindsey L. Cohen  Distinguished University

David Borsook  Professor, Department of

John J. Collins  Head of Department and Senior

Critical Care and Pain Medicine, Boston Children's Hospital, Boston, MA, USA

Anesthesia, Boston Children’s, Massachusetts General and McLean Hospitals, Boston, MA, USA

Susanne Brummelte  Associate Professor,

Psychology, Wayne State University, Detroit, MI, USA

Mariana Bueno  Research Fellow, Child Health

Evaluative Sciences, Research Institute, The Hospital for Sick Children, Toronto, ON, Canada

Fiona Campbell  Professor, Medical Director

Chronic Pain Clinic, Anesthesia and Pain Medicine, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada

Marsha Campbell-​Yeo  Professor and Clinical

Scientist, School of Nursing, Faculty of Health and Centre for Pediatric Pain Research, IWK Health Centre, Dalhousie University, Halifax, NS, Canada

Christine T. Chambers  Professor, Departments of

Psychology and Neuroscience and Pediatrics, Dalhousie University; and Centre for Pediatric Pain Research, IWK Health Centre, Halifax, NS, Canada

Cecil M. Y. Chau  Department of Pediatrics,

University of British Columbia Vancouver, BC; and Brain, Behavior and Development, BC Children’s Hospital Research Institute, Vancouver, BC, Canada

Peter Chira  Clinical Associate Professor,

Department of Pediatrics, Division of Allergy, Immunology, and Rheumatology, University of California San Diego School of Medicine, San Diego, CA, USA

Professor and Chair, Department of Psychology, Georgia State University, Atlanta, GA, USA Staff Specialist, Pain Medicine, The Children’s Hospital at Westmead; and Clinical Associate Professor, Discipline of Child and Adolescent Health, Sydney Medical School, University of Sydney, Sydney, NSW, Australia

Mark A. Connelly  Clinical Psychologist

and Professor of Pediatrics, Division of Developmental and Behavioral Health, Children’s Mercy Kansas City; and University of Missouri-Kansas City School of Medicine, Kansas City, MO, USA

Kenneth D. Craig  Professor Emeritus of

Psychology, Department of Psychology, The University of British Columbia; and Director of the BC Pain Research Network, Vancouver, BC, Canada

Joseph P. Cravero  Professor of Anesthesiology,

Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children’s Hospital, Boston, MA, USA

Carlton Dampier  Professor of Pediatrics, Emory

University School of Medicine; Regulatory Knowledge and Support Program, Georgia Clinical Translational Science Alliance; and Children’s Healthcare of Atlanta, Emory University, Atlanta, GA, USA

Rocío de la Vega  Research Fellow, Center for Child

Health, Behavior and Development, Seattle Children’s Research Institute, Seattle, WA, USA

Pradeep Dinakar  Director, Pediatric Interventional

Pain Program, Anesthesiology, Boston Children’s Hospital, Boston, MA, USA

xviii

Contributors

Matthew Donati  Postdoctoral Fellow, Nemours/

Alfred I. duPont Hospital for Children, Wilmington, DE, USA

Amanda Drews Deacy  Associate Professor,

Division of Gastroenterology, Hepatology, and Nutrition, Children’s Mercy Kansas City; and University of Missouri–Kansas City School of Medicine, Kansas City, MO, USA

Joanne Dudeney  Research Fellow, Department of

Psychology, Macquarie University, Macquarie Park, NSW, Australia

Joyce M. Engel  Professor, College of Health

Sciences, Department of Occupational Science and Technology, University of Wisconsin, Milwaukee, WI, USA

Mats Eriksson  Professor, School of Health

Sciences, Örebro University, Örebro, Sweden

Miriam O. Ezenwa  Associate Professor,

Biobehavioral Nursing Science, University of Florida, Gainesville, FL, USA

Jessica Fales  Associate Professor, Department

of Psychology, Washington State University, Vancouver, WA, USA

Maria Fitzgerald  Professor of Developmental

Neurobiology, Department of Neuroscience, Physiology, and Pharmacology, University College London, London, UK

Paula Forgeron  Associate Professor, School

of Nursing, University of Ottawa, Ottawa, ON, Canada

Stefan J. Friedrichsdorf  Professor of Pediatrics,

Center of Pediatric Pain Medicine, Palliative Care and Integrative Medicine, University of California at San Francisco; Benioff Children’s Hospitals in Oakland and San Francisco, San Francisco, CA, USA

Craig A. Friesen  Professor, Division of

Gastroenterology, Hepatology, and Nutrition, Children’s Mercy Kansas City; and University of Missouri–​Kansas City School of Medicine, Kansas City, MO, USA

Liesbet Goubert  Professor of Clinical Health

Psychology, Department of Experimental-​ Clinical and Health Psychology, Ghent University, Ghent, Belgium

Charles M. Greenspon  Postdoctoral Scholar,

Organismal Biology and Anatomy, University of Chicago, Chicago, IL, USA

Ruth E. Grunau  Professor, Division of Neonatology,

Department of Pediatrics, University of British Columbia; and Brain, Behavior and Development, BC Children’s Hospital Research Institute, Vancouver, BC, Canada

Denise Harrison  Professor, Nursing, University of

Melbourne, Melbourne, VIC, Australia

Caroline Hartley  Sir Henry Dale Fellow,

Department of Paediatrics, University of Oxford, Oxford, UK

Gareth Hathway  Associate Professor of

Neuroscience, School of Life Sciences, University of Nottingham, Nottingham, UK

Andrew D. Hershey  Endowed Chair and Director

Deirdre E. Logan  Associate Professor, Division of

Kristen S. Higgins  Centre for Pediatric Pain

Andrina MacDonald  Pacific Lutheran University,

of Neurology, Professor of Pediatrics and Neurology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA Research, IWK Health Centre; and Department of Psychology and Neuroscience, Dalhousie University, Halifax, NS, Canada

Liisa Holsti  Associate Professor, Occupational

Science and Occupational Therapy, University of British Columbia, Vancouver, BC, Canada

Richard F. Howard  Consultant in Anaesthesia

and Pain Medicine, Department of Anaesthesia and Pain Management, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK

Anna Huguet  Lecturer, Psychology, Universitat

Rovira i Virgili, Tarragona, Spain

Alison M. Hutchinson  Professor, Chair in Nursing,

School of Nursing and Midwifery, Centre for Quality and Patient Safety Research, Institute for Health Transformation, Deakin University, Geelong, VIC, Australia

Pablo Ingelmo  Director, Chronic Pain Service,

Montreal Children’s Hospital; and McGill University, Alan Edwards Centre for Research on Pain, Montreal, QC, Canada

Lindsay A. Jibb  Signy Hildur Eaton Chair in

Pediatric Nursing Research, Child Health Evaluative Sciences, Research Institute Hospital for Sick Children; and Assistant Professor, Lawrence S. Bloomberg Faculty of Nursing, University of Toronto, Toronto, ON, Canada

Celeste Johnston  Emeritus Professor, Ingram

School of Nursing, Faculty of Medicine, McGill University, Montreal, QC, Canada

Joel Katz  Distinguished Research Professor and

Canada Research Chair in Health Psychology, Psychology, York University, Toronto, ON, Canada

Pain Medicine, Department of Anesthesiology, Critical Care and Pain Medicine, Harvard Medical School; and Boston Children's Hospital, Boston, MA, USA Tacoma, WA, USA

Sarah R. Martin  Postdoctoral Scholar, Pediatrics,

David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA, USA

Patrick J. McGrath  Emeritus Professor, Psychiatry,

Dalhousie University and Scientist, IWK Health Centre, Halifax, NS, Canada

C. Meghan McMurtry  Associate Professor, Clinical

Child and Adolescent Psychology, University of Guelph; Clinical and Health Psychologist, Pediatric Chronic Pain Program, McMaster Children’s Hospital; Associate Scientist, Children’s Health Research Institute; and Adjunct Research Professor, Department of Paediatrics, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada

Howard Meng  Resident, Anesthesiology and

Pain Medicine, University of Toronto, Toronto, ON, Canada

Martha Mherekumombe  Palliative Care

Consultant, The Children’s Hospital at Westmead, The Department of Palliative Care, Sydney Children’s Hospital Network, Sydney, NSW, Australia

Jillian Vinall Miller  Assistant Professor,

Department of Anesthesiology, Perioperative and Pain Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada

Jeffrey S. Mogil  E.P. Taylor Professor of Pain Studies,

Psychology and Anesthesia, McGill University, Montreal, QC, Canada

Orla Moriarty  Postdoctoral Researcher, The

International Centre for Neurotherapeutics, Dublin City University, Dublin, Ireland

Robert M. (Bo) Kennedy  Professor, Pediatrics,

Lexa K. Murphy  Postdoctoral Fellow, Center for

Edmund Keogh  Professor, Department of

Melanie Noel  Associate Professor, Psychology,

Washington University in St. Louis School of Medicine, St Louis, MO, USA Psychology, University of Bath, Bath, UK

Sara King  Associate Professor, Co-​ordinator

Child Health Behavior and Development, Seattle Children’s Research Institute, Seattle, WA, USA University of Calgary, Alberta Children’s Hospital Research Institute Calgary, AB, Canada

of School Psychology Program, Faculty of Education, Mount Saint Vincent University, Halifax, NS, Canada

Tim F. Oberlander  Professor, Pediatrics, University

Margot Latimer  Professor, School of Nursing,

of Anesthesiology and Pain Medicine, University of Montreal and Research Center of the Center Hospitalier de l’Université de Montréal (CRCHUM), Montreal, QC, Canada

Dalhousie University, Halifax, NS, Canada

Marc R. Laufer  Chief of Gynecology, Professor

of Obstetrics, Gynecology and Reproductive Biology, Gynecology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA

Shelly-​Anne Li  PhD Student, Lawrence S.

Bloomberg Faculty of Nursing, University of Toronto; and Guideline Development Methodologist, International Affairs and Best Practice Guidelines Centre, Registered Nurses' Association of Ontario, Toronto, ON, Canada

of British Columbia, Vancouver, BC, Canada

M. Gabrielle Pagé  Research Professor, Department

Tonya M. Palermo  Professor, Department

of Anesthesiology and Pain Medicine and Department of Pediatrics and Psychiatry, University of Washington School of Medicine and Seattle Children’s Research Institute, Seattle, WA, USA

Contributors

Greta M. Palmer  Anaesthetist and Specialist

Pain Medicine Physician, Deputy Head of the Children’s Pain Management Service, Department of Anaesthesia and Pain Management, Royal Children's Hospital, University of Melbourne, Murdoch Children’s Research Institute, Melbourne, VIC, Australia

Maria Pavlova  PhD Candidate, Psychology,

University of Calgary, Calgary, AB, Canada

Rebecca Pillai Riddell  Professor, Psychology, York

University, Toronto, ON, Canada

Rebecca Pitt  Clinician Nurse, Anesthesia ​Chronic

Pain, McGill University Health Centre, ​Montreal Children’s Hospital, Montreal, QC, Canada

Sachin Rastogi  Consultant in Pain Management

and Anaesthesia, Perioperative and Critical Care Directorate, Great North Children's Hospital, Newcastle upon Tyne, UK

Brianna Richardson  Doctoral Candidate, School

of Nursing, Dalhousie University, Halifax, NS, Canada

Brittany N. Rosenbloom  Doctoral Candidate,

Department of Psychology, York University, Toronto, ON, Canada

Naama Rotem-​Kohavi  Graduate Program in

Neuroscience, University of British Columbia and BC Children Hospital Research Institute, Vancouver, BC, Canada

Susan L. Sager  Director, Pediatric and Adolescent

Pelvic Pain Program, Critical Care and Pain Medicine, Boston Children’s Hospital, Boston, MA, USA

Laura E. Schanberg  Professor of Pediatric

Rheumatology, Pediatrics, Duke University School of Medicine, Durham, NC, USA

Neil L. Schechter  Associate Professor of

Anesthesia, Harvard Medical School; Director, Chronic Pain Clinic and Senior Associate in Pain Medicine, Department of Anesthesiology, Critical Care, and Pain Medicine, Boston Children’s Hospital, Boston, MA, USA

Jennifer Verrill Schurman  Professor, Division of

Gastroenterology, Hepatology, and Nutrition, Children’s Mercy Kansas City; and University of Missouri, Kansas City School of Medicine, Kansas City, MO, USA

Scott Schwantes  Program Director, Pediatric

Pain Medicine, Department of Pain Medicine, Palliative Care and Integrative Medicine, Children’s Hospitals and Clinics of Minnesota, Minneapolis, MN, USA

Navil F. Sethna  Professor, Department of

Anesthesiology, Critical Care, and Pain Medicine, Harvard Medical School and Boston Children’s Hospital, Boston, MA, USA

Sharon Shih  Doctoral Student, Psychology,

Georgia State University, Atlanta, GA, USA

Adam Shriver  Research Fellow, Philosophy,

University of Oxford, Oxford, UK

Soumitri Sil  Associate Professor, Department

of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA

Laura Simons  Associate Professor, Anesthesiology,

Perioperative, and Pain Medicine, Stanford University, Palo Alto, CA, USA

Sinno H.P. Simons  Clinical Researcher and

Neonatologist, Department of Pediatrics, Division of Neonatology, Erasmus UMC—​ Sophia Children’s Hospital, Rotterdam, The Netherlands

Rebeccah Slater  Professor of Paediatric

Neuroscience and Senior Wellcome Trust Research Fellow, Department of Paediatrics, University of Oxford, Oxford, UK

Jean C.K. Stansbury  Certified Nurse Practitioner,

Gillette Children's Specialty Healthcare, St Paul, MN, USA

Bonnie J. Stevens  Professor, Lawrence S.

Bloomberg Faculties of Nursing and Dentistry, University of Toronto; and Associate Chief of Nursing Research, Senior Scientist Research Institute, The Hospital for Sick Children, Toronto, ON, Canada

Jennifer N. Stinson  Professor, Lawrence

S. Bloomberg Faculty of Nursing, University of Toronto, Mary Jo Haddad Nursing Chair in Child Health, and Senior Scientist, Child Health Evaluative Sciences, Research Institute, The Hospital for Sick Children, Toronto, ON, Canada

Scott A. Strassels  Assistant Professor and Scientific

Director, Center for Surgical Health Assessment, Research and Policy (SHARP), College of Medicine, Department of Surgery, Division of Trauma, Critical Care, and Burn, The Ohio State University, Columbus, OH, USA

Mary Swiggum  Associate Professor, Department of

Physical Therapy, Wingate University, Waxhaw, NC, USA

Frank J. Symons  Professor, Special Education

Program, Department of Educational Psychology, University of Minnesota, Minneapolis, MN, USA

Anna Taddio  Professor, Clinical Social and

Administrative Pharmacy, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada

Dick Tibboel  Professor, Intensive Care and

Department of Pediatric Surgery, Erasmus Mc Sophia Children’s Hospital, Rotterdam, The Netherlands

Daniel S. Tsze  Associate Professor of Pediatrics in

Emergency Medicine, Department of Emergency Medicine, Division of Pediatric Emergency Medicine, Columbia University Medical Center, New York, NY, USA

Susan M. Tupper  Strategy Consultant, Pain Quality

Improvement and Research, Quality, Safety and Strategy, Saskatchewan Health Authority, Saskatoon, SK, Canada

Perri R. Tutelman  PhD Candidate, Department

of Psychology and Neuroscience, Dalhousie University; and Centre for Pediatric Pain Research, IWK Health Centre, Halifax, NS, Canada

Alison Twycross  Senior Lecturer in Children and

Young People’s Nursing, The Open University, Milton Keynes, UK

Kristen Uhl  Psychologist, Psychosocial Oncology

and Palliative Care, Dana Farber Cancer Institute, Boston, MA, USA

Anita M. Unruh†  Formerly Associate Dean, Faculty

of Health, Dalhousie University, Halifax, NS, Canada

Abraham J. Valkenburg  Anesthesiologist, ​Clinical

Pharmacologist, Intensive Care, Erasmus MC, Rotterdam, The Netherlands

Madeleine A. Verriotis  Senior Postdoctoral

Research Associate, Developmental Neurosciences (Pain Research), UCL Great Ormond Street Institute of Child Health, London, UK

Rachel VanEvery  Doctoral Student, Department of

Health, Aging and Society, McMaster University, Hamilton, ON, Canada

Carl L. von Baeyer  Professor Emeritus of

Psychology, University of Saskatchewan, Saskatoon, SK, Canada

Suellen M. Walker  Professor of Paediatric

Anaesthesia and Pain Medicine, Developmental Neurosciences (Pain Research), UCL Great Ormond Street, Institute of Child Health, London, UK

See Wan Tham  Assistant Professor, Department of

Anesthesiology and Pain Medicine, University of Washington School of Medicine and Seattle Children’s Research Institute, Seattle, WA, USA

Mark A. Ware  Associate Professor, Anesthesia and

Family Medicine, McGill University, Montreal, QC, Canada

Steven J. Wesiman  Professor of Anesthesiology

and Pediatrics, Medical College of Wisconsin, Jane B. Pettit Chair in Pain Management, Children’s Wisconsin, Milwaukee, WI, USA

Joy A. Weydert  Professor (Volunteer) Pediatrics/​

Integrative Medicine, University of Kansas Health System, Platte City, MO, USA

Glyn Williams  Consultant in Paediatric

Anaesthesia and Pain Medicine, Department of Anaesthesia and Pain Management, Great Ormond Street Hospital, London, UK

Anna C. Wilson  Associate Professor, Department

of Pediatrics, Oregon Health and Science University, Portland, OR, USA

Laura A. Wright  Pediatric Psychologist, Children’s

Healthcare of Atlanta, Atlanta, GA, USA

Janet Yamada  Associate Professor, Daphne

Cockwell School of Nursing, Ryerson University, Toronto, ON, Canada

Lonnie K. Zeltzer  Distinguished Research Professor

of Pediatrics, Anesthesiology, Psychiatry and Biobehavioral Sciences; and Director, Pediatric Pain Research Program, UCLA David Geffen School of Medicine, Los Angeles, CA, USA

William T. Zempsky  The Francine L. and Robert B.

Goldfarb- William T. Zempsky, MD Endowed Chair for Pain and Palliative Medicine, Associate Chair for Research, Connecticut Children’s Medical Center; and Professor of Pediatrics and Nursing, University of Connecticut, Farmington, CT, USA

xix

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SECTION 1

Introduction

1. History of pain in children  3 Anita M. Unruh† and Patrick J. McGrath

2. Prevalence and distribution of pain in children  11 Bonnie J. Stevens and William T. Zempsky

3. Long-​term effects of early pain and injury: animal models  21 Orla Moriarty and Suellen M. Walker

4. Long-​term effects of pain in infants  38 Ruth E. Grunau, Jillian Vinall Miller, and Cecil M. Y. Chau

5. Prevention of the development and maintenance of pediatric chronic pain and disability  47 Brittany N. Rosenbloom, M. Gabrielle Pagé, Anna Huguet, and Joel Katz

1

History of pain in children Anita M. Unruh† and Patrick J. McGrath

Summary The problem of pain has always concerned humankind as pain is a compelling call for attention and a signal to escape. Early efforts to understand pain, and its origins, features, and treatment reflected the duality between spiritual conceptualizations of pain and physiological explanations depending on the predominance of such views in a given culture (McGrath and Unruh, 1987). When spiritual perspectives dominated, prayer, amulets, supplication, and religious rites controlled approaches to pain treatment. Herbal remedies were often part of such strategies and might themselves been physiologically effective (Unruh, 1992, 2007). In ancient writings about pain and disease, treatments for children were often given alongside discussions about the health of women. In this chapter, we trace early approaches to pain in children to the modern era, highlighting points of transition and improvements in pediatric pain management.

A brief early history from ancient times to the mid-​nineteenth century The earliest medical writings about the pain and diseases of children do not provide much information about symptoms of pain and disease in children, but they do illustrate an understanding that children could not be treated as if they were adults. For example, the Atharva Veda of India (1500–​800 bce) provided pediatric incantations for headache, earache, and musculoskeletal pains (Garrison, 1923). The Susruta Samhita of India (second century bce) gave dosages of drugs and herbal remedies for children separately from adults and advised administering them with milk, clarified butter, or in a plaster spread on the breasts of the nurse (Garrison, 1923). Hippocrates (about 460–​357 bce), Celsus (25 bce  –​50 ce), Soranus (second century ce), Galen (130–​200 ce), Oribasius (325–​403 ce), Aurelianus (fifth century ce), Aetius (sixth century ce), and Aegineta (seventh century ce) all contributed to the treatment of disease in infancy and childhood in their time period and beyond, in Greece and Rome, and in the Arab †  It is with great regret that we report that Anita M. Unruh died in July 2017.

world. The Hippocratic writings of the fifth and fourth centuries bce described constitutional differences between adults and children, and gave different doses of herbal remedies and means of administration (Garrison, 1923; Still, 1931). Crying, restlessness, and sleeplessness were regarded as the primary symptoms of a child’s pain and distress (Unruh, 1992). One of the most reported pains of childhood prior to the eighteenth and nineteenth centuries was teething pain. The treatments for teething pain (Table 1.1) are fascinating to the modern reader and illustrate the underlying concern with which a child-​specific pain was regarded, and the ways in which remedies were passed down and modified over time. It was not uncommon for children to die in infancy and childhood when they were teething, though illness and death were due to issues other than teething Determining whether a child was in pain was a challenge and, unsurprisingly, generally determined by appeals to observation of changes in the child’s behavior. Aurelianus (fifth century ce) illustrates the emphasis on a child’s behavior as an indicator of pain: The child groans in its sleep, rolls about, gnashes its teeth, tends to lie prone, cries out suddenly, or falls silent, is seized with convulsions, sometimes becomes somnolent, the face becomes emaciated and loses its colour; the child gets cold and answers questions with difficulty; sometimes throws itself about with outstretched hands, working itself into perspiration. (Quoted in Garrison, 1923, p. 47)

Though changes in general behavior were important, crying was usually regarded as the chief indicator of a child’s pain. Some physicians, such as Omnibonus Ferrarius (1577) (an Italian physician (Still, 1931)), Starr (1895), and Holt (1897) (both American physicians), believed that children only cried if there was a reason associated with distress. Both associated different features of cries with specific illnesses and severity of pain. For example, a sudden, very loud, and paroxysmal shriek was described as hydrencephalic cry associated with headache (Starr, 1895, p. 6). Holt (1987) described acute pain as having a sharp and piercing cry that was usually accompanied by contracting facial features and drawing up the legs and sometimes falling into an exhausted sleep. He ascribed these pains to earache and colic. Starr (1895) may have been the first physician to describe facial expression of pain. He also used behavior to identify the source of pain:

4

Section 1 Introduction

Table 1.1  Historical treatments of children’s teething pain Source

Treatments

Soranus, second century ce “Before teething, the gums should be gently rubbed with oil or fats, and the child may be permitted to suck fat bacon without swallowing, but this should cease when the teeth appear. The gums should not be irritated by butter or acid substances, and if there is much inflammation, poulticing, and sponging are recommended” (quoted in Garrison, 1923, p. 46) Oribasious, 325–​403 ce

“If they are in pain, smear [the gums] with dog’s milk or with hare’s brain; this works also if eaten. But if a tooth is coming through with difficulty, smear cyperus with butter and oil-​of-​lilies over the part where it is erupting” (quoted in Still, 1931, p. 38)

Aetious, sixth century ce

“He advises the root of colocynth, hung on the child in a gold or silver case, or brambleroot, or the tooth of a viper, especially of a male viper, set in gold, or a green jasper suspended on the neck so as to hang down over the stomach” (quoted in Still, 1931, p. 40)

Rhazes, 859–​932 ce

“And the treatment of it, when the gum is swollen, is that the gum should be rubbed a little with the finger, and afterwards with oil and hen’s fat or hare’s brain or dog’s milk; and apply to the child’s head water in which there have been boiled camomile and dill, and put plasters which have a dispersing effect on his jaws; and if the pain in the part increases after this, take butter and oil of laurels, mix together and apply over the part; or take cow’s butter and marrow from the thigh, and apply; and if the points of the teeth have appeared, put over the whole head and neck clean wool, and let some tepid water be sprinkled on the wool each day” (quoted in Still 1931, pp. 46–​7)

Avicenna, 980–​1036 ce

“For burning pain in the gums apply oil and wax as an epitheme or use salted flesh which is a little ‘high’ ” (quoted in Gruner, 1930, p. 372)

Phaer, 1546 ce

“There be divers things that are good to procure as easy breeding of teeth, among them the chiefest is to anoint the gummes with the braynes of an hare nyxte with as much capons grece and hony, or any of these thynges alone is exceadynge good to supple the gummes and the synewes . . . And whan the peyne is greatte and intolerable with apostema or inflammacion of the gummes, it is good to make an ointment of oile of roses with the juyce of morelle otherwise called nightshade, and in lack of it annoint the jawes within with a little fresshe butter and honye” (quoted in Still, 1931, p. 121)

Sainte-​Marthe, 1569 ce

“Hare’s brain, honey and red coral ring as amulet” (cited in Ruhrah, 1925)

Ferrarius, 1577 ce

“A dead man’s tooth in the opinion of some, through some particular virtue when hung on the neck of an infant, soothes and disperses the pain of teething” (quoted in Still, 1931, p. 156)

Primerose, 1659 ce

“Tooth of a dog, wolf or male viper hung around the neck to ease teething pain” (cited in Still, 1931)

The picture (of a healthy child) is altered by the onset of any illness, the change being in proportion to the severity of the attack. An expression of anxiety or suffering appears, or the features become pinched and the lines are seen about the eyes and mouth. Pain most of all sets its mark upon the countenance, and by noting the features affected it is often possible to fix the seat of serious disease. Thus, contraction of the brow denotes pain in the head; sharpness of the nostrils, pain in the chest; and a drawing up of the upper lip, pain in the abdomen. (Starr, 1895, pp. 3–​4)

At least two surgical procedures—​trepanation (a hole bored in the skull to treat headaches, mental illness, and convulsions) and circumcision—​ were performed on children throughout history (Liskowski, 1967). Other pediatric surgeries included repair of inguinal hernia and harelip, tonsillectomy, and severance of the frenulum of the tongue (Mettler and Mettler, 1947). Opium, Hyoscyamus, Mandragora, and wine were used for pain relief during surgery (e.g., Celsus 25 bce–​50 ce and Avicenna 980–​1036 ce) (McGrath and Unruh, 1987; Mettler and Mettler, 1947), but physical restraint was the more common approach. Surgical procedures were a challenge for the surgeon and Celsus’ advice was: A chirurgien must have a strong, stable and intrepid hand and a mind resolute and merciless; so that to heal him that he taketh in hand, he be not moved to make more haste than the thing requireth, or to cut less than is needful, but which doth all things as if he were nothing affected with their cries. (Quoted in Griffith, 1951, p. 127)

Although there is evidence that children were also cared about, and efforts made to manage their pain (McGrath and Unruh, 1987), it was anesthesia that offered the first prospect of significant pain relief.

Early modern history starts with anesthesia (1840–​1950) The experience of pain was transformed by the development of anesthesia in the nineteenth century. In 1842, Crawford Long used diethyl ether to excise a cyst from a patient’s neck (Long, 1849), and then, in 1846, William Morton gave a public demonstration of the use of ether for a dental procedure (Costarino and Downes, 2005). Children were involved in the earliest clinical applications of anesthesia; the third patient who received ether from Long was an 8-​year-​old boy whose diseased toe was amputated on 8 July 1842 (Stewart, 1989). John Snow (1858), Queen Victoria’s anesthetist, started using diethyl ether for children in 1847 and 10 years later reported on his use of chloroform with several hundred children, 186 of whom were infants (Costarino and Downes, 2005). While children commonly received anesthesia for surgery from the beginning, they were also perceived to have more problems associated with anesthesia, such as nausea and vomiting, hypotension, respiratory depression, and cardiac arrest, especially with chloroform (Costarino and Downes, 2005). The first recorded deaths due to anesthesia occurred in children (Stewart, 1989). Some invasive procedures were considered so short or so minor that anesthesia was thought not to be required. For example, Wharton (1895) did not consider a tracheotomy painful if there was marked dyspnea, and thought that it was only the first incision that was painful. Similarly, Casselberry (1895) did not feel an anesthetic was needed for a tonsillectomy because of the brevity of the procedure unless the adenoids were also to be removed. Pernick (1985) noted that procedures other than amputations of limbs were often considered minor.

CHAPTER 1  History of pain in children

In 1898, August Bier used cocaine to induce spinal anesthesia in six patients, two of whom were children, but he did not perceive spinal anesthesia to be beneficial (Brown, 2012). By 1910, three papers had been published in The Lancet each referring to 100 or more pediatric cases in which spinal anesthetics, rather than general anesthesia, were used (Gray, 1909a, 1909b, 1910). Regional anesthesia may have evolved due to the associated risks of general anesthesia in children, but as pediatric general anesthesia improved in the 1930s–​ 1950s, regional anesthetics were less frequently used and are still not widespread (Brown, 2012). The advancement of pediatric pain management during surgery was dependent on the development of anesthetic agents, management of negative side effects of these agents, adequate training of physicians in the use of anesthetics, and development of anesthetic equipment that was appropriate for use with infants and children. Rendell-​Baker (1992) described the historical evolution of pediatric anesthesia equipment as having different developmental phases, including use of open drop mask for chloroform; introduction of tracheal intubation (beginning in 1909); development of various breathing systems (Magill’s breathing system, Mapleson E T-​piece breathing system, pediatric laryngoscopes, pediatric tracheal tubes, the Crowe–​Davis mouth gag, the laryngeal mask airway); design of cyclopropane and carbon dioxide absorption systems (non-​ rebreathing valves); the T-​piece system; specialization of pediatric anesthesia as a medical subspecialty; use of halothane and low-​ dead-​space pediatric face masks and related equipment; introduction of standard breathing systems; and use of constant positive airway pressure and intermittent mandatory ventilation. The first pediatric anesthetic textbook, Anaesthesia in Children, by Langton Hewer, appeared in 1923, with a second textbook, Leigh and Belton’s Pediatric Anesthesia, available in 1948. The primary advantage of anesthesia was the relief of pain with the secondary effect of permitting increasingly more complex (and invasive) surgical procedures. At the outset, in its earliest period, the beneficiaries were most likely to be women, white people, young children, and people from the upper and middle classes (Jackson Rees, 1991). Children were viewed as more sensitive to pain, and more difficult to control if they were anxious and fearful about the procedure (Pernick, 1985). But with respect to the pain experience of infants, there was disagreement about the best approach. On the one hand, there were those physicians, like Eliza Thomas (1849), who regarded infants as hypersensitive to pain (cited in Pernick, 1985). There were other physicians whose views resonated with Henry Bigelow (1848), who wrote: “The fact that it [infant] has neither the anticipation nor the remembrance of suffering, however severe, seems to render this stage of narcoticism [full anesthesia] unnecessary” (quoted in Pernick 1985, p. 172). Stewart (1989) wrote that infants were considered ideal patients for surgery by some because they were considered relatively insensitive to pain, unable to appreciate it, and even capable of sleeping through the surgery. In 1938, Thorek wrote: “Often no anesthesia is required. A sucker consisting of a sponge dipped in some sugar will often suffice to calm a baby” (p. 2021). This view of relative insensitivity to pain in infants seemed to be supported by studies that endeavored to elicit pain. In 1917, Blanton reported on studies of the response of infants to procedures such as blood draws, lancing of infections, and exposure to pin pricks during sleep. She observed crying and defensive escape behavior

but reported them as complex and advanced, reflexive and instinctive behaviors. In 1941, McGraw used pin pricks to examine the maturation of nerves in 75 children from infancy to 4  years. She maintained that the diffuse body movements of neonates with crying reflected a limited sensitivity to pain in the first 2 weeks of life and that it was unlikely for there to be any neural mediation above the thalamus. But there continued to be opposing points of view. Charles Robson, anesthetist at the Hospital for Sick Children in Toronto, perhaps the first pediatric anesthesiologist (Mai and Yaster, 2011), vehemently rejected outright assumptions about infant insensitivity to pain: First, it has been stated that infants under seven days of age do not require anesthetics for operations—​that their association tracts for pain are not fully established and that minor operations may be carried out without any damaging effects on the infant. Personally, I do not believe this and it is simply vivisection to operate on a conscious screaming wriggling infant without using a general or local anesthetic. (Robson, 1925, p. 235)

Robson used open-​drop ether and cyclopropane along with tracheal intubation for infant anesthesia (Mai and Yaster, 2011). Views such as Robson’s were probably in the minority. There is little discussion about pain in early textbooks about pediatric anesthesia, not even with respect to neonates. Smith’s The Physiology of the Newborn Infant (1945) did not mention pain at all. Leigh and Belton (1948) made only one substantive comment about pain: Newborn infants are not as sensitive to pain and some degree of analgesia is present without anesthetic. Most infants, however, do have some pain sensation even at birth and one cannot rely on the old adage that there is no pain sensation for the first three weeks of life. It is nearer the truth to say that sensitivity to pain is decreased. Since there is some basic analgesia, very low concentrations of anesthetic agent will produce complete analgesia. (p. 30)

By the mid-​twentieth century, the prevailing view, that infants had reduced sensitivity to pain, provided an accepted position for the use of minimal anesthesia for surgery on infants. In the 1950s, Gordon Jackson Rees in Liverpool, England, introduced an approach that came to be known as the Liverpool technique. He modified a part of the pediatric anesthetic equipment to permit better monitoring of respiratory movements of anesthetized children and provide intermittent ventilation if needed (Costarino and Downes, 2005). He also introduced curare and other relaxants into practice and nitrous oxide and oxygen anesthesia without ether (Jackson Rees, 1960). In his 1950 discussion about anesthesia in the newborn, Jackson Rees argued that the newborn was substantially different from an adult in neuromuscular structure and physiology (mechanical differences, sensitivity of the respiratory system, muscle tone). While he supported using muscle relaxants to reduce the amount of anesthetic agents, he believed that control of respiration was possible with light anesthesia without muscle relaxants for infants because of these structural and physiological differences. He believed the “operative risk” to full-​term infants was slight because fetal cord blood levels of corticosteroids at birth paralleled those of the mother; hence, surgical trauma was less at birth but then increased rapidly during the first week of life. The optimum operative period was regarded by Jackson Rees (1950) to be the first 24 hours of life. Jackson Rees (1950) noted that Leigh and Belton (1948) had

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Section 1 Introduction

suggested premedication with morphine for very young infants but believed it was generally not necessary: “This treatment appears to facilitate the smooth maintenance of anesthesia, and would seem to be desirable if respiration is not to be aided or controlled. It does, however, make the induction of anesthesia by inhalation agents—​a tedious process at best—​a very prolonged procedure” (p. 1421). In his 1960 paper, Jackson Rees discussed in some detail the anesthetic complications of pediatric anesthesia such as the tendency for infants under 6  months of age to become hypothermic in response to anesthesia, whereas older infants became hyperthermic. Hypothermia was more readily managed but hyperthermia sometimes led to convulsions and death. Ether anesthesia and atropine premedication contributed to this risk. In summarizing his views, Jackson Rees (1960) wrote: The respiratory deficiencies of the infant during early life and the hazards of hyperthermia in older children suggest that controlled ventilation during the maintenance of anaesthesia has special advantages. It should be regarded as an essential part of the technique for prolonged operations, and is highly desirable for shorter procedures. Anesthesia can be maintained at very light levels with nitrous oxide-​oxygen and a relaxant drug, with the result that recovery is rapid . . . There are, therefore, cogent practical and theoretical reasons for maintaining anaesthesia with controlled ventilation, a relaxant drug, nitrous oxide and oxygen. (pp. 138–​9)

Although Jackson Rees is said to have introduced nitrous oxide and oxygen anesthesia without ether, it had already been in use for some years in the US by some physicians. Mary Botsford in San Francisco (1935) reported using this preparation over a 2-​year period for children from 1 month to 4 years of age for procedures of 4 minutes to 1 hour and 40 minutes. However, for the youngest infants, Botsford regarded ether as the anesthetic of choice. Botsford also noted that by the 1930s, chloroform had been almost completely discontinued for infants and children because of deleterious effects on the liver, cardiac depression, and postoperative acidosis. In the discussion section of Botsford’s paper, where responses were provided from colleagues, two writers, Weeks and Delprat, commented, “We are glad to see that she still allows us to use ether in babies, even though she so strongly favours nitrous oxid[e]‌and oxygen.” Weeks and Delprat maintained that for abdominal surgery nitrous oxide and oxygen provided too little relaxation of the tissues, and they were prepared to risk a less safe anesthetic (ether). Nitrous oxide and oxygen anesthesia with a muscle relaxant was considered for many years a light anesthetic that was sufficient for many pediatric procedures. It appeared to reduce a number of surgical risks, especially for infants, based on the knowledge in this period of the physiology of infants and children. Although there were some efforts to understand the responses of the pediatric patient to surgical procedures, evidence of informed decision-​making was typically on the basis of published clinical series. Such papers provided clinical information but very limited data about an infant’s physiological stress response to invasive procedures. Pediatric pain research during this period was limited and focused on the first epidemiological studies and not clinical care.

Scientific approaches to pain in children The second half of the twentieth century can rightly be considered the modern era of pediatric pain research and management. Major

developments occurred that brought scientific thinking to the area and widespread realization in the health system that pediatric pain was an important issue. Development of the field of pediatric pain was, and continues to be, uneven. Even in developed countries, the provision of services is not at all uniform. In the developing world, pediatric pain research is just beginning (e.g., Forgeron et al., 2009). There were significant landmark events that led to the modern era of pediatric pain. Recurrent pain in children certainly was known and written about earlier (e.g., Matthews, 1938), but programs of research about pain in children developed primarily in postwar Europe. The seminal work in headache was by Bo Vahlquist (1955); and later by his protégé Bo Bille (1962) in Sweden. Vahlquist defined criteria for diagnosis of headache in children and presented clinical series and described common features. Bille’s doctoral dissertation, published as a monograph in Acta Paediatrica, was a large-​scale epidemiological study of the children of Uppsala. He described the prevalence and correlates of migraine, and provided a more detailed set of laboratory studies and interviews with a subgroup of children who had pronounced migraine. Bille personally followed the group of 73 children with pronounced migraine for 40 years (Bille, 1997). This work was foundational for subsequent studies of migraine and other headaches in children and adolescents. John Apley and colleague (Naish and Apley, 1951)  in Bristol, England, published epidemiological research on recurrent limb pains, demonstrating that about 4% of children had such pain. This paper was followed by his groundbreaking epidemiological and etiological studies on recurrent abdominal pain (Apley, 1959). Apley found that recurrent abdominal pain was common, affecting 10.8% of children. Girls were more likely to have recurrent abdominal pain than boys. He linked recurrent abdominal pain to psychosocial problems and argued that overmedicalization of recurrent pain led to long-​term consequences. Apley’s studies still inform our understanding of recurrent limb and abdominal pain. While these studies on recurrent pains in children were well known in the pediatric literature, and stimulated clinical practice, they did not trigger much systematic research interest until the 1980s. In 1965, Melzack and Wall introduced an imaginative and comprehensive theory, the gate control theory of pain. They used recently discovered physiological data and clinical data to suggest that a mechanism in the substantia gelatinosa of the dorsal horn of the spinal cord gated sensations of pain from pain receptors before they were interpreted or reacted to as pain. This theory changed how pain was conceptualized and united clinical observations with physiology. Although not specifically describing mechanisms of action for the role of attention, thoughts, and emotions in pain, Melzack and Wall included these phenomena by hypothesizing a central control trigger that could mediate specific central activities. The development of modern models of pain increased interest in pain research and in the integration of clinical observation with the biology of pain. But drawing attention specifically to pain in children did not come easily. Interest was sporadic and research still almost nonexistent. Jo Eland was the first North American clinician scientist to bring pain in children to the forefront. In 1971, she was a faculty member supervising students on a pediatric oncology unit in Omaha, Nebraska. Children were typically diagnosed late, received ineffective treatment, and died in pain with little pain relief. In her President’s Message at the American Society of Pain Management

CHAPTER 1  History of pain in children

Nurses in 2012, Eland said of this experience: “Watching so many children die in unrelieved pain caused me to begin reading everything I could about pain and soon found there was virtually nothing written about pediatric pain. The memories of so many children dying in unrelieved pain left a lasting impression that has never left me” (reproduced with kind permission of Jo Eland). Eland and Anderson (1977) noted that only 33 scientific articles had been published on pain in children by the mid-​1970s and most of these papers were on pediatric recurrent pain. Their own important contribution to pediatric pain was a comparative chart review of the pain relief given to adults and children following similar surgical procedures. In the review of 25 children aged 4–​8  years, 21 children had been ordered analgesics, but only 12 received any medication. Eighteen of the children were then matched with adults receiving similar surgery. The adult group were given 372 opioid analgesic doses and 299 non-​opioid pain doses. There were methodological limitations to this review as a study: it was not experimentally well controlled; it used questionable matching; and did not measure pain (McGrath, 2011). It is unknown whether the data from the adult sample came from a similar time period to that of the children or from the same institution. Nevertheless, the difference in the provision of pain relief between child and adult patients was startling and overwhelming in illustrating that children and adults were not treated similarly for pain. This study triggered two methodologically superior studies with similar, though less extreme, results. Beyer and colleagues (1983) compared 50 children with 50 adults on the postoperative analgesia they received following similar cardiac surgeries. The only patients who were not prescribed any analgesics at all were six children. Overall, children received less than 50% of the analgesic doses given to adults. Schechter et al. (1986) reviewed charts for the postoperative analgesics received by 90 children and 90 adults who were randomly selected and matched for sex and diagnosis. Adults received an average of 2.2 doses of opioids narcotics per day, whereas children received half this amount (McGrath, 2011). It is unknown whether the children in these studies were in more pain than adults, as pain was not measured. Nevertheless, these three studies critically established that children’s pain was significantly undertreated in hospitals. This problem has continued, somewhat abated (Stevens et al., 2012). Along with these early studies which identified the problem of recurrent pains, abdominal pain, and headache in childhood, and undertreatment of postoperative pain in children, work was beginning to untangle the cry of infants, crying long being regarded as symptomatic of pain and distress in infants. In the 1960s, auditory and spectographic cry analysis of infants was systematized by Ole Wasz-​Höckert and colleagues in Finland (Wasz-​Höckert et al., 1968). This work was sophisticated and well respected, and dealt with pain and other types of cries, but did not influence the investigation of pain outside of cry analysis. The most seminal developments to draw attention to pain in infants and children were two events in the 1980s. The first was a series of studies by Kanwaljeet Singh Anand as a PhD student at Oxford University. With support from a Rhodes Scholarship and the John Radcliffe Hospital, Anand began one of the first research programs on pain in neonates. Anand developed sophisticated methods of measuring hormonal stress responses using very small samples of blood (Anand et al., 1985). He then demonstrated in clinical series and well-​controlled, randomized trials that term and preterm neonates mounted a major stress response following surgery for patent

ductus repair (e.g., Anand and Hickey, 1987; Anand et  al., 1990). These studies showed that neonates receiving minimal anesthetic, the “Liverpool” technique that had been standard care since the 1950s, compared to neonates receiving halothane anesthesia, had significantly elevated levels of plasma epinephrine, norepinephrine, cortisol, glucagon, beta endorphins, and insulin, as well as increased mortality in the postoperative period. Anand’s research was well received in the academic community. Anand won the 1986 Dr.  Michael Blacow prize for the best paper by a trainee at the annual meeting of the British Paediatric Society (Royal College of Paediatrics and Child Health, n. d.). For the public, the realization that infants were exposed to surgery with minimal anesthesia came as a profound shock and was met with initial disbelief. In the media, Anand was viciously attacked in the Daily Mail (UK newspaper) in a story titled “Pain killer shock in babies operation” (Anonymous, 1987). Anand and colleagues were accused of experimenting on babies by withholding anesthesia. The All Party Parliamentary Pro Life Group demanded that the General Medical Council investigate these experiments. Many distinguished medical scientists insisted that these studies were ethical and methodologically rigorous challenges of then current standard of anesthetic procedure for infants undergoing surgery, and would lead to better care. In 1988, Sir Bernard Braine, head of the All Party Group, publicly apologized for his accusations (Anonymous, 1988). The second seminal event was related to Anand’s work but occurred in the US and was not research but one family’s experience. Like Anand’s research, the story of Jeffrey Lawson focused on neonatal anesthesia and it too was debated in the public arena through the media. Jeffrey Lawson was born in February 1985, at 25–​26 weeks’ gestational age, weighing 760 grams, and was admitted to the Washington National Children’s Hospital for treatment of patent ductus arteriosus—​a not uncommon problem in a premature infant. The ductus arteriosus is a blood vessel that permits blood to circulate through the baby’s lungs before birth, closing a few days after birth. A patent ductus arteriosus leads to abnormal blood flow between the aorta and pulmonary artery, two major blood vessels that carry blood from the heart. After some medical attempts to correct this condition, Jeffrey Lawson underwent open heart surgery to correct this abnormality. His mother described Jeffrey’s anesthesia during the surgery in this way: Jeffrey was awake through it all. The anesthesiologist paralyzed him with pavulon, a drug that left him unable to move, but totally conscious. When I questioned the anesthesiologist later she said Jeffrey was too sick to tolerate powerful anesthetics. Anyway, she said, it had never been demonstrated to her that premature babies feel pain. (Lawson, 1986, pp. 124–​5)

Following surgery, Jeffrey went into shock, catabolized, and suffered heart, kidney, and liver failure. He died on 31 March 1985, 5 weeks following surgery. Ms. Lawson contacted many professional and social service agencies and other individuals to support her belief that babies should receive pain control for surgical procedures before her story was picked up by the media. In writing the story of Jeffrey Lawson for the Washington Post, Sandy Rovner quoted Willis McGill, Chair of Anesthesia at the Children’s Hospital National Medical Centre. Dr.  McGill asserted that there were risks with anesthesia and that “it doesn’t do any good to have a dead patient who doesn’t feel pain” (Rovner, 1986, p.  7). The article in the Washington Post triggered other coverage

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Section 1 Introduction

emphasizing that babies were undergoing surgery without anesthesia. The American Society of Anesthesiologists (1987) and the American Academy of Pediatrics (1987) asserted that anesthesia should not be routinely withheld from neonates. In 1996, the American Pain Society established the Jeffrey Lawson Award for Advocacy in Children’s Pain Relief to honor Jeffrey Lawson and the contribution of his mother to the advancement of pain in infants and children (McGrath, 2011). The Anand story in England and the Lawson case in the US were followed by a dramatic increase in professional and scientific interest in pain in children. Between 1981 and 1990, there were 2966 articles on pediatric pain, with a striking increase occurring in the 1980s (Guardiola and Baños, 1993) and an upsurge in articles on pain in neonates (Baños et al., 2001), a trend that has continued (Caes et al., 2016). Books on some specific pains in childhood, such as Apley’s book on abdominal pain (1959), had already appeared, but now the first books covering the broad area of childhood pain were published. Most of these books were directed to health professionals, but some focused on helping parents to manage their children’s pain. The International Association for the Study of Pain established a Special Interest Group on Pain in Childhood (http://​childpain.org) in the 1980s. One of its activities is the International Symposium on Pediatric Pain (https://​www.ispp2019.org/​2019.html), the first was held in Seattle in 1988. The PEDIATRIC-​PAIN electronic discussion list began in the 1990s (PEDIATRIC-​[email protected]). At present, it has over 800 members and remains an active discussion forum. The Pediatric Pain Letter (http://​ppl.childpain.org) began in 1996. The International Pediatric Pain Forum is another pediatric pain meeting. It is held every 2–​3 years on a focused theme (http://​ pediatric-​pain.ca/​content/​IFPP). It is difficult to know how much of this increased attention on children’s pain was due to the public attention and debate that surrounded the research of Anand, or the tragic story of Jeffrey Lawson. The research in this area was gaining sufficient momentum for the first pediatric pain books to appear and the first pediatric pain conferences to be held. Nevertheless, there is no doubt that these events highlighted in undeniable ways the assumptions and misconceptions that prevailed and persisted in children’s pain, their serious potential for harm, and lent urgency to the need for change. An important element of the development of a new scientific field is the development of new training opportunities. From 2002 until 2015, the Canadian Institutes of Health Research funded Pain in Child Health (PICH) as part of the Strategic Training in Health Research program. The Mayday Fund in New  York supported participation by international students. Von Baeyer et  al. (2014) detail the work of PICH and noted that 218 trainees, of which two thirds were Canadian, in 17 disciplines participated in PICH. Trainees published 697 peer-​reviewed papers during their average of 3 years in PICH (Von Baeyer et al., 2014). PICH held 16 training institutes (2002–​2013) in Canada and continues today in a modified form. The twenty-​first century saw the emergence of standards for pain care. Perhaps the most important was the issuance in 2001 of a pain standard (Baker, 2017)  by the US Joint Commission on the Accreditation of Healthcare Organizations (now the Joint

Commission). This pain standard applied to both pediatric and adult patients and had a requirement for pain measurement, recording, and action. Although the Joint Commission’s pain standard has been criticized as contributing to the opioid crisis, the Joint Commission remains committed to adequate and safe pain management. International consensus meetings based on rigorous systematic reviews have promoted standardization and increasing sophistication in diagnosis of some pain disorders, for example, the Rome Criteria for functional gastrointestinal disorders (Drossman, 2016), and in the development of more standardized methodologies in pain research, for example, in clinical trials (McGrath et al., 2008). Pediatric pain curricula have been developed to enable teaching health professionals about pediatric pain. The Hospital for Sick Children in Toronto developed the Online Pediatric Pain Curriculum (http://​www.sickkids.ca/​pain-​centre/​Health-​care-​ professionals/​Online%20Pain%20Curriculum/​index.html). The 10, free online modules cover basic science, and clinical and ethical aspects of pain in infants, children, and youth.

The contributions of modern science to pediatric pain and the future Science relies on assessment and measurement. Until the last three decades of the twentieth century, measurement of children’s pain relied on unstandardized, largely descriptive approaches to determine whether a child was in pain. Facial characteristics of a child in pain, the features noted by Starr in 1895 with respect to the brow, the nostrils, and the upper lip, are characteristics of the pain face now captured in pediatric pain measures such as the Neonatal Facial Action Coding System (Grunau and Craig, 1987). In the 1970s and 1980s, the first self-​report measures of pain were developed and, later, self-​report measures based on facial characteristics, for example, the Faces Pain Scale (Bieri et al., 1990) and the Faces Pain Scale—​ Revised (Hicks et  al., 2001). In addition, observational measures of children’s pain behavior, particularly in the postoperative context, were constructed and validated. Measures were also developed for children with developmental disabilities and for pain in infants. Such tools provided the capacity to measure the effectiveness of pain intervention for infants, children, and adolescents (see Chapters 36, 37, and 38). In addition to pain measurement, attention was drawn to special areas of pain in infants, children, and adolescents and its treatment such as in burns, procedural pain, cancer pain, arthritis, and so on. There was greater appreciation of the immediate and long-​ term consequences of pain in childhood due to physical and sexual abuse. In the last 10 years, there has been a more solid focus on the social and cultural context of children’s pain and the role of parents in children’s learning about pain. A great deal of work has focused on children’s pain in the Western world. Recently, researchers have come to recognize that the pain of children in underdeveloped countries is even more greatly challenged by the lack of education about child pain and limited or no access to appropriate pain management. The developmental neurobiology of pain has made significant advances thanks to the work of scientists such as Maria Fitzgerald (see Chapter 8), Simon Beggs (see Chapter 7), and Suellen Walker (see Chapter 3), but so much more needs to be discovered.

CHAPTER 1  History of pain in children

PERSPECTIVE Only fools try to predict the future but some emerging trends are evident. There will certainly be greater advances in our understanding of the biomedical, social, cultural, clinical, and health systems science of pain in children. The yet-​to-​be-​resolved problem of insufficient access to scientifically demonstrated treatments for pain for infants, children, and adolescents is slowly being recognized, and is leading to new ways of developing interventions such as web-​ based alternatives (see Chapter 61). The need for personalized approaches to care is being understood. But progress in science does not necessarily translate to the real world. Will ever-​present resource limitations and ideological biases lead to less care for the most vulnerable who have the least ability to demand better care? Will there be better solutions to the inadequate management of pain in children for marginalized children in the developed world and for the vast majority of children in the developing world? We need to consider and take responsibility for narrowing the gap between the generation of evidence and its application in the real world.   

ACKNOWLEDGMENTS Anita M. Unruh died in July 2017 and the chapter was revised by Patrick J. McGrath. Patrick J. McGrath’s research is supported by grants from the Canadian Institutes of Health Research. Some of the themes and ideas were explored in previous publications, including McGrath and Unruh (1987) and Unruh (1992).   

REFERENCES American Academy of Pediatrics Committee on Fetus and Newborn, Committee on Drugs, Section on Anesthesiology, Section on Surgery. (1987). Neonatal anesthesia. Pediatrics, 80, 446. American Pain Society, Jeffrey Lawson Award for Advocacy in Children’s Pain Relief. Available at:  http://​americanpainsociety. org/​get-​involved/​awards-​grants/​jeffrey-​lawson-​award (accessed June 26, 2018). American Society of Anesthesiologists. (1987). Neonatal anesthesia. ASA Newsletter, December 15, 2. Anand, K. J., Brown, M. J., Bloom, S. R., and Aynsley-​Green, A. (1985). Studies on the hormonal regulation of fuel metabolism in the human newborn infant undergoing anaesthesia and surgery. Horm Res, 22, 115–​28. Anand, K. J., Hansen, D. D., and Hickey, P. R. (1990). Hormonal-​ metabolic stress response in neonates undergoing cardiac survery. Anesthesiology, 73, 661–​70. Anand, K. J. and Hickey, P. R. (1987). Pain and its effects in the human neonate and fetus. N Engl J Med, 317, 1321–​9. Anonymous. (1987). Pain killer shock in babies’ operations. Daily Mail, July 28. Anonymous. (1988). MP apologizes. Br Med J, 297, 865. Apley, J. (1959). The child with abdominal pains. Springfield, IL: Charles C. Thomas. Baker DW. (2017). History of The Joint Commission’s pain standards: Lessons for today’s prescription opioid epidemic. JAMA, 317, 1117–​18.

Baños, J. E., Ruiz, G., and Guardiola, E. (2001). An analysis of articles on neonatal pain published from 1965 to 1999. Pain Res Manag, 6,  45–​50. Beyer, J. E., DeGood, D. E., Ashley, L. C., and Russell, G. A. (1983). Patterns of postoperative analgesic use with adults and children following cardiac surgery. Pain, 17,  71–​81. Bieri, D., Reeve, R., Champion, G. D., Addicoat, L., and Ziegler, J. (1990). The Faces Pain Scale for the self-​assessment of the severity of pain experienced by children: Development, initial validation and preliminary investigation for ratio scale properties. Pain, 41, 139–​50. Bille, B. (1962). Migraine in school children. A  study of the incidence and short-​term prognosis, and a clinical, psychological and electroencephalographic comparison between children with migraine and matched controls. Acta Paediatr Suppl, 136,  1–​151. Bille, B. (1997). A 40-​year follow-​up of school children with migraine. Cephalalgia, 17, 488–​91. Blanton, M. G. (1917). The behavior of the human infant in the first 30 days of life. Psychol Rev, 24, 456–​83. Botsford, M. E. (1935). Anesthesia in infant surgery. Cal West Med, 43,  271–​3. Brown, T. C.  K. (2012). History of pediatric regional anesthesia. Pediatr Anesth, 22,  3–​9. Caes L., Boerner K. E., Chambers C. T., Campbell-​Yeo M., Stinson J., Birnie K.A., et al. (2016). A comprehensive categorical and bibliometric analysis of published research articles on pediatric pain from 1975 to 2010. Pain, 157, 302–​13. Casselberry, W. E. (1895). Diseases of pharynx and the nasopharynx. In: L. Starr and T. S. Westcott (eds.) An American text-​book of the diseases of children, pp. 431–​56. Philadelphia, PA: Saunders. Costarino, A. T. and Downes, J. T. (2005). Pediatric anesthesia historical perspective. Anesthesiol Clin North America, 23, 573–​95. Drossman, D. A. (2016). Functional gastrointestinal disorders: History, pathophysiology, clinical features and Rome IV. Gastroenterology, S0016-​5085, 00233–​7. Eland, J. M. and Anderson, J. E. (1977). The experience of pain in children. In:  A. Jacox (ed.) Pain:  A source-​book for nurses and other health care professionals, pp. 453–​78. Boston, MA:  Little, Brown & Co. Forgeron, P. A., Jongudomkarn, D., Evans, J., Finley, G. A., Thienthong, S., Siripul, P., et  al. (2009). Children’s pain assessment in northeastern Thailand: Perspectives of health professionals. Qual Health Res, 19, 71–​81. Garrison, F. H. (1923). A system of pediatrics. Philadelphia, PA: Saunders. Gray, H. T. (1909a). A study of spinal anesthesia in children and infants. Lancet, 2, 913–​17. Gray, H. T. (1909b). A study of spinal anesthesia in children and infants. Lancet, 2,  991–​6. Gray, H. T. (1910). A further study on spinal anesthesia in children and infants. Lancet, 2, 1611–​16. Griffith, E. F. (1951). Doctors by themselves: An anthology. London: Cassell. Grunau, R. and Craig, K. (1987). Pain expression in neonates: Facial action and cry. Pain, 28, 395–​410. Gruner, O. C. (1930). A treatise on the canon of medicine of Avicenna incorporating a translation of the first book. London: Luzac. Guardiola, E. and Baños, J. E. (1993). Is there an increasing interest in pediatric pain? Analysis of the biomedical articles published in the 1980s. J Pain Symptom Manag, 8, 449–​50. Hewer, C. L. (1923). Anaesthesia in children. New York: Paul B. Hober.

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Hicks, C. L., von Baeyer, C. L., Spafford, P., van Korlaar, I., and Goodenough, B. (2001). The Faces Pain Scale—​Revised: Toward a common metric in pediatric pain measurement. Pain, 93, 173–​83. Holt, L. E. (1897). The diseases of infancy and childhood: For the use of students and practitioners of medicine. New York: Appleton. Jackson Rees, G. (1950). Anaesthesia in the newborn. Br Med J, 23, 1419–​22. Jackson Rees, G. (1960). Paediatric anaesthesia. Br J Anaesth, 32, 132–​40. Jackson Rees, G. (1991). An early history of paediatric anaesthesia. Paediatr Anaesthes, 1,  3–​11. Lawson, J. R. (1986). Letter. Birth, 13,  124–​5. Leigh, M. D. and Belton, M. K. (1948). Pediatric anaesthesiology. New York: Macmillan. Liskowski, F. P. (1967). Prehistoric and early history of trepanation. In: D. Brothwell and A. T. Sandison (eds.) Diseases of antiquity: A survey of the diseases, injuries and surgery of early populations, pp. 651–​67. Springfield, IL: Charles T. Thomas. Long, C. W. (1849). An account of the first use of sulphuric ether by inhalation as an anesthetic in surgical operation. South Med Surg J, 5, 705–​13. Mai, C. M. and Yaster, M. (2011). Pediatric anesthesia:  A historical perspective. Am Soc Anesthesiol, 75,  10–​13. Matthews, J. S. (1938). Recurrent abdominal pain in children. Ulster Med J, 7, 179–​206. McGrath P. J. (2011). Science is not enough: The modern history of pediatric pain, Pain, 152, 24579. McGrath, P. J. and Unruh, A. M. (1987). Pain in children and adolescents. Amsterdam: Elsevier. McGrath P. J., Walco G., Turk D. C., Dworkin R. H., Brown M. T., Davidson K., et  al. (2008). Core outcome domains and measures for pediatric acute and chronic/​ recurrent pain clinical trials: PedIMMPACT recommendations. J Pain, 9, 771–​83. McGraw, M. (1941). Neural maturation as exemplified in the changing reactions of the infant to pin prick. Child Dev, 12,  31–​42. Melzack, R. and Wall, P. D. (1965). Pain mechanisms: A new theory. Science, 150,  971–​9. Mettler, C. C. and Mettler, F. A. (1947). History of medicine. Philadelphia, PA: The Blakiston Co. Naish, J. M. and Apley, J. (1951). ‘Growing pains’: A clinical study of non-​arthritic limb pains in children. Arch Dis Child, 26, 134–​40. Pernick, M. S. (1985). A calculus of suffering: Pain, professionalism, and anesthesia in nineteenth-​century America. New  York:  Columbia University Press. Rendell-​Baker, L. (1992). History and evolution of pediatric anesthesia equipment. Int Anesthesiol Clin, 30,  1–​34.

Robson, C. (1925). Anesthesia in children. Anesth Analg, August, 235–​40. Rovner, S. (1986). Surgery without anesthesia: Can preemies feel pain? Washington Post, August 13, pp. 7–​8. Royal College of Paediatrics and Child Health. Dr Michael Blacow Memorial Prize. Available at: https://​www.rcpch.ac.uk/​education-​ careers/​fellowships-​and-​prizes/​dr-​michael-​blacow-​memorial-​ prize (accessed June 12, 2020). Ruhrah, J. (1925). Pediatrics of the past. New York: Paul B. Hoeber. Schechter, N. L., Allen, D. A., and Hanson, K. (1986). Status of pediatric pain control: A comparison of hospital analgesic usage in children and adults. Pediatrics, 77,  11–​15. Snow, J. (1858). On chloroform and other anesthetics:  Their action and administration. London: John Churchill. Starr, L. (1895). The clinical investigation of disease and the general management of children In: L. Starr and T. S. Westcott (eds.) An American text-​ book of the diseases of children, pp. 3–​ 4. Philadelphia, PA: Saunders. Stevens, B. J., Harrison, D., Rashotte, J., Yamada, J., Abbott, L. K., Coburn, G., et al.; CIHR Team in Children's Pain (2012). Pain assessment and intensity in hospitalized children in Canada. J Pain, 13, 857–​65. Stewart, D. J. (1989). History of pediatric anesthesia. In: G. A. Gregory (ed.) Pediatric anesthesia (2nd edn.), pp. 1–​14. New York: Churchill Livingstone. Still, G. F. (1931). The history of pediatrics: The progress of the study of diseases of children up to the end of the XVIIIth century. London: Oxford University Press. Thorek, M. (1938). Modern surgical technique. Philadelphia, PA: Lippincott. Unruh, A. M. (1992). Voices from the past: Ancient views of pain in childhood. Clin J Pain, 8, 247–​54. Unruh, A. M. (2007). Spirituality, religion and pain. Can J Nurs Res, 39,  66–​86. Vahlquist, B. (1955). Migraine in children. Int Arch Allergy, 7, 348–​55. Von Baeyer, C. L., Stevens, B., Chambers, C. T., Craig, K. D., Finley, G. A., Grunau, R. E. (2014). Training highly qualified health research personnel: The Pain in Child Health Consortium. Pain Res Manage, 19, 267–​74. Wasz-​Höckert, O., Lind, J., Partanen, T., Valanne, E. and Vuorenkoski, V. (1968). The infant cry: A spectrographic and auditory analysis. London: Heinemann. Wharton, H. R. (1895). Tracheotomy. In L. Starr and T. S. Westcott (eds.) An American text-​book of the diseases of children, pp. 290–​ 310. Philadelphia, PA: Saunders.

2

Prevalence and distribution of pain in children Bonnie J. Stevens and William T. Zempsky

Summary Historically, only a few studies addressed the prevalence of acute and chronic pain in infants, older children, and adolescents across multiple settings. Typically, there was a preponderance of single-​site studies that reported local pain prevalence and distribution in children. The generalizability of these results was questionable given small sample sizes; thus, results from local studies garnered only a general estimate at best. However, recent systematic reviews that synthesize evidence and critically appraise the quality of the studies provide a much clearer idea of the prevalence of acute and chronic pain in children. Studies of pain prevalence vary as to the pain and prevalence definitions used, the reporting period (i.e., point prevalence, period prevalence), and stratification by duration of involvement, which makes comparison of findings challenging. In this chapter, we will clarify definitions of prevalence and acute and chronic pain and use these definitions to explore the prevalence and distribution of pain across the broader system that delivers health care to children (e.g., hospitals and in community healthcare settings). Perspectives on clinical practice, knowledge translation (KT), and future research will be shared via a case example and perspective box.

Definitions There are several definitions related to prevalence of acute and chronic pain in children. • Prevalence is the proportion of a population that has a condition (typically a disease) and is determined by comparing the number of individuals with the condition with the total number who are studied. • Point prevalence is the proportion of a population that has the condition at a specific point in time (e.g., spring 2018). • Period prevalence is the proportion of a population that has the condition at some time during a given period (e.g., neonatal period during the first year of life). • Prevalence is different from incidence, which is a measure of new cases arising in a population over a given period.

Pain has typically been defined as acute and chronic. However, further delineation may be useful. Anand (2017) calls out for definitional clarity for pain in infants considering characteristics of the pain experience and behavioral and physical response patterns. Anand suggests that the characteristics of the pain, including the temporal features, character of the pain, and secondary effects, would assist in defining types and prevalence of pain. Acute pain signals a specific nociceptive event, injury, or illness, and is usually limited to a short period of time. Acute pain is frequently associated with sudden-​onset, short, sharp, tissue-​damaging procedures (e.g., heel lances, finger pricks, intravenous (IV) starts, intramuscular injections, lumbar punctures) for diagnostic purposes, non-​tissue-​damaging procedures (e.g., suctioning) for therapeutic purposes, or tissue-​damaging events (e.g., burns). Acute pain that is associated with one event, or is episodic, is usually well localized, and typically subsides quickly with effective treatment after the painful event (e.g., heel lance) or when the illness or injury resolves. However, acute pain can also be (i)  recurrent, reappearing in multiple episodes over time; or (ii) prolonged, extending beyond the experience of the short-​sharp, tissue-​damaging procedural pain but usually having a predictable course that coincides with a “usual” healing time and subsides within a few hours or days (e.g., pain from circumcision, postoperative pain). While acute episodic pain is usually of mild-​to-​moderate intensity, acute recurrent or prolonged pain may have moderate-​to-​severe intensity. Chronic pain is frequently defined as pain without apparent biological value that has persisted beyond the normal or expected tissue healing time. Chronic pain in older children and adults can either be recurrent (e.g., episodic acute pains such as headaches and stomach aches), prolonged (e.g., for those who are on a ventilator for a prolonged period), or persistent (e.g., more enduring pains, including backaches and neuropathic pain). Chronic pain promotes an extended and maladaptive stress response that includes neuroendocrine dysregulation, fatigue, dysphoria, myalgia, and impaired psychological and social functioning. The temporal delineation of “healing time” is frequently debated but is usually stated as somewhere between 3 and 6 months. The International Association for the Study of Pain defines chronic pain as pain that lasts longer than 3 months (https://​www.iasp-​pain. org/​Education/​Content.aspx?ItemNumber=1698

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The temporal delineation presents a dilemma when considering chronic pain in infants and young children and in those with disabilities who either are incapable of or may have difficulty in reporting their pain. Anand (2017) has proposed an empirical framework to facilitate the development of clearer definitions for pain that is acute (episodic, recurrent) and prolonged, persistent, and chronic. More precise definitions will provide more accurate methods for assessing diverse types of pain, and their prevalence and incidence. For further discussion on assessment of pain in infants and children see Chapters 36–​39 (this edition). Acute pain during infancy was ignored until approximately three decades ago owing to biases and misconceptions regarding the maturity of the infant’s developing nervous system, their inability to verbally report pain, and their perceived inability to remember pain. Many infants endured frequent invasive medical procedures such as repetitive skin-​breaking procedures (e.g., heel sticks) and surgery without benefit of anesthesia or analgesia. Today, these beliefs and misconceptions are rarely stated or acknowledged owing to enhanced understanding of the developmental neurobiology of infant pain pathways and supraspinal processing (see Chapter 40, “Brain responses in infants”). However, hospitalized neonates and infants continue to be exposed to multiple painful procedures for diagnostic and treatment purposes and persistent, prolonged, or even chronic pain. Researchers have documented the incidence, prevalence, and frequency of acute episodic pain associated with skin-​breaking procedures in infants hospitalized in the Neonatal Intensive Care Unit (NICU). Johnston et  al. (2011) conducted a prospective observational study in 14 Canadian NICUs documenting both tissue-​ damaging and non-​ tissue-​ damaging procedures over a 1-​ week period. A total of 3508 tissue-​damaging (mean 5.8, standard deviation [SD] 15) and 14,085 (mean 25.6, SD 15) non-​tissue-​damaging procedures were recorded for 582 infants. Twelve years earlier, Johnston et al. (1997) reported that the average number of painful procedures per infants was 14, similar to other prevalence surveys of infant procedural pain at the time (Simons et al., 2003). In Johnston et  al.’s 2011 study, the mean of 5.8 (SD 15, range 0–​89) tissue-​damaging procedures per infant appears to be a significant improvement. In 1997, no infants received pharmacological interventions for heel lancing—​the most common of the tissue-​damaging procedures—​whereas in 2011, of the 46% of infants who were exposed to tissue-​damaging procedures, 14.5% were administered opioids and 14.3% received sweet-​tasting solutions such as sucrose or glucose. Johnston et al. concluded that although the prevalence of painful procedures was lower in the more recent survey, procedural pain management had generally not improved significantly. In other countries, hospitalized infants were reported to experience an average of 12 tissue-​damaging procedures per day (Carbajal et al., 2008). Carbajal et al. reported that, of 42,413 painful procedures performed on 430 infants in four NICUs in France, 79.2% received no preprocedural analgesia, 2.1% received pharmacological interventions, and 18.2% were managed using non-​pharmacological strategies. More recently, Courtois et al. (2016) reported the number of painful procedures and analgesic therapies in neonates from 16 NICUs in Paris over a 2-​month period. For the 589 neonates, the mean (SD) number of days recorded was 7.4 (4.5) days. A total of 103,239 procedures were performed in all neonates (40,927 were classified as painful and 62,312 were stressful). The median (range)

number of all procedures, painful procedures, and stressful procedures per infant were, respectively, 124 (0–​699), 44 (0–​353), and 78 (0–​406). Analgesic therapy was given before 28.1% of painful procedures. Continuous infusions of sedatives and/​or analgesics were given during 38.8% of painful procedures. Overall, 61.8% of painful procedures were performed with an analgesic given before the procedures and/​or while the neonate was receiving continuous sedation/​analgesia. The authors concluded that there is an urgent need to reduce the number of procedures and the pain produced by routine NICU procedures in neonates. Cruz et al. (2016) conducted a critical appraisal and synthesis of the published epidemiological studies on procedural pain in neonates in the NICU. Of the 18 studies reviewed, six with the same study duration identified 6832–​42,413 invasive procedures, with an average of 7.5–​17.3 painful procedures per neonate per day. The most frequent procedures were heel lance, suctioning, venipuncture and insertion of peripheral venous catheters. Pharmacological, behavioral, and physical approaches were inconsistently applied. Predictors of the frequency of procedures and analgesic use included the neonate’s clinical condition, day of NICU stay, type of procedure, parental presence, and pain assessment. The existence of pain protocols was not a predictor of analgesia administration. In Kenya, Kyololo et al. (2014) completed a cross-​sectional survey of Level 1 and Level 2 NICUs to determine the prevalence of painful procedures and treatments. Of the 95 infants who were observed for 24 hours, there was a total of 404 painful procedures (mean 404; SD 2.0). Peripheral cannula insertion (27%) and intramuscular injections (22%) were the most common procedures; only one infant received any analgesia. These prevalence data continue to support a significant number of painful procedures still being performed on hospitalized infants and a gross undertreatment of procedural pain in infants that are recorded. A better understanding of organizational factors (e.g., leadership, unit culture, resources) and how they influence outcomes may be useful in promoting a context of care more favorable to pain prevention and treatment (see Chapter 59).

Children and adolescents The prevalence of acute pain in hospitalized children and adolescents has also been documented. In an audit of the epidemiology of procedural pain and pain management in 32 hospital units in eight pediatric hospitals in Canada, 2987 of 3822 children had undergone at least one painful procedure in the preceding 24 hours with a mean of 6.3 painful procedures per child (Stevens et al., 2011). Of those who had a painful procedure, 78.1% had a pain management intervention recorded; however, only 28.3% had one or more pain management interventions administered and documented specifically for the painful procedure (Stevens et al., 2011). Murphy et al. (2015) reported on the period prevalence of acute pain in children who arrived by ambulance at four children’s hospitals Emergency Departments (EDs) in Ireland over a 1-​year period. Of the 6371 children studied, 2635 (41.4%, 95% confidence interval (CI) 40.2–​42.3) had pain documented while being transported by ambulance. Overall, 32.5% (n  =  856) of children who complained of pain were subject to a formal pain assessment during the prehospital phase of care. Younger age, short transfer time to

CHAPTER 2  Prevalence and distribution of pain in children

the ED, and emergency transports between midnight and 6 am were independently associated with decreased likelihood of having a documented assessment of pain intensity during the prehospital phase of care. Of the 2635 children who had documented pain on the ambulance patient care record, 26.1% (n  =  689) received some form of analgesic agent prior to arrival at the ED. Upon arrival at the ED 54.0% (n  =  1422) of children had a documented pain assessment and some form of analgesic agent was administered to 50.2% (n  =  1324). The authors concluded that the treatment of acute pain in children transferred by ambulance to the ED in Ireland is currently poor. In Canada, Coburn et  al. (2016) reported results from a retrospective chart audit that examined 104 patient records of pediatric trauma patients who arrived by ambulance to a major pediatric trauma center from April 2013 to March 2014. Ninety of 104 (86.5%) pediatric trauma patients had a pain assessment recorded:  60/​ 90 (67%) via narrative notation and 30/​90 (33%) with a validated pain tool. Opioid analgesics were administered to 76/​104 (73.1%) of patients. Median (interquartile range) time from the traumatic event to administration of the first opioid analgesia was 99 (77–​180) minutes. Pain intensity was related to gender; females had a greater decrease in pain intensity score than males (–​2.70; 95% CI  –​4.83 to –​0.57; T (1) = 2.48; p = .013). Pain intensity was also related to injury severity; children with higher Injury Severity Scores experienced a significant change in pain intensity (–​0.18; 95% CI –​0.36 to 0.003; T (1) = 1.98; p = .053). Pain intensity was significantly more likely to increase with an abdominal injury (2.53; 95% CI 0.02–​ 5.04; T (1) = 1.99; p = .048). Pain assessment and management for pediatric trauma patients in the ED still has room for improvement (Coburn et al., 2016). Other researchers have focused specifically on acute pain intensity that is moderate to severe (e.g., >3 or 4 on a 10-​point scale). Generally, prevalence rates from these studies are consistent and high. Groenewald et  al. (2012) reported a prevalence rate of 27% of moderate-​to-​severe pain in hospitalized children in the US. Adolescents and infants exhibited higher prevalence rates (38% and 32%, respectively) than other children (17%). In addition, those hospitalized on surgical units demonstrated much higher rates of moderate-​to-​severe pain (44%) than those on medical units (13%). Taylor et al. (2008), in a study of hospitalized children from one tertiary-​level academic pediatric hospital, reported moderate-​to-​ severe pain during their stay, with 23% reporting persistent pain. A total of 241/​290 (83.1%) inpatients or their caregivers were interviewed about their pain. Twenty-​seven percent reported that they had pain before admission, and 77% experienced pain during admission. Of these, 23% had moderate or severe pain at interview and 64% had moderate or severe pain sometime in the previous 24 hours. Analgesics were largely intermittent and single-​agent, although 90% of patients found these helpful. Fifty-​eight percent of those with pain received analgesics in the preceding 24 hours, but only 25% received regular analgesia. Only 27% of children had any pain score documented in the preceding 24 hours. It was concluded that pain was infrequently assessed yet occurred commonly across all age groups and services and was often moderate or severe. Although effective, analgesic therapy was largely single-​agent and intermittent. Widespread dissemination of results to all professional groups has resulted in the development of a continuous quality assurance program for pain.

In a follow-​up of Taylor et al.’s (2008) study by Zhu et al. (2012), of the 265 inpatients 63% underwent a documented pain assessment versus 27% in an audit conducted previously (p 2–​6 months), inclusion of a range of surgical procedures, and variable durations between time of surgery and pain report (Rabbitts et al., 2017a; Williams et al., 2017). A recent meta-​analysis of studies published between 2012 and 2016 reported a median prevalence of PPSP of 20% at 1 year following surgery, based on four studies with 628 participants having a range of different surgeries, but many of which had scoliosis or major chest wall surgery during adolescence (Rabbitts et  al., 2017a). A  more recent study similarly reported a high incidence of persistent pain following scoliosis (Julien-​ Marsollier et al., 2017). Further research is needed to identify the prevalence of PPSP after specific surgical interventions. In adults, presurgical risk factors for developing PPSP include older age, female sex, greater pre-​and post-​surgical pain, and higher levels of presurgical anxiety and pain catastrophizing (Rabbitts et al., 2017a; Williams et al., 2017). Surveys suggest that older age may also be associated with higher risk for developing PPSP in children, although recall bias in children undergoing surgery at a younger age cannot be ruled out (Williams et al., 2017). A meta-​analysis based on three studies found no effect of either age or sex on the incidence of PPSP, although the majority of patients were female (Rabbitts et  al., 2017a). Preoperative pain was associated with increased incidence of PPSP in some studies but not others (Walker, 2015; Rabbitts et al., 2017a; Williams et al., 2017; Voepel-​Lewis et al., 2017). A small number of studies reported that higher pain intensity within 2 weeks following surgery was associated with increased risk of PPSP or slower recovery and higher pain scores at 4 and 12 months (Williams et al., 2017). Other medical factors, including scoliosis severity and time since scoliosis diagnosis did not predict PPSP (Rabbitts et  al., 2017a; Williams et al., 2017). Nonmedical factors, including presurgery child anxiety and poorer pain coping efficacy, and parental pain catastrophizing preoperatively and 2–​3  days postoperatively have also been associated with increased pain intensity 6–​12 months following surgery (Rabbitts et al., 2017a; Williams et al., 2017). Interestingly, pain unpleasantness 2–​3 days postoperatively predicted the transition from high acute postoperative pain to PPSP at 6 months, whilst anxiety sensitivity predicted the maintenance of PPSP from 6 to 12 months (Pagé et  al., 2013). Greater dissatisfaction with body image may also be associated with slower postsurgical pain recovery (Williams et al., 2017). Poorer sleep quality was associated with greater pain intensity the following day in 10–​18-​year-​olds followed u ​ p longitudinally over 4 months postsurgery, but further research is required to assess whether disruption of sleep postsurgery contributes to the transition to PPSP (Rabbitts et al., 2017b). Whilst there is limited reporting of the contribution of NP to PPSP, both early and delayed onset of pain with neuropathic descriptors has been reported in small series (e.g., Howard et al., 2014; Julien-​Marsollier et al., 2017). Using Quantitative Sensory Testing,

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SECTION 4  Pain in specific populations and diseases

persistent mixed patterns of sensory gain and loss have been associated with scars related to inguinal surgery (Kristensen et  al., 2012)  or thoracotomy (Kristensen et  al., 2010)  in childhood and following neonatal surgery in extremely preterm-​born young adults (Walker et al., 2018). In summary, NP can occur following surgery in children, but additional, larger studies are required to evaluate the prevalence and duration of symptoms, associated risk factors, potential for nerve damage associated with different types of surgery, and impact of perioperative analgesic and anesthetic regimens.

Phantom limb pain Limb amputation is associated with nerve damage and can lead to altered sensory function that is classified as nonpainful phantom sensations or phantom limb pain. The majority of current literature is based on retrospective case series with differing methodology, variable response rates and wide variability in prevalence (Howard et al., 2014; DeMoss et al., 2018). Characteristics of phantom pain Pain that is experienced in the region of the missing limb following amputation (i.e., phantom limb pain) has been described by children as sharp, tingling, stabbing, pins and needles, throbbing, piercing, squeezing, tight, and uncomfortable (Howard et  al., 2014; DeMoss et al., 2018). Phantom pain is frequently of moderate or severe intensity, with reported mean ± standard deviation ratings of 5.29 ± 2.4 (Wilkins et al., 1998) and 6.4 ± 1.8 out of 10 (Wilkins et al., 2004). Typically, pain is episodic, lasts for seconds or minutes, with a frequency varying from daily to monthly, and only a small proportion of children have reported constant pain. Exercise, objects approaching the stump, cold weather, and “feeling nervous” have been reported to trigger episodes of phantom pain. Psychosocial triggers were more common in girls, whereas pain was triggered by physical stimuli in a higher proportion of boys (Howard et al., 2014). Associated phenomena Nonpainful sensations experienced in the region of the missing limb (i.e., phantom sensations) are reported by 50–​100% of children following surgical amputation and in 7–​20% of children with congenitally deficient limbs (Howard et al., 2014). These have been described as tingling, pins and needles, tickling, “feels asleep”, numb, itching, and prickling (Howard et  al., 2014), and appear to have minimal impact on daily activities (Wilkins et al., 2004, 1998). Stump pain often co-​exists with phantom limb pain but may also occur in isolation. A higher incidence has been reported following surgery than in children with a congenitally absent limb (Wilkins et al., 1998, 2004). Incidence of phantom limb pain It is now well established that NP can follow amputation in children, but it is difficult to estimate accurately the incidence. Much of the data come from retrospective questionnaires with response rates below 50% or from medical case notes that may not accurately record all symptoms. Samples are often small, may be derived from the community or clinics, and the duration between surgery and assessment is often variable. Factors that have been associated with

an increased incidence in children include (Howard et  al., 2014; DeMoss et al., 2018): • Surgical amputation (49–​76%) versus congenitally deficient limbs (3–​4%). • Older age at time of amputation. A negative correlation has been reported between age at amputation and onset of a phantom limb, but it is not clear if this relationship holds for phantom pain, as well as phantom sensations (Melzack et al., 1997). • Cancer and chemotherapy. Phantom pain following amputations for cancer has been reported in 48–​90% of children, and was higher than following amputations for trauma (n = 32/​67 vs. n = 1/​8). Perioperative chemotherapy may also increase the risk of phantom pain (74% incidence) versus postoperative (44%) or no (12%) chemotherapy. Other causes of cancer-​related NP are discussed later in the chapter. • Major burns due to electrical (n = 10/​19) versus flame (n = 3/​15) injury (Thomas et al., 2003). • Preoperative pain. The presence of pain prior to amputation was reported in 35–​75% of patients who developed phantom pain (Krane and Heller, 1995; Wilkins et al., 1998), and in one series both patients with the most persistent pain had also experienced pain prior to amputation (Burgoyne et al., 2012). Time course Pain onset in the early postoperative period is common (53–​85%) (Krane and Heller, 1995; Wilkins et al., 1998), but may be delayed for weeks to years in some cases (Melzack et al., 1997). Earlier onset is more common in those receiving perioperative chemotherapy (Howard et al., 2014). There is a perception that phantom limb pain resolves more rapidly in children than in adults, but there is limited supporting evidence. Phantom pain is often poorly documented in medical case notes (Krane and Heller, 1995), and there has been little prospective follow-​up. Phantom limb pain can persist for months or years (Krane and Heller, 1995; Burgoyne et al., 2012). More detailed prospective studies are needed to further evaluate prevalence and time course.

Obstetric brachial plexus injury The brachial plexus innervates the upper limb and is formed from the lower cervical (C5, C6, C7, and C8) and the first thoracic (T1) nerve roots. Obstetric complications, such as shoulder dystocia or breech delivery, can be associated with traction injuries of the brachial plexus in the newborn. The associated nerve lesions range in degree from neuropraxia to complete root avulsion, and can affect part or all of the plexus. Surgical exploration and repair, where possible, is often performed if there is no spontaneous recovery or elbow flexion by 3–​6 months (Malessy and Pondaag, 2011). The incidence of obstetric brachial plexus injury (OBPI) ranges between 0.38 and 4.6 cases per 1000 births (Smania et al., 2012). Associations between OBPI and pain or sensory function in later life have been assessed in a small number of series, which vary in the outcomes measured and the time since injury. In addition, it is difficult to differentiate NP associated with the initial injury from pain related to reinnervation following early microsurgical repair and nerve grafts; subsequent surgical procedures (e.g., tendon transfers or rotational osteotomies) that may be required throughout childhood to

CHAPTER 22  Neuropathic pain in children

improve function; trophic injuries associated with reduced sensory function; and musculoskeletal pain. A recent systematic review of 29 articles (mean follow-​up of 10.8  years) that assessed sensory function, pain, or proprioception, highlights the large proportion of patients having poor sensory function in the affected versus unaffected limb (Corkum et al., 2017). In a small number of studies, patients subjectively reported normal tactile sensation (93.7%), whereas the majority of studies using objective measures (Semmes-​Weinstein monofilament and two-​point discrimination) found a significant proportion (41.2%) of patients with abnormal sensation. In one series, QST demonstrated reduced thermal sensitivity in 16% of patients (Strömbeck et al., 2007), and altered sensitivity to pinprick has been reported in 30.9% (Corkum et al., 2017). Retrospective surveys that included pain questions showed mixed results, with prevalence ranging from pain of low intensity and minimal impact on patients’ lives in 66.2% to significant pain affecting function in 50% of patients. The severity of the injury may have an impact, as patients with complete brachial plexus injury (BPI) were less likely to recover tactile sensation and reported increased pain (Corkum et al., 2017). There is often limited information on the specific type of pain. Although some studies suggest NP is rare following OBPI (Anand and Birch, 2002; Strömbeck et  al., 2007), this may be influenced by the severity of the injury or subsequent surgery. Twenty-​one of 46 children with OBPI requiring microsurgery (nerve grafting or transfer) before 12 months reported that their affected limb felt different from their unaffected limb, and used words that are suggestive of neuropathic origin but did not always describe these sensations as pain (Ho et al., 2015). Similarly, self-​mutilation behavior, which may reflect sensory loss, and/​or painful dysesthesias in a hypoesthetic or reinnervated area, was more common following microsurgery involving the plexus (29%; n = 7/​24) (McCann et al., 2004). These studies highlight that altered sensation and pain are relatively common, but higher-​quality studies assessing sensory function, pain, and quality of life using objective measures and validated tools are required (Corkum et al., 2017).

Trauma during childhood Brachial plexus injury during childhood Trauma during childhood can result in BPI, but the number of reports and details of associated pain are limited. Ten children aged 3–​16 years had BPI and fractures following motor vehicle accidents. Reconstructive surgery was performed 1–​8 months later, and there were no reports of deafferentation pain (El-​Gammal et al., 2003). In a further 25 cases of traumatic BPI (2 months–​14 years) related to motor vehicle accidents, 16 required plexus exploration and several subsequent orthopedic procedures. Two teenagers with root avulsions complained of moderate pain, but there are no further details of the nature or time course of symptoms (Dumontier and Gilbert, 1990). By contrast, BPI in association with proximal humerus fracture in four patients (aged 10–​14 years) was associated with neurological recovery by 5–​9 months, but all had NP (often described as burning) for at least 6 months (Hwang et al., 2008). Peripheral nerve injury Neuropathic symptoms and increased sensitivity to thermal or pinprick stimuli were more common in older children (>5  years of

age) during an average 2-​year follow-​up of 49 children with distal upper limb nerve injury (Atherton et  al., 2008). Pins and needles and painful dysesthesias were associated with nerve injury in 13.3% of 166 children with supracondylar fracture (Kwok et al., 2016). Spinal cord injury Pain after spinal cord injury (SCI) in adults is classified as nociceptive (musculoskeletal, visceral, other) or neuropathic (Bryce et al., 2012), with the latter categorized as: • “at level SCI pain” occurring in a segmental pattern within three dermatomes of the neurological level of the injury, and likely due to injury to the nerve roots and/​or cord; • “below-​level SCI pain” occurring more than three dermatomes below the neurological level of injury, which is a result of damage to the spinal cord, and can occur following either complete (no motor function preserved below the level) or incomplete injuries; • other coexistent causes of NP not related to the spinal lesion (e.g., trigeminal neuralgia). Only 3–​5% of new cases of SCI are in children, but SCI can occur in neonates as a complication of delivery, and tends to have a better recovery than seen at older ages (Pape, 2012). Complete cord lesions are more common in younger age groups, and there is a male predominance at all ages. Follow-​up, on average, of 15 years following SCI (mean age at injury 14 years, n = 216) reported an overall incidence of pain at any site of 69%, with younger age at injury associated with orthopedic complications such as scoliosis and hip subluxation, and older age at injury associated with ankle pain and spasticity (Vogel et al., 2002). Adults with pediatric-​onset injury report lower levels of pain and improved function than those injured during adulthood, although values are still worse relative to healthy controls (Ma et al., 2016). In adults with pediatric-​onset injury, pain interference is associated with poorer sleep (January et  al., 2015)  and is predictive of depressive symptoms (January et  al., 2014), whilst factors associated with increased pain intensity, duration, frequency, and/​or interference include older age at injury, longer duration of injury, and psychological (depression and anxiety symptoms) factors (Murray et al., 2017). Similarly, NP has also been reported to be less common if injury occurs at a younger age: 26% (n = 24/​91) before 20 years of age versus 44.7% (n = 139/​ 311) at older ages (Werhagen et al., 2004). In a series of 31 participants, aged between 5 months and 18 years at the time of SCI, 65% reported chronic pain, and this had neuropathic features in 19% but was associated with less interference in daily activities than in adults (Jan and Wilson, 2004).

Cancer-​related neuropathic pain NP occurs in 20–​40% of adult patients with cancer (Howard et al., 2014). The overall rate of cancer-​related NP is likely to be lower in children, but, as noted earlier, phantom limb pain is more common in children who require amputations for cancer and perioperative chemotherapy. Significant pain may occur in specific populations: • Primary tumors within the nervous system. Neurofibromatosis (NF) type 1 and type 2 are neurocutaneous disorders associated with tumors affecting the central and peripheral nervous systems

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SECTION 4  Pain in specific populations and diseases

(Schulz et al., 2018; Ardern-​Holmes et al., 2017). Pain is experienced by 46–​ 71% of children with plexiform neurofibromas (Howard et  al., 2014; Lai et  al., 2017), and increasing pain and rapid growth of the tumor may indicate development of a malignant nerve sheath tumor (Ardern-​Holmes and North, 2011). Pain can also have significant impact on health-​related quality of life in children with NF (Krab et al., 2009; Nutakki et al., 2017; Wolters et al., 2015), and this condition is also discussed in Chapter 33. • Tumor invasion or compression of neural structures (spinal cord, spinal nerve roots, nerve plexus, peripheral nerves). As the incidence of solid tumors is lower in children, tumor invasion/​compression is less common in children than in adults, but can result in severe pain with high analgesic requirements, which may be difficult to control with opioids alone, and in some cases requires regional blockade with local anesthetic (Howard et al., 2014). • Neurovascular compression (e.g., trigeminal neuralgia; see the next subsection)

et al., 2016), no studies have assessed sensory changes in children and adolescents, and screening tools for detecting peripheral neuropathy and NP in this cohort have not been validated. Treatment of high-​risk neuroblastoma with a monoclonal antibody directed against the tumor-​ associated disialoganglioside GD2 can result in severe acute pain in children (Anghelescu et al., 2015; Mora, 2016). Laboratory studies have confirmed mechanical allodynia as a result of C-​fiber activation (Xiao et  al., 1997)  and complement activation (Sorkin et  al., 2010), which is reduced by gabapentin (Gillin and Sorkin, 1998). Current clinical treatment protocols incorporate NP management strategies, such as oral gabapentin, and addition of intravenous (IV) ketamine or lidocaine if pain is inadequately controlled by IV opioid (Wallace et al., 1997) (see also Chapter 48).

Cancer treatment-​related NP

Fabry’s disease

Treatment-​ related NP may occur following surgery (e.g., postamputation pain; see “Phantom limb pain” section) or chemotherapy. Perioperative chemotherapy has also been associated with an increased incidence and earlier onset of postamputation pain (Smith and Thompson, 1995). Peripheral neuropathy occurs in 50–​90% of those treated with platinum compounds (cisplatin) and almost half of those with vinca alkaloids (vincristine) (Vondracek et al., 2009). In 21 children with solid tumors and nine with leukemia aged between 10 and 17 years, NP symptoms (paresthesia, numbness and burning pain in the fingers and toes, hyperalgesia, and tactile allodynia) commenced within days of beginning chemotherapy. In addition, pain was severe (mean baseline visual analog scale score >75/​100) (Vondracek et al., 2009). In a retrospective review, 174/​498 patients developed peripheral neurotoxicity with vincristine treatment for acute lymphoblastic leukemia (Anghelescu et al., 2011). Associated NP occurred in 35%, with recurrent episodes in 16–​30.6%. Age at diagnosis ranged from 1 to 19  years but had minimal influence on the rate of NP, which varied from 31% in the 1–​5-​year-​old group, to 40% in those aged 16–​20 years. Pain was described as aching, burning, cramping, tingling, numbness, sharp, or stinging, and was most common in the lower limbs, back, and jaw (Anghelescu et al., 2011). Data from a large US Childhood Cancer Survivor Study (>388,000 from 1975 to 2011; diagnosis 1970–​86) indicates persistent pain of moderate or excruciating severity in 12.3% of childhood cancer survivors, but there is no information about the proportion with NP (Lu et  al., 2011). Increased risk of back pain was reported in this study (Bowers et  al., 2012), consistent with adult research where neuropathy was associated with the number of intrathecal chemotherapy injections (Ness et  al., 2017). Whilst survival following childhood cancer is increasing, self-​reported health has not significantly improved (Ness et al., 2017). Further studies are required to assess incidence and severity of chemotherapy-​induced peripheral neuropathy and NP, their impact on quality of life and function, potential risk factors, and management of pain (Kandula et al., 2016; Mohrmann et al., 2017). While somatosensory changes associated with chemotherapy-​induced peripheral neuropathy and NP have been reported in adults using QST (e.g., Velasco et al., 2015; Reddy

Metabolic disorders

Clinical features Pain is a common presenting symptom in Fabry’s disease, and often has an onset during childhood (Howard et al., 2014; Laney et al., 2015; Hopkin et al., 2016). As pain may be the only feature for some years, Fabry’s disease should be considered in the differential diagnosis of pain clinic referrals (Pagnini et  al., 2011). Episodic burning pain and “pins and needles” may initially be restricted to the hands and feet, but pain becomes more persistent and generalized with time (Howard et  al., 2014; Hopkin et al., 2016), and can be triggered by changes in environmental or body temperature, exercise, or emotional stress. Pain is present in >70%, with a higher incidence in males (80% vs. 65%) (Hoffmann et al., 2007), and has a significant impact on quality of life. Other features of Fabry’s disease include hypo-​or hyperhidrosis, gastrointestinal disturbances and abdominal pain, angiokeratomas, and ophthalmologic abnormalities (cornea verticillata) (Mehta et al., 2010; Laney et al., 2015). Pathophysiology Fabry’s disease is an X-​linked recessive disorder, and females typically have less severe symptoms that develop at a later age (Rodrigues and Kang, 2016). Mutations in the GLA gene that encodes the lysosomal enzyme alpha-​galactosidase A result in failure to catabolize lipids containing alpha-​ d-​ galactosyl moieties. Accumulation of glycolipids, including globotriaosylceramide (Gb3) in cells and tissues results in dysfunction of multiple organ systems, including heart, kidney, gastrointestinal tract, and nervous system (Howard et al., 2014; Rodrigues and Kang, 2016). NP symptoms are predominantly related to Aδ small fiber loss in peripheral tissues identified with QST in adults (Üçeyler et al., 2014; Hopkin et al., 2016), and may also be related to glycolipid accumulation in peripheral nerves or altered channel kinetics in dorsal root ganglia neurons (Borsook, 2012; Choi et al., 2015). Age Reported ages at diagnosis range from 5 to 77 years (Pagnini et al., 2011). However, acroparesthesia/​ NP has been reported from

CHAPTER 22  Neuropathic pain in children

2 years of age (Laney et al., 2015). Overall, NP was reported in 59% of boys (median 7 years) and 41% of girls (median 9 years) (Hopkin et al., 2008).

Postherpetic neuralgia

Reactivation of varicella zoster virus infection, which has been dormant within sensory neurons, results in painful eruptions along the distribution of the nerve (also known as shingles), and apDiagnosis and management proximately 14% of adults develop persistent NP (i.e., postherpetic The diagnosis is based on measurement of plasma alpha-​ neuralgia (PHN)) (Delaney et  al., 2009). Overall, zoster infection galactosidase A activity (although levels may be normal in carrier and PHN are less common in children, and incidence increases females), and of plasma or urinary Gb3 or lyso-​Gb3, and is con- with age (Hall et  al., 2013), but children who are immunocomfirmed by genetic analysis of GLA (Mehta et al., 2010). promised (Gershon et  al., 2015), particularly in association with Enzyme replacement therapy with alpha-​ galactosidase A  re- cancer treatment, are at higher risk. In a series of 226 children with duces glycolipid storage in tissues, but effects on pain take time. acute lymphoblastic leukemia, zoster eruptions occurred 90 times, Improvement in all dimensions of pain perception after 24 months has with recurrent episodes in 14 children. All experienced pain with been reported (Howard et al., 2014), with reductions in neuropathic the acute eruption and were treated with aciclovir, and five devel“pain at its worst” scores in both boys and girls (from 2.8 to 1.5) and oped PHN, which persisted for more than 2 months in two patients “average pain” from 2.2 to 0.9, and a reduced requirement for neuro- (Sørensen et al., 2011). pathic treatment with anticonvulsants (Howard et al., 2014). In others, the overall prevalence of pain was not altered by enzyme replacement therapy, but those with pain at the onset of therapy did show a deTrigeminal neuralgia crease in severity (Ramaswami et al., 2012).

Clinical features

Neurological disorders NP is a feature of several neurological conditions. Pain associated with NF, Guillain-​Barré syndrome, neuromuscular disorders, and pain associated with HIV are covered in Chapter 33.

Multiple sclerosis Multiple sclerosis (MS) is a chronic inflammatory disease producing demyelination and axonal damage in the brain and spinal cord (Mariotti et al., 2010). Pain is common in adults with a prevalence from 57% to 65%, and 43–​54% have pain at the time of diagnosis. Patients with MS may experience multiple types of pain (including tonic spasms, back pain, and headache) but, additionally, may experience central neuropathic pains. • Dysesthetic extremity pain occurs in up to 23% of patients. Pain is burning, typically bilateral, often in the legs and feet, is worse at night, and is exacerbated by exercise. • Trigeminal neuralgia is more common than in the general population, with a higher rate of bilateral symptoms. • Brief electric shock sensations in the back of the neck, lower back, or other parts of body, are brought on by neck flexion (Lhermitte’s sign). An estimated 2–​5% of patients experience their first symptoms of MS before 16  years of age, with the onset usually between 8 and 14  years, and a higher incidence in females (ranging from 1.3 to three times). Cohorts of pediatric patients with MS report sensory symptoms in 13–​69%, but there is little information about the proportion with NP (Ness et al., 2007). Headache is more frequent in pediatric than in adult patients with MS (Mariotti et al., 2010). The course of the disease may be slower in children, but it can have a significant impact on schooling and psychosocial function (Ness et al., 2007); further reductions in quality of life have been associated with increasing age and duration of illness. The impact of disease-​ modifying therapies, such as interferon, on pain symptoms are not clear (O’Connor et al., 2008).

Clinical features of trigeminal neuralgia include (Bender et  al., 2011; Howard et al., 2014): • Unilateral pain in the distribution of the trigeminal nerve. The trigeminal innervation is divided into three zones: V1 ophthalmic (scalp, forehead, upper eyelid, eye); V2 maxillary (lower eyelid, cheek, nose, and upper teeth and gums); and V3 mandibular (lower teeth and gums, jaw, parts of external ear). Pain may be experienced in one or more zones; most commonly V2 followed by V2/​3 combined. • Pain is described as sharp, lancinating or shooting, electric-​shock like, and occasionally burning. • Pain is intermittent and paroxysmal. • Intermittent paroxysms of pain can be triggered by light touch in the trigeminal region (cutaneous trigger zones), chewing, brushing the teeth, cold wind, or exercise. Pain may also be associated with spasm of the facial muscles, or tic doloureux.

Incidence The incidence of trigeminal neuralgia is much lower in children (Hall et  al., 2013), and 6 years). However, NP can occur at younger ages, particularly in higher-​risk populations (e.g., cancer, chemotherapy, and immunosuppression) or in association with specific conditions (e.g., Fabry’s disease). Pharmacological management of NP is largely extrapolated from adult studies (see Chapter 48). However, pain is often severe and only partially responsive to pharmacological interventions, and multidisciplinary care is required. As discussed in other chapters throughout this book, assessment and management of chronic pain (including NP) must also encompass nonpharmacological and psychological interventions, include family or caregivers, and address issues related to poor sleep and school attendance.

Age-​dependent effects

PERSPECTIVE

The degree of change in channel kinetics varies with the site of the mutation, and larger depolarizing shifts have been associated with onset of symptoms at younger ages. However, variable expression of neonatal and adult isoforms of the channel may also influence the age at which symptoms first appear (Howard et al., 2014).

My 14-​ year-​ old daughter had routine appendectomy last year. Although the pain from her surgery resolved within several days, she now has abdominal pain that began 3 months after her surgery. This has been difficult to understand because there is no visible injury, and the area around her surgical scar is not swollen or red. In addition, her symptoms are unusual; she describes her pain as burning, shooting, and stabbing, and her abdomen is sensitive to touch. Her pain has become more severe in the last 6 months, and she experiences pain more frequently, and often without any apparent trigger. She has now stopped wearing tight-​fitting trousers, no longer participates in physical exercise at school, and is increasingly avoiding stairs. She has become very anxious about taking part in any activity that could provoke pain and is beginning to spend less time with her friends. She is now sleeping poorly as a result of her pain and is missing school more frequently. Recently, my daughter was referred to a specialist Chronic Pain Service, where she was seen by a multidisciplinary team of clinicians, who explained that she has NP and requires different types of treatment. The physiotherapist who assessed her found that she was weak in her core and lower limb muscles as a result of her reduced activity. The psychologist spoke to her about her poor sleep and her anxiety and low mood. We now have a better plan for managing her pain.   

Management Diverse views of the pathophysiology of EM have resulted in a range of treatments directed at vascular (vasoactive drugs such as topical glyceryl trinitrate, sodium nitroprusside infusion, clonidine) (Cohen, 2000), anti-​inflammatory, and neuropathic etiologies (amitriptyline, gabapentin, lidocaine patches) (Natkunarajah et al., 2009; Cook-​Norris et al., 2012). With awareness of the potential involvement of Nav1.7 in EM, there has been increased use of drugs with sodium channel blocking activity. Different EM-​related mutations may be more responsive to either mexiletine or carbamazepine (Howard et al., 2014). Specific Nav1.7 antagonists are also being developed for NP (Zakrzewska et al., 2017; Yang et al., 2018).

Paroxysmal extreme pain disorder paroxysmal extreme pain disorder (PEPD) can present soon after birth with episodic pain in association with redness over the buttocks,

CHAPTER 22  Neuropathic pain in children

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CHAPTER 22  Neuropathic pain in children

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23

Inflammatory arthritis and arthropathy Peter Chira and Laura E. Schanberg

Introduction The evaluation of children with musculoskeletal pain is challenging for healthcare providers owing to the extensive differential diagnoses. Identifying any underlying pathologic process in a thoughtful, expeditious manner minimizes patient and family distress and prevents long-​term disability. Many practitioners lack comfort and familiarity determining if musculoskeletal pain complaints are related to an inflammatory arthritis such as juvenile idiopathic arthritis (JIA) or other inflammatory disorders. Prompt diagnosis of an underlying rheumatic disorder allows early treatment to reduce pain, prevent long-​term damage to joint or muscles, and limit physical disability and emotional distress. Additionally, controlling inflammation may decrease pain signaling and prevent long-​term alteration of pain processing. However, aggressive medical therapy alone is not sufficient to optimally treat pain in children with rheumatic conditions. Concomitant factors besides disease activity impact pain perception and management. A biopsychosocial model of pain most completely addresses all factors contributing to the pain symptoms of a child with rheumatic disease, serving as an effective framework for treatment (Figure 23.1).

Mechanisms of arthritis pain Much of what is understood about the biology of joint pain comes from study of neural pathways in mice models of experimental inflammatory arthritis (McDougall and Larson, 2006). Schaible’s extensive work on the basis of pain caused by inflammatory arthritides such as rheumatoid arthritis (RA) and JIA (Schaible et al., 2009) has described two primary mechanisms:  Peripheral sensitization (increased sensitivity of nociceptive primary afferent neurons) and central sensitization (hyperexcitability of nociceptive neurons in the central nervous system (CNS)). Degenerative processes within joints, along with inflammation, can trigger and exacerbate sensitization of pain pathways, resulting in the development and perpetuation of chronic pain. Current mechanistic theories behind the development of pain in children with rheumatic disease have been reviewed, and animal models suggest that childhood, rather than infancy, may be the most vulnerable period for chronic pain development (La Hausse de Lalouviere et al., 2014). Quantitative models

in children show lower pain thresholds, exacerbated by inflammatory conditions such as JIA (Cornelissen et al., 2014). Primary afferent neurons have three main functions in nociception: Detection of noxious or damaging stimuli (transduction); conveyance of sensory input from the periphery to the spinal cord (conduction); and synaptic transfer of input to neurons within specific laminae of the dorsal horn of the spinal cord (transmission) (Kidd and Urban, 2001). In inflammatory arthritis, a complex interplay of mechanical factors and chemical mediators (bradykinins, prostaglandins including cyclooxygenases I  and II, neuropeptides (nerve growth factor and substance P), cytokines (interleukins (ILs) and tumor necrosis factor (TNF)), and ion channels) is triggered, prompting a decrease in the normal pain threshold within a joint and causing hyperalgesia and allodynia in local afferent nerves. Pain conduction occurs within normally quiescent nerve fibers via Aδ-​and C-​fibers. These fibers start firing with routine movement in the presence of inflammation or joint damage from trauma or tissue injury. However, anticitrullinated peptide antibodies from patients with RA induce pain independent of synovial inflammation through osteoclast activation and release of IL-​8 in mouse models, suggesting another important mechanism for pain initiation in RA (Wigerblad et al., 2016). Neuronal activation thresholds drop causing increased sensitivity to mechanical or thermal stimuli facilitated by various immune cells (Totsch and Sorge, 2017). Mediators of the inflammatory response (e.g., prostaglandin E2 and bradykinin) also can sensitize C-​fibers, which have broad receptive fields and are activated by thermal, mechanical, and chemical stimuli. Once sensitization occurs, non-​ noxious low-​ level stimulation elicits neural activity (Giordano, 2006). Therefore, C-​ fibers are likely to underlie persistent secondary pain, hyperalgesia, and hypersensitivity associated with inflamed tissue. Inflammatory cytokines such as TNF-​α, IL-​1, and IL-​6 contribute to the pain stimulus by direct nerve stimulation, as well as through inflammation itself, which helps initiate and perpetuate the pain signal (Oen et al., 2005). Thus, anticytokine therapies used to control inflammatory arthritis may affect arthritis pain directly, as well as indirectly by decreasing disease activity. With joint inflammation, spinal neurons become hyperexcitable. Central sensitization occurs when neurotransmitters (e.g., l-​ glutamate) and neuropeptides (e.g., substance P and neurokinin A) activate and/​or modulate synapses within the spinal cord, leading

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SECTION 4  Pain in specific populations and diseases

Disease modifying agents Analgesics

Biological Factors: Disease activity, genetics, pain processing, medications, physical activity, sleep

Physical therapy Biologics

Child's Pain Experience

Family therapy Peer support group

Parenting training

Environmental Factors: Parental pain and stress response, family relationships, social and school relationships

Individualized educational plan

Breathing exercises Cognitive-Behavioral Factors: Stress, mood, psychological adjustment, self efficacy, coping skills

Guided imagery

Psychotherapy

Learning not to “catastrophize”

Figure 23.1  Biopsychosocial model of pain. Arthritis pain has multiple factors (biological, environmental, and cognitive behavioral) that can contribute to a child’s perception of pain. Treatment strategies should address the various components that can include pharmacological and nonpharmacological therapies.

to perpetuation of the pain signal and potential expansion of pain receptive fields via postsynaptic receptor activation (Schaible et al., 2009). Pain-​modulating systems dampen or attenuate the development of hyperexcitability through antagonism of postsynaptic receptors (N-​methyl-​d-​aspartate, α-​amino-​3-​hydroxy-​5-​methyl-​ 4-​isoxazolepropionic acid, and metabotropic glutamate), reducing central sensitization (Schaible et al., 2006). Additionally, pain modulation occurs through local interneuron circuits within the dorsal horn that inhibit release of endogenous opioid peptides (dynorphin and encephalin) and γ-​aminobutyric acid, as well as within the rostral medulla where serotonin and norepinephrine can turn “on” and “off ” neurons that modulate pain (Schaible et al., 2009). These cortical processes have been shown to have a major role in the mediation of pain processing that includes elements of cognition, arousal state, attention, and expectation (Seifert and Maihofner, 2009). These inhibitory mechanisms may not be as robust in childhood, limiting a child’s ability to modulate the pain signal (Hathway et al., 2012) and resulting in permanent alterations of nociceptive inputs. Altered nociceptive input may cause “priming” of the dorsal horn circuits and a predisposition to pain hyper-​responsiveness with reinjury later in life (Beggs et al., 2012). Increasingly recognized as an important factor in the establishment of adult chronic pain is the role of accessory glial cells (microglia and astrocytes) in the perpetuation of pain signals for

neuropathic and inflammatory pain (Milligan and Watkins, 2009). In pediatric inflammatory arthritides such as JIA, the role of glial cells may be less robust in perpetuating pain than in adults, based on rat models (Hathway et al., 2009). In adult models of arthritis, growing evidence suggests that activated microglia augment primary afferent input and release pronociceptive mediators such as cytokines and chemokines, affecting pathways such as the CX3CL1 loop and purinergic receptors that mediate neuropathic pain (Old et al., 2015). Astrocytes become reactive because of microglial activation and can lead to pain maintenance by causing increased extracellular glutamate levels. The interplay of the various mediators released as part of the inflammatory cascade can affect and alter glial-​mediated central pain processing, resulting in dysfunctional pain signaling (Milligan and Watkins 2009). Chronic pain in children with rheumatic disease is the result of an integration of biological processes (e.g., glial cell activation, and peripheral and central sensitization), psychological factors (e.g., anxiety and poor coping), and sociocultural contexts (e.g., parental emotional distress and peer relationships) within a developmental framework (Zeltzer et  al., 1997). Disease activity and day-​to-​day life experiences, including emotional state, sleep quality, and family and peer relationships, all influence the severity, characteristics, and regularity of pain with time. Ongoing pain can result in sensitization of the peripheral and central nervous systems, which produce

CHAPTER 23  Inflammatory arthritis and arthropathy

neurophysiological, neurochemical, and neuroanatomical changes (Woolf and Salter, 2000), which may continue despite low disease activity or the absence of tissue damage. Interestingly, mouse models show that early life (neonatal–​childhood) injury may alter pain pathway plasticity causing increased sensitivity with reinjury as adults leading to hyperalgesia and chronic pain (Schwaller and Fitzgerald, 2014). Secondary hyperalgesia, as observed by altered pressure pain thresholds in patients with JIA, has been posited to arise from persistent nociceptive bombardment from inflamed joints leading to peripheral and central hyperexcitability of nociceptive afferents; however, the role of inefficient descending endogenous inhibitory nociceptive pathways has yet to be determined (Pas et al., 2018). In addition, the extent of disability associated with a specific chronic pain level varies from person to person based on genetics, as well as many of the same factors that affect pain perception. In summary, pain perception is multifactorial and best understood using a biopsychosocial framework, including developmental status, coping ability, mood, and stress levels, as well as environmental and family factors, in addition to disease status and severity (Weiss et al., 2014; Martin and Zeltzer, 2018).

Clinical presentation Children and adolescents with rheumatic disease may not present with musculoskeletal pain. Interestingly, McGhee et al. (2002) reported that of 111 patients presenting to a pediatric rheumatology clinic with an initial chief complaint of isolated musculoskeletal pain, only one had arthritis or other rheumatic disease. These confirmed an earlier, larger study which showed that the majority of patients referred to pediatric rheumatology clinics across the US do not have primary rheumatic disease, but rather nonspecific musculoskeletal complaints or abnormal laboratory studies (Bowyer and Roettcher, 1996). Both studies highlight the need for healthcare professionals to distinguish those with nonspecific musculoskeletal pain from those with inflammatory conditions. When joint pain is the primary complaint for a patient presenting with JIA, overt abnormalities are found on examination such as swelling and/​or pain on movement with limitation of motion, or tenderness noted at the joint line along with limitation. The pain of arthritis is typically described as mild to moderate, with a dull or achy discomfort, and joint stiffness that worsens with inactivity (sleeping or sitting for prolonged periods) and improves with movement. Pain at rest is unusual. Pain commonly varies from day to day; however, physical examination abnormalities are constantly present. Stiffness or “gelling” occurs most commonly in the morning, although the pathophysiology is not understood. Arthritis pain rarely causes night awakening; therefore, other causes of joint or bone pain must be ruled out, including malignancy, infection, or bone tumors (osteoid osteoma) if night pain is present. Other signs of chronic inflammatory arthritis include limp, warmth of the joint (not necessarily associated with erythema), and muscle atrophy of proximally or distally affected areas. If there is erythema and/​or exquisite tenderness with palpation of joints or bones, infection (osteomyelitis or septic arthritis), reactive processes (rheumatic fever or Henoch-​Schönlein purpura), malignancy (leukemia, lymphoma, or neuroblastoma), or trauma should be considered. Table 23.1 lists the differential diagnoses for children with musculoskeletal pain.

Pain intensity reported by children and adolescents with JIA is quite variable. Early studies of pain in children with JIA erroneously suggested the condition was less painful than RA (Laaksonen and Laine, 1961). Studies in the 1990s, incorporating developmentally appropriate measures, showed disease-​related pain is often underestimated in children with JIA and other rheumatic disorders. In fact, using daily diary methodology, Schanberg et  al. (2003) reported that children with JIA report pain on 70% of days. Most children reported mild-​to-​moderate pain, but 25% reported pain in the severe range. Interestingly, disease activity predicts less than half of reported pain variance and day-​to-​day variations of pain are influenced by factors such as mood, stress, parental and child coping, and parental pain and health beliefs (Schanberg et al., 2003; Schanberg et  al., 2005). E-​pain diaries have been instrumental in further characterizing the daily variations of JIA pain, revealing that within-​patient differences in symptom report varies throughout the day; stiffness intensity is highest in the morning, pain fluctuates throughout the day, and fatigue intensity is highest in the evening. The momentary assessment of symptoms may help guide interventions to increase patient functionality and decrease the negative impact of arthritis (Bromberg et al., 2014). Additionally, greater pain variability within and across days predicted worsening health related quality of life (Tupper et al., 2013). While there is a relationship between increased disease activity and increased pain, disease status variables typically predict only a small-​to-​medium proportion of the variance in child pain ratings (8–​28%) (Schanberg et al., 1997). Disease activity accounts for only about 2% of pain variance in adults with JIA (Packham et al., 2002). Self-​reported pain does not correlate well with physician global assessment in the Childhood and Rheumatology Research Alliance (CARRA) Registry, with the subgroup of those with enthesitis-​ related arthritis reporting most pain (Weiss et al., 2012). Therefore, it is important to delineate other influential factors in the pain experience of children with JIA. The role of psychosocial variables such as emotional distress, mood, stress, and pain-​coping strategies in children’s pain reporting has been studied in many settings. Schanberg et al. (2005) investigated interrelationships of daily stress, daily mood, and disease expression. Results of multilevel random-​effects models indicated that day-​to-​day fluctuations in mood and stressful events were related to daily symptoms in children with polyarticular forms of juvenile chronic arthritis. Specifically, worse mood and more stressful events predicted increased daily pain, fatigue, and stiffness. These results confirm other studies which indicate that increased psychological distress (e.g., stress, depression, and anxiety) is related to increased pain reporting and poorer functional outcomes, such as decreased participation in school and social activities (Hoff et al., 2006). Children’s pain coping is another influential factor. In adolescents with JIA, catastrophizing (i.e., engaging in overly negative thinking about pain) is associated with depression and anxiety (Garnefski et al., 2009). In a laboratory setting, catastrophizing also predicted increased pain in children with JIA undergoing experimental cold pressor pain (Thastum et  al., 2001). Studies by Thastum and colleagues underscore the impact of cognitive health beliefs on pain in children with JIA (Thastum and Herlin, 2011), showing that beliefs about control over pain influence the development of effective pain-​coping strategies, whilst dysfunctional health beliefs persist over time in patients with high pain. Connelly et al. (2012) reported

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SECTION 4  Pain in specific populations and diseases

Table 23.1  Differential diagnoses for musculoskeletal pains in children. Category

Diagnosis

Hallmarks

Anatomical or mechanical issues

Avascular necrosis

Pain with weight bearing

Osteochondroses (e.g., Legg–​Calve–​Perthes)

Hip pain and limp

Apophysitis (e.g., Osgood Schlatter)

Tibial tuberosity pain

Ligamentous laxity (e.g., patellar dislocation)

Mobile patella with pain

Benign hypermobility syndrome

Multijoint hyperextensibility

Fracture

Multiple fractures in young children suggest child abuse; growth plate fractures not seen on X-​ray

Sprain, muscular strain

Physically active teenagers, unusual in those 40,000 children die annually; 55% are infants younger than 1 year of age (Child Trends, 2019). The leading causes of pediatric deaths include accidents (n  =  >7000), suicide (n = >2000), and homicide (n = >2000). Leading life-​limiting conditions include congenital malformations and chromosomal abnormalities (n = >5500) followed by malignancies (n = >1800). The aim of PPC is to match treatment to patient goals. PPC is specialized medical care for children with serious illness that is focused on relieving pain, distressing symptoms, and stress of a serious illness. PPC is appropriate at any age and at any stage, together with curative treatment. The primary goal is to improve quality of life for the child and his or her family (Friedrichsdorf, 2017a).

Pain in palliative care Children living with serious illnesses commonly experience pain, which is among the most distressing and prevalent symptoms (Feudtner et al., 2011). Nearly all studies of pain and other distressing symptoms in PPC were undertaken in children with malignancies and show a significant symptom burden in this population (Wolfe et  al., 2000, 2008, 2015; Friedrichsdorf et  al., 2015a). Self-​reports in verbal children with malignancies showed high distress from pain in 39% with advanced cancer, which increased to 58% during the end-​of-​life period (Wolfe et al., 2015). Pediatric patients enrolled into PPC programs experience an average of nine distressing symptoms (Feudtner et al., 2011) and, in children with advanced serious illness, the majority of distressing

1  Section “Pediatric palliative care” adapted from Friedrichsdorf S.J. and Bruera E. (2018). ‘Delivering Pediatric Palliative Care:  From Denial, Palliphobia, Pallilalia, to Palliactive’. Children (Basel). 5(9):  120. DOI:  10.3390/​ children5090120 under a Creative Commons Attribution 4.0 International (CC BY 4.0) license, https://​creativecommons.org/​licenses/​by/​4.0/​.

symptoms, such as unrelieved pain, are not treated during the end-​of-​life period, and, when treated, the therapy is commonly ineffective (Wolfe et  al., 2000, 2008, 2015; Hechler et  al., 2008, Friedrichsdorf et  al., 2015a, 2017). Evidence on adults obtained through randomized controlled trials (RCTs) suggests that the integration of palliative care improves the quality of life and prolongs life (Bakitas et al., 2015); this has also been described in pediatric case reports. “Parents of children with cancer who received PPC reported less distress from pain, dyspnea and anxiety during the end-​of-​life period”(Friedrichsdorf and Bruera 2018, p.  6; Wolfe et  al., 2008). Children who received PPC at home were more likely to have fun (70% vs. 45%) and to experience events that added meaning to life (89% vs. 63%) (Friedrichsdorf et al., 2015a). “Families who received PPC services report improved communication and children receiving PPC experience shorter hospitalizations and fewer emergency department visits” (Friedrichsdorf and Bruera 2018, p. 6; Ananth et al., 2015).

Multimodal analgesia Multimodal analgesia has been implemented as a successful treatment strategy in postoperative pain and subsequently utilized in many other clinical scenarios, including cancer treatment and trauma care (Michelson et al., 2013; Friedrichsdorf, 2016). To advance pain treatment strategies in PPC, many centers, experts, and curricula in PPC now emphasize the importance of multimodal analgesia. Although pharmacology remains a pillar of advanced pain treatment and prevention in children with serious illness, it has become clear that medications alone often do not provide adequate analgesia in a large number of children with complex conditions and PPC needs. In fact, the paradigm shift away from “medications only” toward offering multimodal analgesia to children with serious illness experiencing pain has proven to be a “game changer” in the care of seriously ill children. Multimodal analgesia as a concept is now integral to state-​of-​the art clinical care, as well as PPC curricula (Friedrichsdorf et al., 2019), so that children with life-​limiting diseases can live as long as possible, as well as possible.

10.1093/​med/​9780198818762.003.0029

CHAPTER 29  Pain treatment and prevention in pediatric palliative care

Psychology Basic Analgesics • Acetaminophen (Paracetamol) • NSAIDs/COX-2 Inhibitor ibuprofen, Celecoxib

• CBT Cognitive

Behavioral Therapy, Skillbased Training

Family Support such as • Social Work

Psycho-education, Supportive Counseling etc.

Integrative Therapies • Mind-Body Techniques

Hypnosis, Biofeedback, Abdominal Breathing, Progressive Muscle Relaxation, Mindfulness, Distraction

• Acupressure, Acupuncture • Aromatherapy, Massage

Adjuvants • Alpha-Agonist Clonidine,

• Neuraxial infusion • Peripheral / Plexus Nerve block • Neurolytic block • Intrathecal port / pump

Dexmedetomidine

• Gabapentinoids • TCAs Amitriptyline, Nortriptyline • NDMA-Antagonists low-

Pediatric Multimodal Analgesia

dose ketamine, (Methadone)

• Na-channel blocker

• Intraventricular opioids? Percutaneous cervical cordotomy?

Lidoacaine

Rehabilitation • Exercise • Physical Therapy incl

graded motor imagery, mirror therapy

• Occupational Therapy • Speech Therapy

Regional Anesthesia

Other Modalities Opioids • Tramadol (”Weak”) • Morphine (”strong”)

Alternatives: Fentanyl, Hydromorphone, Oxycodone, Methadone (UK: Diamorphine)

• Scheduled Administration “By the

• Spirituality • Child Life • Normalizing Life • School attendance • Sleep hygiene • Social • Sports/Exercise

Clock”

Figure 29.1  Multimodal analgesia treatment options for children with serious illness. CBT, cognitive behavior therapy; TCA, tricyclic antidepressant; NMDA, N-​methyl-​d-​aspartate; NSAID, nonsteroidal anti-​inflammatory drug; COX, cyclooxygenase. Reproduced with permission of Stefan Friedrichsdorf, Medical Director, Center of Pediatric Pain Medicine, Palliative Care and Integrative Medicine, Benioff Children’s Hospitals in Oakland and San Francisco, University of California at San Francisco (UCSF), USA.

Advanced pain management for children with serious illness receiving PPC often requires multimodal analgesia, similar to children with pain caused by trauma, burns, cancers, or vaso-​occlusive sickle cell disease. This approach includes “utilizing multiple analgesic agents (such as basic analgesia, opioids, adjuvant analgesia), regional anesthesia,” rehabilitation, psychological, “and integrative (formally known as “non-​ pharmacological”) therapies (such as massage, hypnosis) which usually act synergistically for more effective pediatric pain control with fewer side effects than a single analgesic or modality” (Friedrichsdorf and Bruera 2018, p.6; Friedrichsdorf, 2016). Advanced multimodal therapies that may be offered to children with serious illness include: • basic analgesia (such as paracetamol/​acetaminophen and ibuprofen/​cyclooxygenase (COX)-​2 inhibitors) • opioids (such as tramadol, morphine, and methadone) • adjuvant analgesia (such as gabapentin, clonidine, amitriptyline, and lidocaine) • regional anesthesia (such as neuraxial infusion, peripheral/​plexus nerve block, neurolytic block, and intrathecal port/​pump) • rehabilitation (such as physical therapy, graded motor imagery, and occupational therapy),

• psychological and psychiatric modalities (such as cognitive behavior therapy) • social work and spirituality (such as chaplain support) • integrative (“nonpharmacologic”) therapies (such as mind–​body techniques, including diaphragmatic breathing, bubble blowing, self-​hypnosis, progressive muscle relaxation, biofeedback plus massage, aromatherapy, acupressure, and acupuncture). Figure 29.1 shows the components of multimodal analgesia, with the implication that an individual child may require one, several, or all of the components listed in each circle to achieve excellent analgesia. Each of these therapeutic options will be described in more detail.

Considerations for treating pain in children with serious illness There are yet no agreed-​upon consensus guidelines on pain treatment and prevention in PPC. This chapter suggests a step-​by-​step approach for consideration in the pain treatment of a 0–​17-​year-​ old child with serious illness, based on the Education in Palliative and End-​of-​Life Care–​Pediatrics curriculum (Friedrichsdorf et al.,

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2019). Obviously, the appropriate treatment choices remain the responsibility of the treating clinicians and depend, among other things, on the underlying pain pathophysiologies, the clinical scenario and context (including cancer vs. nonmalignant disease, infant vs. older child, verbal vs. nonverbal child, etc.), the goals of care, and can only be seen as a guideline. See Box 29.1 for 12 steps in the considerations for advanced pain treatment in children with serious illness.

Step 1: Evaluation The key to successfully treating a child with serious illness in pain is to take a detailed history, including medication history, and to perform a comprehensive clinical examination. Based on the results of these evaluations, medical tests (which would guide further treatment) may be ordered, and treatment options may be discussed. The majority of patients with serious illnesses “experience different distinct and at times overlapping entities of pain pathophysiology concurrently and/​or subsequently, explaining the need of advanced protocols providing multi-​modal analgesia” (Friedrichsdorf and Goubert, 2020). We need to evaluate, which of the following six pain pathophysiologies may be present alone or concurrently in the individual patient, as this will guide the treatment. Acute somatic pain2 Acute somatic nociceptive pain may be caused by tissue injury of the underlying disease or the treatment (such as chemotherapy-​ induced mucositis). The key to preventing long-​lasting pain appears to be initiating “multi-​modal analgesia” (Friedrichsdorf, 2016) pain protocols on day one of a hospitalization. If pain is not adequately controlled right after a trauma, there is an increased risk of post-​ traumatic stress disorder (PTSD) (Stoddard et al., 2009). Acute pain management usually requires scheduling pain medications around-​ the-​clock with the addition of “as-​needed” (or “breakthrough,” “rescue,” or pro re nata “PRN”) medication, as will be discussed in greater detail. Procedural pain Procedural pain and anxiety might be caused by dressing changes, intravenous (IV) access, blood draws, injections, and so on. Patients report that repetitive needle procedures are among the worst kind of pain they experience during their hospitalization (Friedrichsdorf et al., 2015b). Although this kind of pain and anxiety can be completely prevented or significantly reduced by simple strategies, many hospitals may not offer these strategies to all their patients. Failure to prevent or minimize treatable procedural pain in children is now considered both inappropriate and unethical (Friedrichsdorf et al., 2016b). A successful example of providing system-​wide pain management is the “Children’s Comfort Promise: We promise to do everything to prevent and treat pain” (Friedrichsdorf et  al., 2018)  (see Chapter  59). For pain caused by elective needle procedures, such as blood draws, injections, vaccinations, IV cannulation, and so

2 Section “Acute somatic pain” adapted by permission from Springer Nature:  Treatment and Prevention of Pain in Children and Adults with Burn Injuries, pp. 323–​338 by Friedrichsdorf SJ. in Handbook of Burns Volume 1: Acute Burn Care edited by Jeschke MG.  et  al. Copyright © 2020, Springer Nature Switzerland AG. https://​doi.org/​10.1007/​978-​3-​030-​18940-​2_​25.

Box 29.1  Steps in the considerations for pain treatment in children with serious illness 1 Evaluation • Taking history and perform clinical exam (medical tests only as required) 2 Treat underlying causes • If within goals of care. (Palliative CNS emergency? Radiation, glucocorticosteroids, surgery?) 3 Integrative therapies • E.g. Active mind-​body techniques; acupuncture/​acupressure; music/​art/​pet therapy, massage, aromatherapy, apps 4 Social work, rehabilitation, psychology, spirituality, child life • Family support, psycho-​education, supportive counselling, parent guidance. Respite needed? • Manage comorbidities e.g. anxiety, depression, sleep disturbances, poor exercise tolerance/​deconditioned, school absenteeism etc. 5 Basic analgesia and opioids • Acetaminophen (paracetamol) and NSAIDs/​COX-​2 inhibitor • Opioids for new-​onset neuropathic pain, tissue injury (not for chronic pain/​primary pain disorders).Tramadol? Methadone? 6 Gabapentinoids and/​or tricyclic antidepressants • Gabapentin (or pregabaline); amitriptyline (or nortriptyline) 7 Alpha-​2-​adrenergic agonists • Clonidine or dexmedetomidine 8 NMDA-​receptor-​channel blocker • Low-​dose ketamine (and/​or methadone?) 9 Sodium-​channel blockers • Lidocaine (Transdermal patch? Intravenous?) 10 Regional anesthesia • e.g. Neuraxial infusion (epidural: Tunneled catheter); peripheral/​ plexus nerve block; neurolytic block; intrathecal port/​pump 11 Other adjuvants • Botox A? Low-​dose propofol? Benzodiazepines? Capsaicin? SNRI? Cannabinoids? 12 Palliative sedation • For intractable (not merely difficult to treat) pain or suffering of patient (not of parents or clinicians) in end-​of-​life period • Propofol? Midazolam? Ketamine? Barbiturates? Reproduced with permission of Stefan Friedrichsdorf, Medical Director, Center of Pediatric Pain Medicine, Palliative Care and Integrative Medicine, Benioff Children’s Hospitals in Oakland and San Francisco, University of California at San Francisco (UCSF), USA.

on, overwhelming evidence now demands offering a bundle of four modalities (or three for children older than 1 year of age) to all children all the time (see Box 29.2). If the strategies outlined in Box 29.2 are ineffective or not feasible, offer nitrous gas analgesia and sedation. Children receiving nitrous gas before and during painful procedures have lower levels of distress, lower pain intensity scores, are more relaxed, and many have no recollection of the procedure afterwards (Pedersen et  al., 2013; Friedrichsdorf, 2017b). Poorly managed procedural pain has serious short-​and long-​term consequences. Inadequate analgesia and the memory of previous painful experience for procedures in children diminish the effects of adequate analgesia in subsequent procedures (Weisman et al., 1998) and unrelieved pain increases the risk of PTSD, even in very young children (Stoddard et al., 2009). Alternatively, many centers are achieving excellent results in eliminating procedural pain and decreasing stress and anxiety using moderate-​to-​deep sedation, usually with the help of the general

CHAPTER 29  Pain treatment and prevention in pediatric palliative care

Box 29.2  Prevention and treatment of needle pain 1 Topical anesthesia “Numb the skin,” e.g. 4% lidocaine cream (administered 30 minutes prior to the procedure), EMLA (lidocaine 2.5% and prilocaine 2.5%) cream (60 minutes prior), amethocaine (tetracaine) 4% gel (30–​60 minutes prior), or needle-​less lidocaine application via pressurized gas to propel medication through the skin (1 minute prior). 2 Sucrose or breastfeeding a few minutes prior to (sucrose) and during the procedure (breastfeeding) for infants 0–​12 months. 3 Comfort positioning: “Do not hold children down”. For infants, consider parent–​infant skin-​to-​skin (kangaroo care) contact. If not feasible, consider swaddling, warmth, facilitated tucking, and/​or co-​ bedding for twins. For children aged 6 months and older, offer the upright position with parents holding them on their lap or sitting nearby. 4 Age-​appropriate distraction, such as toys, books, blowing bubbles, or pinwheels for younger children, and stress balls and using apps, videos, or games on electronic devices for older children. Adapted with permission from Friedrichsdorf SJ.  and Goubert L.  (2020). Pediatric pain treatment and prevention for hospitalized children. PAIN Reports. 5(1):  e804. Published by Wolters Kluwer Health, Inc. on behalf of The International Association for the Study of Pain. DOI:10.1097/​PR9.0000000000000804.

anesthetic propofol, often with the addition of an opioid such as fentanyl (Anghelescu et al., 2013). Neuropathic pain3 Neuropathic pain is defined by the International Association for the Study of Pain as pain arising as a direct consequence of a lesion or disease affecting the “somatosensory” (i.e., nervous) system. A  significant number of pediatric palliative patients may develop neuropathic pain as a result of nerve damage caused by the underlying condition and/​ or the disease-​ directed treatment (Portilla et  al., 2013). In addition to nonsteroidal anti-​inflammatory drugs (NSAIDs) and opioids (for the initial post-​traumatic hospitalization only) several adjuvant pain medications, including gabapentinoids, low-​dose tricyclic antidepressants (TCAs), alpha-​agonists, and/​or N-​methyl-​d-​aspartate (NMDA) channel blockers, are commonly administered to mitigate pain. Although several medications may assist with controlling neuropathic pain, physical therapy and psychology (and for some patients nerve blocks) are usually required components of excellent pain control and should not be omitted (see Chapter 22). Visceral pain Visceral pain results from the activation of nociceptors of the thoracic, pelvic, or abdominal viscera, and may be described by verbal children as poorly localized, dull, crampy, or achy. Examples include bladder spasms or intrahepatic tumors.

3 Section “Neuropathic pain” adapted by permission from Springer Nature: Treatment and Prevention of Pain in Children and Adults with Burn Injuries, pp. 323–​338 by Friedrichsdorf S.J. in Handbook of Burns Volume 1: Acute Burn Care edited by Jeschke M.G. et al. Copyright © 2020, Springer Nature Switzerland AG. https://​doi.org/​10.1007/​978-​3-​030-​18940-​2_​25.

Total pain (psycho–​spiritual–​emotional pain) The suffering that encompasses all of a child’s physical, psychological, social, spiritual, and practical struggles is referred to as total pain. The psychological and emotional impact of a serious illness results in real existing measurable pain to the child and the family; however, this pain cannot be treated by opioids (or other analgesics), but rather by addressing those needs through family and social support, as well as an interdisciplinary care team, which includes disciplines such as social work, chaplaincy, and/​or psychology (Friedrichsdorf and Goubert, 2020). Chronic pain (primary pain disorder)4 A significant subset of children with serious illness also experience chronic pain in addition to their acute, neuropathic, visceral, and total pain. Pain can persist after healing of the underlying tissue injury (including surgery). Children with an underlying serious illness may be at higher risk of developing chronic persistent pain. Common chronic pain locations include not only the previous tissue injury site, but also primary pain disorders (formerly functional pain syndromes), which include primary headaches (including tension headaches and migraines), centrally mediated abdominal pain syndromes (functional abdominal pain), and/​ or widespread pain in muscles, joints, and bones (Friedrichsdorf et al., 2016a). Effective treatments of these common pain disorders for children with serious illness during the palliative phase (less so during end-​of-​life or hospice care) usually does not rely on medications, but rather on four rehabilitative strategies (discussed in the next paragraph) utilized concurrently. Patients with primary pain disorders may need to be reminded that sometimes pain gets worse before it gets better, especially when they are deconditioned because of inactivity due to the underlying disease (see Chapter 24). The four rehabilitative strategies, as appropriate for children with serious illness and the progression of the life-​limiting disease, will be discussed in more detail later and include (1) physical therapy/​ exercise, (2) integrative therapies, (3) psychology, and (4) normalizing life. An effective pain control strategy appears to normalize function, which then improves pain (unfortunately, it is not the other way around). Specific strategies include returning to school or work, normalizing sleep, and normalizing exercise and social life, as much as possible in light of the underlying serious illness. Medications are usually ineffective for a large number of patients with chronic and persistent pain, if not accompanied by the aforementioned four strategies. Opioids are usually not indicated for chronic persistent pain (unless there is repetitive new tissue injury, such as in osteogenesis imperfecta or epidermolysis imperfecta, or advancing metastatic cancer). Some adjuvant analgesia, especially for nerve pain, appear to be well tolerated and might be effective, as shall be described.

4

  Section “Chronic pain (primary pain disorder)” adapted by permission from Springer Nature: Treatment and Prevention of Pain in Children and Adults with Burn Injuries, pp. 323–338 by Friedrichsdorf S.J. in Handbook of Burns Volume 1: Acute Burn Care edited by Jeschke M.G. et al. Copyright © 2020, Springer Nature Switzerland AG. https://doi.org/10.1007/978-3-030-18940-2_25

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Pain in nonverbal children with impairment of the central nervous system Most published data in PPC originates children with cancer. However, the majority of pediatric patients with serious illness in high-​income countries do not have cancer, but metabolic, genetic, or neurological diseases, with impairment of the central nervous system (CNS), which leaves them nonverbal (Friedrichsdorf et al., 2017; Feudtner et al., 2011). Pain in these nonverbal children can be measured by multidimensional observational tools (Voepel-​Lewis et al., 2008), which is complicated by the fact that pain processing may be altered in many children (Defrin et al., 2015). Identifying the exact underlying pain pathology in nonverbal pediatric patients with impairment of the CNS who have underlying genetic, metabolic, or progressive neurological diseases remains a challenge for clinicians and caregivers alike. The pain experience may be fueled by the underlying disease, comorbidities, and/​or painful procedures and interventions. Many children of this children may experience several of the following pathophysiologies concurrently: • acute somatic pain due to tissue injury (e.g., occult fracture, hip dysplasia, corneal abrasions, and dental abscess) • neuropathic pain • visceral pain (e.g., pancreatitis, bladder spasms, and constipation) • for patients with artificial hydration and nutrition (including feeding tubes), feeding intolerance and visceral hyperalgesia • chronic postoperative pain • primary pain disorder/​chronic pain (e.g., functional abdominal pain, primary headaches, medication overuse headaches, and widespread musculoskeletal pain) • spasticity/​contractures • reflux • delirium • nausea. A subgroup of these children may display episodes of dysautonomia and it is important to keep in mind that autonomic stress response, for example, changes in blood pressure, heart rate, temperature, respiratory rate, and epinephrine/​norepinephrine serum levels, usually do not correlate with severity of pain (Ledowski et al., 2012). For more information on pain in children with impairment to the CNS, please see Chapters 17 and 22.

Step 2: Treat underlying causes As always, when a child with serious illness presents with a distressing symptom, one needs to try to identify and treat the underlying disease process, if this is feasible and within the goals of care for this particular child and family. Untreated anxiety, depression, nausea, sleep disturbance, feeding intolerance, visceral hyperalgesia, fluid overload, constipation, seizure disorder, spasticity/​contractures, reflux, medication withdrawal, delirium, and so on may significantly contribute to the pain experience. A true palliative emergency may include tumor growth within the spinal cord, resulting in loss of bladder control and paralysis of the legs. Rapid treatment with radiation, glucocorticosteroids, and/​ or surgery may return the child to normal functioning for a period of time.

Step 3: Integrative (“nonpharmacological”) therapies Integrative modalities (sometimes referred to as complementary and alternative medicine; see Chapter 56) that are effective in the management of pain in PPC include active mind–​body techniques for verbal, interactive children, such as hypnosis, biofeedback, mindfulness, guided imagery, abdominal breathing, bubble blowing, apps, and yoga. Additional therapies include acupuncture, acupressure, aromatherapy, music/​art/​pet therapy, and massage. Active mind–​body techniques individually and collectively evoke pain modulation by engaging a number of mechanisms within the analgesic neuraxis (Friedrichsdorf and Goubert, 2020)  (see Chapters 51 and 52).

Step 4: Social work, rehabilitation, psychology, spirituality, and/​or child life It is now accepted standard of care that children with serious illness do need to receive care by an interdisciplinary clinical team. A physician or a nurse practitioner alone cannot provide comprehensive excellent pain treatment for this population. It is essential to address comorbidities, such as anxiety, depression, sleep disturbances, poor exercise tolerance/​being deconditioned, school absenteeism, as well as total pain. Social work All advanced PPC teams now include social workers, who provide or coordinate psychoeducation, supportive counseling, parent guidance, and empower appropriate limits and expectations. Social workers help in processing the experience of this complex journey and provide assessment, whether the 24-​hour care of a child at home has become unattainable for the parents/​caregivers and respite care (volunteer support, home care nursing, hospitalization, and/​or referral to freestanding hospice house or unit) needs to be implemented. Rehabilitation Physical therapy and exercise are key modalities in the treatment of children with serious illness, who often also experience chronic pain/​primary pain disorder as a result of their underlying condition resulting in low exercise tolerance and deconditioning (Lynch-​ Jordan et  al., 2014; Odell and Logan, 2013). Patients with serious illness usually have a lower physical activity level resulting in chronic pain and physical activity has been shown to reduce the risk for depression. “In patients participating in a rehabilitative pain program, the rate of improvement in function was significantly more rapid than the decrease in pain” (Friedrichsdorf and Goubert, 2020; Lynch-​Jordan et al., 2014) (see Chapter 53). Psychology Children with serious illness frequently suffer from pain and other distressing symptoms, and often are not able to interact at home with siblings, friends, and attending school. These children experience total pain (i.e., suffering that encompasses all of a child’s physical, psychological, social, spiritual, and practical struggles). Anxiety, depressive, and behavior disorders are risk factors of pain in children with serious illness. Also, parental distress and anxiety is naturally increased when taking care of a child in palliative care and offering coping strategies to caregivers appears to be effective to increase the patient’s quality of life. While there are no published PPC data, “psychological treatments significantly reduce pain intensity

CHAPTER 29  Pain treatment and prevention in pediatric palliative care

that is reported by children and adolescents with headache, abdominal pain, and musculoskeletal/​joint pain” (Friedrichsdorf 2016a, p.10; Palermo et al., 2010; Eccleston et al., 2014). “Cognitive behavioral therapy (CBT) led to significant improvements in pain coping, catastrophizing, and efficacy that were sustained over time in adolescents with chronic pain” (Friedrichsdorf 2016a, p. 10; Kashikar-​ Zuck et al., 2013) (see also Chapter 10). Spirituality Religion, spirituality, or life philosophy play an important role in the lives of most parents whose children are receiving PPC. Spirituality screenings tools, such as the Faiths or Beliefs; Importance or Influence; Community; Address these issues (FICA), have been successfully implemented into clinical PPC (Borneman et al., 2010). A  link between spiritual coping and quality of live in adolescents with serious illness has been described (Grossoehme et al., 2013). Child life Child life specialists work with children and families in medical settings to help them cope with the challenges of hospitalization, serious illness, and disability. They provide children with age-​appropriate preparation for medical procedures, pain treatment/​prevention and teaching coping strategies engaging in age-​appropriate play and self-​ expression activities. When dealing with seriously ill children they may also provide information, support, and guidance to parents, siblings (including memory-​making), and classmates.

Step 5: Basic analgesia and opioids The basic analgesics includes the nonopioid analgesics acetaminophen (paracetamol), NSAIDs, and COX-​2 inhibitors. In some countries dipyrone (metamizole), is included under basic analgesia (de Leeuw et al., 2017). Acetaminophen appears to be opioid-​sparing and works synergistically with opioids at normal opioid starting doses, but with high-​dose opioids does not seem to add benefit (Israel et al., 2010). Celecoxib (a COX-​2—​more than COX-​1—​inhibitor) is commonly used in children with serious illness if classical NSAIDs are contraindicated (e.g., owing to bleeding risks or gastrointestinal side effects). It is unclear whether it displays less renal toxicity versus classic NSAIDs (Friedrichsdorf and Goubert, 2020). Dipyrone (metamizole) has analgesic, spasmolytic, and antipyretic effects, and is used to treat pediatric pain in many parts of the world (de Leeuw et al., 2017). Owing to a possible risk of agranulocytosis with the use of dipyrone, it has been banned in a number of countries, including the US. The analgesic efficacy of IV dipyrone appears similar to that of IV acetaminophen (paracetamol) (de Leeuw et al., 2017). There is no evidence to support that dipyrone is equivalent or even superior to NSAIDs in pediatric pain (de Leeuw et al., 2017). Opioids Opioids remain a mainstay in the analgesic treatment of acute somatic pain (and dyspnea) in children with serious illness (see Chapter 45). “Weak” opioids Weak opioids are those which carry a ceiling effect (i.e., escalating the dose beyond recommended maximum dose usually does not

provide increased analgesia but increases risks of adverse effects). This heterogenous group includes mixed agonist/​antagonist, partial opioid agonists, and multimechanism analgesics. With the exception of tramadol, and possibly buprenorphine, these weak opioids can usually not be recommended in children with serious illness. Mixed agonist/​antagonist (such as nalbuphine and butorphanol) can precipitate withdrawal symptoms when used in opioid-​ tolerant patients. Tapentadol, a μ (and, to a lesser degree, δ and κ) receptor agonist and a norepinephrine reuptake inhibitor is a close chemical and structural relative of tramadol. So far it is unclear whether it has any advantage over tramadol (Prommer, 2010). The high price and lack of pediatric data currently makes it an unlikely choice when there are inexpensive, safe, and efficacious alternatives. The use of codeine and hydrocodone can no longer be recommended, owing to polymorphism of the CYP 2D6 enzyme metabolizing codeine to morphine and hydrocodone to hydromorphone, with deaths reported in CYP2D6 ultrarapid metabolizers for both medications (Morrow and Faris, 1987; Madadi et  al., 2010; Friedrichsdorf et al., 2013) (see Chapter 45). Tramadol5 Tramadol plays in important role in PPC. It is a multimechanistic analgesic commonly used worldwide for pediatric pain management and in PPC (Pruskowski and Arnold, 2015; Moore and McQuay, 1997; Bamigbade and Langford, 1998a, 1998b). Studies examining efficacy and safety have been conducted worldwide, and support its use in children (Finkel et al., 2002; Murphy et al., 2010; Alencar et  al., 2012; Friedrichsdorf et  al., 2015c). The analgesic potency of tramadol falls somewhere between ibuprofen and morphine (Hain et  al., 2005). Although only commercially available in tablet form in the US, an oral suspension may be compounded into a stable and inexpensive liquid (Allen Lloyd, 2006). Outside the US, both IV and liquid tramadol are readily available. Although tramadol is metabolized into the more potent O-​desmethyltramadol, tramadol (unlike codeine) itself appears to be a potent analgesic. For poor CYP2D6 metabolizers, the parent compound tramadol remains active; hence, these individuals experience no decrease or only a slightly diminished analgesic effect, possibly supported by a parallel CYP3A4 metabolism (Hain et  al., 2005). Tramadol administration may result in fewer side effects than with full µ-​opioid agonists (Desmeules, 2000) and tramadol appears far safer than codeine in relation to risk of respiratory depression. One study examining statewide poison control center data in the US (Marquardt et al., 2005) reported no respiratory depression in children 6000 pediatric tramadol scripts have been filled in 2018, mostly for outpatient postoperative analgesia for procedures such as tonsillectomy. However, it plays a key role in treating neuropathic pain and visceral hyperalgesia (Friedrichsdorf et  al., 2017)  presenting as episodes of inconsolability in children with neurological, metabolic, or chromosomally based conditions with impairment of the CNS, such as mitochondropathies. Adapting treatment to the individual child Analgesic treatment should be individualized according to the child’s pain and response to treatment, and frequently reassessed and modified as needed. Opioid dose titration for severe acute pain is usually performed at 50% increments of the current dose (not of the starting dose), if no oversedation or significant opioid-​induced adverse effects are present (see Tables 29.1, 29.2, and 29.3 for starting doses). These increments could be far higher or lower depending upon the clinical circumstances. If there are no dose-​limiting side effects such as oversedation or respiratory depression, the opioid can be titrated to effect and increased accordingly (Friedrichsdorf, 2014). Because of their increased risk of tolerance, some children may require extremely high doses of opioids (sometimes more than 10–​100 times the starting dose) to control severe acute or neuropathic pain (usually in children with advanced cancer). In our clinical practice, we usually rotate the opioid if a high dose (e.g., >10 times a normal starting dose) appears to be ineffective, with methadone commonly used in children with serious illness. Adjuvant analgesics (e.g., low-​dose TCAs, gabapentinoids, low-​dose ketamine, and α-​agonists) may serve as valuable adjuncts, and they are usually given in addition to, not in lieu of, opioids (Friedrichsdorf and Nugent, 2013; Horvath et al., 2015). Buprenorphine This opioid displays a somewhat unique pharmacology compared to what we are otherwise used to and is commonly used in PPC patients in the UK and other European countries. As a partial μ-​ opioid receptor agonist with a long duration of action, it can cause an “opioid blockade.” It is also a δ-​opioid receptor antagonist and κ-​ opioid (partial agonist) receptor antagonist (i.e., possibly less likely to cause psychomimetic effects such as dysphoria/​hallucinations). However, the main liver metabolite, norbuprenorphine, is a partial κ-​agonist, and full μ-​and δ-​opioid receptor agonist, and, as such, might be antagonized by buprenorphine (Huang et al., 2001; Yassen et  al., 2006). In the US, transdermal patches are available at low doses only: 5, 10, and 20 μg/​h, whereas in most other countries, such as the UK, patches releasing 35, 52.5, and 70 μg/​h buprenorphine are available. In practice, this drug might be useful in children with mild-​to-​moderate pain with nonmalignant life-​limiting conditions, especially when there is concern of opioid-​induced constipation. “Strong” opioids6 This group of drugs are full μ-​opioid receptor agonists, with methadone representing additionally a multimechanistic analgesic.

6 Section “ ‘Strong’ opioids” adapted by permission from Springer Nature: Treatment and Prevention of Pain in Children and Adults with Burn Injuries, pp. 323–​338 by Friedrichsdorf S.J. in Handbook of Burns Volume 1: Acute Burn Care edited by Jeschke M.G. et al. Copyright © 2020, Springer Nature Switzerland AG. https://​doi.org/​10.1007/​978-​3-​030-​18940-​2_​25.

CHAPTER 29  Pain treatment and prevention in pediatric palliative care

Table 29.1  Basic analgesia for children older than 6 months. Medication (route of administration)

Pediatric dose

Maximal dose

Dosing interval Comment

PO/​PR

10–​15 mg/​kg

q6h • 6–​24 months = 60 mg/​kg/​day • >2 years: 90 mg/​kg/​day (maximum 650 mg q6h)

IV

2 years (13 years (>50 kg) = 1000 mg 4000 mg/​day

q6h

Ibuprofen (PO)

5–​10 mg/​kg

400–​600 mg/​dose (2400 mg/​day)

q6h

Ibuprofen–​sodium (PO) 256 mg tablet = 200 mg ibuprofen

5(–​10) mg/​kg

200–​(400) mg/​dose

q6h

Fast-​acting, compared to regular ibuprofen: Onset after 10 minutes, lasts longer, and only half the dose required

Ketorolac (IV)

6–​24 months = 0.25 mg/​kg

30 mg/​dose

q6h

Recommend dosing no longer than 5 days

>2 years = 0.5 mg/​kg

30 mg/​dose

q6h

Recommend dosing no longer than 5 days

5–​6 mg /​kg

250–​375 mg/​dose

q12h

1–​2 mg/​kg

100 mg

q12–​24h

Acetaminophen/​Paracetamol

Due to high price only if enteral rectal or oral administration contraindicated; re-​evaluate daily

NSAIDs

Naproxen (PO) COX-​2 inhibitor Celecoxib (PO)

If classic NSAIDs contraindicated; safety and efficacy has been established only in children ≥2 years of age and for a maximum of 6 months of treatment in JRA

PO, by mouth (or enterally via gastric/​jejunal tube); PR, rectally; IV, intravenous; NSAID, nonsteroidal anti-​inflammatory drug; COX, cyclooxygenase; JRA, juvenile rheumatoid arthritis. Reproduced with permission of Stefan Friedrichsdorf, Medical Director, Center of Pediatric Pain Medicine, Palliative Care and Integrative Medicine, Benioff Children’s Hospitals in Oakland and San Francisco, University of California at San Francisco (UCSF), USA.

Morphine, fentanyl, oxycodone, and hydromorphone (in the UK only diamorphine) are very effective in providing analgesia (and treatment of dyspnea and end of life) at equianalgesic doses (see Tables 29.1, 29.2, and 29.3 for starting doses). One opioid is not “stronger” or “more effective” than the other. However, especially for children with serious illness, opioid rotation may be necessary if tolerance develops or dose-​limiting opioid toxicity occurs. A switch from one opioid to another is often accompanied by a change in the balance between analgesia and side effects (Drake et al., 2004). A favorable change in the opioid side effect profile may be experienced if there is less cross-​tolerance at the opioid receptors mediating analgesia than at those mediating adverse effects. If rotating opioids because of decreasing effectiveness or limiting side effects (i.e., because of incomplete cross-​tolerance), it can begin at around 50% of the equianalgesic dose and be titrated to effect. However, the required decrease for incomplete cross-​tolerance may be higher or lower, depending on the clinical context of the individual patient (Friedrichsdorf, 2014). Opioid-​ associated side effects (e.g., constipation, pruritus, and nausea) should be anticipated and treated accordingly. Of note, in children with serious illness with renal and/​or liver failure, opioids with no active metabolites, namely fentanyl or methadone, are preferred if accumulation of “bad metabolites” such as morphine-​3-​glucoronide (for morphine) or hydromorphone-​3-​ glucoronide (for hydromorphone) cause side effects (see Chapter 45).

Methadone7 Methadone is an excellent opioid choice in advanced pediatric analgesia and pediatric palliative care, but it remains underutilized (Davies et  al., 2008; Anghelescu et  al., 2011; Fife et  al., 2016). It is a full µ (and partial δ and κ) opioid receptor agonist, a NMDA channel blocker, and a presynaptic blocker of serotonin and norepinephrine reuptake. Methadone has the advantage of a long half-​life (allowing every 8–​12-​hour dosing), high effectiveness in complex pain conditions, decreased incidence of constipation, lack of active metabolites, and safe usage in renal failure and in stable liver disease. Cross-​tolerance is believed to be avoided secondary to its activity at NMDA receptors. There are several disadvantages, including wide dosing variation, a long half-​life (which may lead to accumulation, making quick titration difficult), and a more complex equianalgesic conversion, which requires longer and closer patient observation than with other opioids. Methadone displays typical opioid-​induced side effects such as sedation, nausea, constipation, and, at higher doses, opioid-​ induced neurotoxicity (including myoclonus, hallucinations, and nightmares) and

7 Section “Methadone” adapted with permission from Friedrichsdorf S.J. (2019). From Tramadol to Methadone Opioids in the Treatment of Pain and Dyspnea in Pediatric Palliative Care. Clin J Pain. 35(6): 501–​508. DOI: 10.1097/​ AJP.0000000000000704.

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Table 29.2  Opioid starting doses for children older than 6 months with acute pain. • Dosing range: Younger children with smaller pain start on the lower end of the range; older children with severe pain start on the higher end of the dosing range; doses will then be titrated to effect. • Maximum per kg dose capped at 50 kg body weight. • For strong opioids: Rescue (“breakthrough” or “PRN”) dose = 10% of total daily dose. Medication (route of administration)

Paediatric dose

Maximal dose

Dosing Comment interval

Partial µ-​receptor agonists (“weak opioid”) Tramadol (PO, SL, PR)

0.5–​1 mg/​kg 25–​50 mg (maximum 100 (maximum 2 mg/​ mg)/​dose dose)

q4–​6h

Analgesic ceiling effect: maximum 8 mg/​kg/​day (>50 kg: maximum of 400 mg/​day)

Full µ-​receptor agonists (“strong opioids”) Morphine (PO, SL, PR)

0.15–​0.3 mg/​kg

7.5–​15 mg/​dose

q4h

Morphine (IV, SC)

0.05–​0.1 mg/​kg

2.5–​5 mg/​dose

q4h

Oxycodone (PO, SL, PR)

0.15–​0.3 mg/​kg

7.5–​15 mg/​dose

q6h

Oxycodone can be administered every 6 hours due to longer half-​ life; alternatively, may be given every 4 hours: 0.1–​0.2 mg/​kg q4h (maximum 5–​10 mg q4h)

Fentanyl (IV, SC, SL, transdermal, 0.5–​1 µg/​kg buccal)

25–​50 µg

NA

Due to short half-​life, consider starting continuous infusion 0.5–​1 µg/​kg/​h (maximum 50 µg/​h), if scheduled analgesia required

Hydromorphone (PO, SL, PR)

40–​60 µg/​kg

2,000–​3,000 µg (= 2–​3 mg)

q4h

Hydromorphone (IV, SC)

10–​20 µg/​kg

0.5–​1 mg

q4h

Multimechanistic full µ-​receptor agonists (“strong opioid”) Methadone (PO, PR, SL)

0.05–​0.1 mg/​kg

2.5–​5 mg

q8–​12h

Methadone should not be prescribed by those unfamiliar with its use! Its effects should be closely monitored for several days, particularly when it is first started and after any dose changes.

Methadone (IV, SC)

0.04–​0.08 mg/​kg

2–​4 mg

q8–​12h

Whereas in pediatrics due to high bioavailability about 80% of the enteral dose appears to be the equianalgesic IV dose (e.g. 1 mg PO = 0.8 mg IV), adult recommendations suggest 50% conversion (e.g. 1 mg PO = 0.5 mg IV)

PRN, pro re nata; PO, by mouth (or enterally via gastric/​jejunal tube); SL, sublingual; PR, rectally; IV, intravenous; SC, subcutaneous; NA, not available. Reproduced with permission of Stefan Friedrichsdorf, Medical Director, Center of Pediatric Pain Medicine, Palliative Care and Integrative Medicine, Benioff Children’s Hospitals in Oakland and San Francisco, University of California at San Francisco (UCSF), USA.

respiratory depression, with some case reports of hypoglycemia. Usual starting doses for opioid-​naïve children at the Pain Medicine and Palliative Care service at the Children’s Minnesota are 0.05–​ 0.1 mg/​kg/​dose (maximum 2.5–​5 mg PO q8–​12h) (Friedrichsdorf,

2019). For conversion rates from other opioids (via oral morphine equivalent), see Table 29.4. Despite its advantages, conversion to methadone remains complicated in pediatric patients. There are significant problems with

Table 29.3  Starting doses for patient (or nurse)-​controlled analgesia (PCA) pumps for children older than 6 months in acute pain. • Dosing range: Younger children with smaller pain start at the lower end of the range; older children with severe pain start at the higher end of the dosing range. • Doses will then be titrated to effect with escalation usually in (33–​) 50% increments both for continuous and PCA bolus dose. • PCA dose usually = continuous infusion (might differ in individual patients). • Maximum per kg dose capped at 50 kg body weight. • Consider adding low-​dose naloxone infusion 0.5–​2 µg/​kg/​h (maximum 25–​100 µg/​h) to treat potential opioid-​induced side effects, such as pruritus, nausea, constipation, urinary retention, hallucinations, etc. PCA dose

Maximum PCA dose (for patients >50 kg)

Continuous infusion (basal rate)

Maximum continuous infusion (for patients >50 kg)

Lock-​out time

Number of maximum boluses

500–​1000 µg (= 0.5–​1 mg)

10–​20 µg/​kg/​h

500–​1000 µg (= 0.5–​1 mg)/​h

5–​10 minutes

4–​6 boluses/​h

25–​50 µg

0.5–​1 µg/​kg/​h

25–​50 µg/​h

5–​10 minutes

4–​6 boluses/​h

100–​200 µg

2–​4 µg/​kg/​h

100–​200 µg/​h

5–​10 minutes

4–​6 boluses/​h

Morphine 10–​20 µg/​kg Fentanyl 0.5–​1 µg/​kg Hydromorphone 2–​4 µg/​kg

Reproduced with permission of Stefan Friedrichsdorf, Medical Director, Center of Pediatric Pain Medicine, Palliative Care and Integrative Medicine, Benioff Children’s Hospitals in Oakland and San Francisco, University of California at San Francisco (UCSF), USA.

CHAPTER 29  Pain treatment and prevention in pediatric palliative care

Table 29.4  Adjuvant analgesia for infants, children, and adolescents. Medication (route of administration)

Pediatric dose

Maximum dose (for patients >50 kg)

Dosing interval

Comments/​side effects

Gabapentin (PO)

6 mg/​kg (titrated up to 24 mg/​kg)

300 mg (titrated up to q8h 1200 mg) q8h

• In schoolchildren may start at lower doses to reduce risk of initial sedation • Can not be administered rectally (missing active transporter = no absorption) • Infants 3 months

Nortriptyline (PO)

0.1 mg/​kg (titrated to maximum 0.5 mg/​kg)

5 mg (titrated to maximum 25 mg)

qHS

• Despite the name, medication not potent as an antidepressant • Consider ECG to rule out QTc prolongation • For infants >3 months

Gabapentinoids

Alpha-​agonists

• Transdermal application usually 1:1 conversion to total daily enteral dose

NMDA channel blocker Low-​dose ketamine (IV)

TCAs

PO, by mouth (or enterally via gastric/​jejunal tube); IV, intravenous; NMDA, N-​methyl-​d-​asparate; PRN, pro re nata; qHS, every night at bedtime; ECG, electrocardiogram. Reproduced with permission of Stefan Friedrichsdorf, Medical Director, Center of Pediatric Pain Medicine, Palliative Care and Integrative Medicine, Benioff Children’s Hospitals in Oakland and San Francisco, University of California at San Francisco (UCSF), USA.

adult-​based conversion tables used in pediatrics, including tremendous interindividual variability in relative potency estimates; tolerance development with repetitive dosing (dose reduction 25–​ 75% or more for incomplete cross-​ tolerance, often inadequately portrayed); erroneous assumption that relative potency ratios remain irrespective of level of opioid; and no accounting for unidirectional cross-​tolerance or for the possibility of active metabolite accumulation. Methadone should not be prescribed by those unfamiliar with its use. Safe use requires that the effects of methadone should be closely monitored for several days, particularly when it is first started and after any dosing change (Friedrichsdorf, 2019). Opioids for chronic pain (primary pain disorders) Opioids should not be administered to PPC patients to treat their primary pain disorders, (i.e., chronic pain that extends beyond the expected time of healing which lacks the acute warning function of physiological nociception, even when they have an underlying

serious illness). Opioids may cause more harm than good in the treatment of primary pain disorders in children in palliative care, who, in addition to their serious illness, also display tension headaches/​migraines, and/​or chronic musculoskeletal pain/​fibromyalgia, and/​or functional abdominal pain/​centrally mediated abdominal pain syndrome. Opioids administered for primary pain disorders have low long-​term efficacy, a poor safety profile, and, commonly, a worse clinical outcome (Chaparro et al., 2014; Chen et al., 2013) Conversely, “in persistent pain conditions (i.e. long-​lasting and/​or repetitive nociceptive pain caused by tissue injury, such as in children with junctional epidermylosis bullosa, osteogenesis imperfecta, or advanced metastasized bone tumors (e.g. Ewing sarcoma)” (Friedrichsdorf et  al., 2016a, p.13) opioids do play an important role in long-​term analgesic management. Clinical experiences suggest that applying the 2012 World Health Organization (WHO) “Guidelines on the pharmacological treatment of persisting pain in children with medical illness” results in good pain relief for the majority of children with acute somatic pain

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SECTION 4  Pain in specific populations and diseases

in palliative care (World Health Organization, 2012). The WHO has recently retracted the guidelines and new guidelines are in the making. However, this author, probably like the vast majority of pediatric experts in the field, strongly believe that the correct use of analgesics, including opioids, will be a key pillar in a multimodal analgesic strategy to relieve pain in children with persisting pain due to medical illness. Analgesia administration relies on the following four key concepts: 1. “By the ladder”: Using a two-​step treatment strategy commencing with nonopioids and increasing to strong opioids 2. “By the clock”: Dosing at regular intervals 3. “By the appropriate route”:  Using the appropriate route of administration—​use the least invasive route of administration 4. “By the child”:  Adapting treatment to the individual child—​ individualize treatment according to the child’s pain and response to treatment. Dosing at regular intervals “by the clock”8 Regular scheduling ensures a steady blood level, reducing the peaks and troughs of PRN i.e., “as needed”) dosing. The “PRN only” method may take several hours and higher opioid doses to relieve pain and result in a vicious cycle of undermedication and pain, alternating with periods of overmedication and medication toxicity (APS, 2008). The “PRN only” method dosing might be appropriate if pain episodes are truly intermittent and unpredictable, such as in breakthrough pain. However, “PRN only” (without scheduled dosing) may translate into “patient receives nothing” or “give as little as possible.” Pain in children is systematically undertreated: In one study, 69% of hospitalized pediatric patients for whom analgesics had been ordered did not receive a single dose (Howard, 2003). Commonly used opioid drug regimens include immediate-​release oral morphine every 4 hours or controlled-​release morphine twice daily plus (for both strategies) a PRN dose of 10% of the 24-​hour morphine requirement as an hourly immediate-​release breakthrough pain medication as needed (Friedrichsdorf et  al., 2007; Friedrichsdorf and Postier, 2014) (Box 29.1 and Table 29.1). For starting doses of opioid continuous infusions plus patient-​(or nurse-​) controlled analgesia (PCA), see Table 29.2.

illness and their care providers. Absorption efficiency and kinetics are variable and may be influenced by the type of diet taken by the patient, delayed gastric emptying, and first-​pass metabolism (Friedrichsdorf and Nugent, 2013). Sublingual or buccal application The sublingual or buccal application of opioids (morphine, fentanyl, oxycodone, hydromorphone, and methadone) appear to be safe and well-​liked by children and caregivers. These routes are often the preferred route of pediatric opioid application if oral administration is not feasible and there is no IV access. The data for the absorption and bioavailability of sublingual opioid shows a wide variability, with morphine having a reported bioavailability ranging between 9% and 61% (Weinberg et  al., 1988; McQuay, 1986). Although morphine has hydrophilic properties (and thus it would appear not to be ideal for the sublingual route), the bioavailability of sublingual and orally administered morphine is not meaningfully different from that of lipophilic medications (Davis et al., 1993; Osborne et al., 1990). The sublingual bioavailability of oxycodone is 60 hours to reach peak concentrations in children), the inability to rapidly titrate drug delivery, and a long elimination half-​life (up to 24 hours) (Collins et al., 1999; Christensen et al., 1996). Patches can be applied to intact, healthy skin every 48–​72 hours. They must not be used for opioid-​naïve children; patients need to be on the equivalent of 30–​60 mg oral morphine/​24 hours to safely rotate to a fentanyl patch. The smallest patch delivers 12 µg/​hour. Asufficient immediate-​release breakthrough (rescue) opioid needs to be provided. Transdermal

Oral (or enteral) administration The oral route (or the enteral route via nasogastric tube or percutaneous endoscopic gastrostomy or jejunal tube) is convenient, noninvasive, and usually preferred by pediatric patients with serious

8  Section “Dosing at regular intervals ‘by the clock’ ” adapted with permission from Friedrichsdorf S.J. ‘Pain Management in Children with Cancer’. Oncopedia #72. Release on Oncopedia:  10/​22/​2013. https://​www.cure4kids.org/​ums/​ oncopedia/​case_​detail/​chapter/​index.php?id=72

9

 Section “Transdermal administration” adapted with permission from Friedrichsdorf S.J. ‘Pain Management in Children with Cancer’. Oncopedia #72. Release on Oncopedia: 10/​22/​2013. https://​www.cure4kids.org/​ums/​oncopedia/​ case_​detail/​chapter/​index.php?id=72

CHAPTER 29  Pain treatment and prevention in pediatric palliative care

fentanyl has a role in stable acute pain or drug tolerance, when children require opioids for more than a week. In our PPC practice buprenorphine and fentanyl patches are rarely used owing to the efficacy of tramadol and/​or methadone, mostly when IV and enteral administration is not possible (Friedrichsdorf, 2014). Rectal application10 Rectal (PR) application is unpopular by caregivers and verbal and some nonverbal children. The administration may result in wide variability in therapeutic blood levels through variable absorption. However, adequate analgesia can be achieved in children when suppositories (or liquid opioids via a small catheter rectally) are administered. In the US, suppositories are available for hydromorphone (3 mg), oxymorphone (5 mg), and morphine (5 mg, 10 mg, 20 mg, and 30 mg). Adult data show that controlled-​ (extended/​sustained) release morphine tablets may be administered PR at an oral:rectal conversion ratio of 1:1 (APS, 2008; Walsh and Tropiano, 2002). IV administration11 The IV administration of opioids has the advantage of predictable bioavailability and rapid onset, and it is especially advantageous when there is already a central line in place (venous cannulation needle pain needs to be relieved by topical anesthetics). Opioids administered intravenously will typically have an onset of action within 4–​6 minutes (faster for fentanyl) and are relatively easy to titrate (with the exception of IV methadone). Titration of strong opioids by parenteral administration allows for the adjustment of the medication to meet patients’ needs and minimizes the potential for toxicity by allowing patients to regulate administration. PCA or nurse-​controlled pumps, with (as opposed to perioperative adult practice) a continuous background infusion and an as-​needed bolus, often provide excellent pain management (George et  al., 2010). Opioids in pediatric PCA pumps may include morphine, fentanyl, hydromorphone, (also diamorphine, but not available outside UK), and, occasionally—​under certain circumstances—​methadone. In our PPC practice, we commonly discharge patients in their end-​of-​life period home with a portable pump delivering IV or SC continuous infusion plus patient-​or parent/​nurse administered PCA bolus. SC route12 Alternatively, opioid analgesics may be administered subcutaneously in the same dose as for IV administration in a high concentration–​low volume preparation (25 weeks’ Facial actions: GA—​18 months Brow bulge; eye squeeze; nasolabial furrow; mouth open; horizontal mouth; vertical mouth stretch; taut tongue; chin quiver

Preterm/​full-​ term neonates

Unidimensional multiple-​domains measures: Behavioral

Acute (procedural)

ABC Scale (Bellieni et al., 2005, 2007)

Unidimensional single-​domain measures: Behavioral

Pain scale (Author, year) Type of pain

Intrarater reliability: r = 0.98–​0.99 IRR: r = 0.86–​0.97 Construct validity: F = 41,3; p