GEOFFREY DAVID CHAMPIONMB, BS, MD, FRACP, FFPMANZCA

SELECTIVE CURRICULUM VITAE; PAEDIATRIC PAIN MEDICINE Including the Pain Research Unit, Sydney Children`s Hospital, current research and

abstracts

January 2016

Personal

Professional Address: St Vincent’s Clinic438 Victoria Street, Darlinghurst NSW 2010Tel: (02) 8382 6950, 8382 6951Fax: (02) 8382 6954email: dchampion@stvincents.com.au

Home address: 77 Cabramatta RoadMosman, NSW 2066Tel: (02) 9904 4321email: dchamp@bigpond.net.au

Degrees and Specialist MB, BS 1962, University of SydneyQualifications: MD by published work 1998, University of NSW

The anti-rheumatic gold complexes, chemistry, cellular metabolism, pharmacology and therapeuticsFellow, Royal Australasian College of Physicians 1972 (MRACP 1966)

Fellow, Faculty Pain Medicine, Australian and New Zealand College of Anaesthetists (FFPMANZCA). Foundation Diplomate 1999

University of NSW: Conjoint Associate Professor* St Vincent’s Clinical School (retired Jan. 2008)* School of Women’s and Children’s Health

Registration: Australian Department of HealthRegistration, Consultant Physician 1971

NSW Medical Board Registration renewed November 2014

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CAREER HIGHLIGHTS IN PAEDIATRIC PAIN MEDICINE AND RESEARCH Clinical pain medicine in the Paediatric Rheumatology Clinic at Sydney Children`s Hospital I attended the Paediatric Rheumatology Clinic from 1975 (maybe earlier) until 2012, forming for many of these years a team with John Ziegler and John Feller (we became the 3 grandfathers), and with Tony Yee. My attendance was honorary for many early years and the final years. From about1990, increasingly, I was consulted about the chronic pain disorders which were referred to the clinic. In the later years, some such patients benefited from referral to the Chronic Pain Clinic with it`s multidisciplinary/interdisciplinary advantages.

The Pain Research Unit at Sydney Children`s Hospital

The following description and history of the Pain Research Unit has been extracted, with some modification, from the website:http://www.schn.health.nsw.gov.au/parents-and-carers/our-services/pain-medicine/sch-0

The Pain Research Unit at Sydney Children’s Hospital, Randwick, is dedicated to improving the understanding, assessment and management of children’s acute and chronic pain through high quality interdisciplinary research. The Unit was established in the late 1980’s at a time when the field of paediatric pain was still very much in its infancy. Over the past 25 years the Unit has made significant, internationally-acknowledged contributions. The Pain Research Unit is located within the Sydney Children’s Hospital and benefits from close interaction and collaboration between researchers and clinicians. The research team is currently part of the Department of Pain and Palliative Care.

The Pain Research Unit at Sydney Children's Hospital (SCH) was founded by David Champion in the late 1980’s. After 25 years of leadership, Associate Professor Champion has since January 2014, passed this role to Dr Tiina Jaaniste who heads the research team. The early focus of the Pain Research Unit was primarily on children’s self-report and behavioural measures of pain intensity. Through his work in the Rheumatology Department, Dr Champion and colleagues such as Dr John Ziegler, considered what health professionals were responding to when making global assessments of pain based on children's behavioural responses. Investigations were carried out to determine whether children were able to provide reliable and valid information about their pain intensity levels. An appreciation of the ability of children to provide meaningful self-report information about pain intensity lead to researchers in the Pain Research Unit developing the Faces Pain Scale (FPS). The FPS, and more specifically the 6-face revised version of the scale (the Faces Pain Scale – Revised), has become one of the most widely used pain assessment tools for children worldwide. (www.iasp-pain.org/FPSR ).

Over many years, the team used the needle pain model for examining child and parental influences on children’s pain outcomes. Children’s ability to draw distinction between pain-related anxiety and pain intensity was considered. Our team found parental influences on pain-related distress following immunisation injections to be strongly evident as early as 4 to 6 months of age, and that brief parental guidance could improve outcomes.

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Over the years, the Pain Research Unit’s research interests have diversified. The team has developed particular expertise in areas such as: twin studies and paediatric pain; children’s attention and distraction; information provision; somatosensory testing in children, and pain and the family. In 2003 the Pain Research Unit was honoured to host the 6th International Symposium on Paediatric Pain in Sydney. A.Prof David Champion and Dr Belinda Goodenough were co-convenors, with A.Prof Champion also chairing the Scientific Program Committee. Tiina Jaaniste was the Secretary of the Steering Committee.

Up until 2007, the Pain Research Unit was a relatively independent unit funded through competitive grants, donations (notably BBM Ltd, Jim and Ruth Fay and Denis Ashton), and a fund-raising committee. This committee, chaired by Mrs Gay Windeyer, included friends of David and Caroline Champion (June Buckingham, Judy Bull, Caroline Champion ,Christine Cole, Claire Dixon, Merrie Lane, Helen Wright), and David`s sister Susan James, remarkably raised a quarter of a million dollars which helped the Unit through some difficult years. In 2007, the Sydney Children’s Hospital Foundation Gold Dinner and supplementary State Government funding enabled paediatric pain research to be incorporated into the Department of Pain and Palliative Care and supported as part of the broader department. This not only provided greater funding security, but also ensured a close and mutually beneficial link between the research and practice that is carried out by the team.

The Pain Research Unit consists of researchers from a range of disciplines with a variety of research interests. By working with medical students from the University of NSW, BSc (Med) Honours and Independent Learning Project Scheme students, funded through the School of Women`s and Children`s Health, also medical students from The Netherlands, and by extensive external collaboration, the research has been low cost.

The team’s current research priorities are:

1. Twin-family studies investigating possible genetic and other potential causal associations across various pain conditions.

2. Somatosensory testing with paediatric chronic pain patients. 3. Self-report pain assessment in very young children.4. Information provision to children and families 5. Chronic paediatric pain and the family. 6. Paediatric chronic pain trajectory

High quality research needs to shape understanding and to shape practice. The role of Pain Research Team is thus to:

1. Identify key questions in the understanding, assessment and management of children’s pain.

2. Identify the best strategy(-ies) for answering important questions: Can the question be answered with a narrative or systematic review of the literature? Is a new study needed? What is the most appropriate study design?

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3. Support clinicians and students in their ability to identify key questions and in their ability to find answers. This may involve participation in educational meetings, collaboration, and the provision of supervision.

4. Disseminate information from recent studies and articles to relevant stake holders (e.g., health professionals, patients, families, community).

5. Advocacy for greater awareness of and response to all aspects of pain medicine in infants, children and adolescents with a view to improved experiences and outcomes for these young patients and thus eventually a reduced burden of pain in adults.

The Dutch connection

From 1993 to the present we have benefited from the conscientious research contributions by students from The Netherlands in their student electives. This connection was initiated by Huda Abu-Saad, Professor of Nursing, because of a common interest in pain measurement and assessment. The first student was Suzanne Arts (Reference 5) and we have been fortunate to have received a student virtually every year since. The current student, Natasja Lammers, is continuing a recent collaboration with Perth colleagues from Curtin University and University of Western Australia utilising data from the Raine birth cohort.

Self-report measures of pain intensity, particularly Faces Pain Scales

The publication Bieri D, Reeve RA, Champion GD, Addicoat L, Ziegler JB (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 1990; 41:139-150), written by GDC after meticulous research involving 553 children by Daiva Bieri, has received 839 citations. It was the third most cited publication in paediatric pain 1975-2010.

Although not published until 5 years later, the publication by Goodenough B, Piira T, von Baeyer CL, Chua K, Wu E, Trieu JDH, Champion GD (Comparing six self-report measures of pain intensity in children. The Suffering Child 2005; 8:19 June. http://www.usask.ca/childpain/research/6scales/6scales.pdf), reveals the initial painstaking art work by Duc Trieu (medical student) involving 100 just noticeable differences from first to last face, enabled the effective collaboration between Belinda Goodenough of our Pain Research Unit and Prof Carl von Baeyer and Canadian author Hicks and co-authors to reduce the faces to 6 thus resulting in a 0-5 metric applied as a 0-10 scale. This derivative scale by Hicks CL, von Bayer CL, Spafford PA, von Korlaar I, Goodenough B (The Faces Pain Scale – Revised: toward a common metric in pain measurement. Pain 2001; 93:173-183), The Faces Pain Scale-Revised (FPS-R) has been endorsed by the International Association for The Study of Pain (999 references available through the IASP website) and cited 956 times. It is an international standard for children especially in the 5-12 years age range, but has also been applied for adults including those with cognitive problems.

Champion GD, Goodenough B, von Baeyer CL and Thomas W (Reference 10) wrote the most comprehensive review yet published on self-report measures of pain in children. References 13, 17 and 21 also focused on facial expression and related

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scales. Our current pain assessment research includes a three face Canadian scale for 3-4 year olds.

Twin family case-control studies into the genetics and associations of the common paediatric primary pain disorders

The first paediatric pain publication by GDC was a modest review about growing pains. Shanthi Pathirana elected to study growing pains for her BSC Med Hons thesis for which she received first class Honours in 2009. In her case-control study on growing pains, in 69% of the cases the condition was familial. That led to the first twin family case-control study in collaboration with the Australian Twin Registry in which we found that growing pains was probably genetically influenced and genetically associated with restless legs syndrome (reference 28).

The second twin family case control study has had broader aims, investigating the genetic influence and associations of common primary pain disorders of childhood. A selection of abstracts from 2015-6 is included at the end of this CV. Six sub-studies have been completed and manuscripts are in preparation for submission for publication in 2016. The abstract of the first paper is presented here:

Common paediatric primary pain disorders: clinical comorbidities and associationsBott A, Donnelly T, Bui M, Goh S, Jaaniste T, Chapman C, Crawford M, HopperJ, Champion D. Background Childhood primary pain conditions (non-migraine headache, migraine, recurrent abdominal pain, growing pains, low back pain) and chronic pain tend to associate, and have significant implications for later life. Emerging evidence suggests likely associations between these pain conditions and restless legs syndrome, iron deficiency, anxiety and depression. The aim of this twin family case-control study was to investigate these associations to facilitate subsequent research into shared causal influences. Methods Surveys were sent to twin families via the Australian Twin Registry across 3 phases, with 1189 evaluable responses received. The lifetime prevalence of the common primary pain disorders of childhood and of chronic pain, restless legs syndrome and iron deficiency, and last 6-month prevalence of anxiety and depression were determined by questionnaires. Random-effects logistic regression modelling was used to investigate univariate and multivariate associations between the conditions. Results Associations were found between each of the primary pain conditions and chronic pain, and between the pain conditions with restless legs syndrome, iron deficiency, anxiety and depression at the univariate level. Subsequent multivariate analyses revealed a number of significant associations exemplified by chronic pain with migraine (OR=3.61, p<0.001), headache (OR=2.36, p<0.01), recurrent abdominal pain (OR=6.15, p<0.001), RLS (OR=2.01 p<0.05) and iron deficiency (OR=3.70, p<0.001). Iron deficiency also remained significant in multivariate analyses predicting migraine, chronic pain and RLS.Conclusions The implication of the associations is that the primary pain conditions, chronic pain, restless legs syndrome, iron deficiency, anxiety and depression are likely to involve substantial common causal influences such as shared genes.

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A guiding model for the twin family study on primary paediatric pain disorders and how they tend to be associated in individuals and families was published in the Journal of Pediatric Psychology (Reference 26) and is presented below:

Below is an hypothetical model in progress as we increasingly understand the causal influences on the common paediatric primary pain disorders and their associations. This model was developed together with Henry Vo and Aneeka Bott.

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In September 2013, based on our relationship with the Australian Twin Registry, we were honoured to co-host a function for Princess Mary and Crown Prince Frederick of Denmark with Professor John Hopper and the Public Relations Department of Sydney Children`s Hospital. Princess Mary is the Patron for the Australian and Danish Twin Registries and had expressed an interest in knowing more about twin research. The function involved PowerPoint presentations, meeting with child and adolescent twins who had been involved in our research and their families, and lunch. It was a very enjoyable occasion.

CURRENT HOSPITAL AND PROFESSIONAL APPOINTMENTS

St Vincent’s Clinic, Consultant Physician in Rheumatology, Musculoskeletal Medicine and Pain Medicine, recently limited to medico-legal practice.Chairman, Department of Rheumatology (1991-1996). Retired from adult medical

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private practice January 2008.

Sydney Children's Hospital (formerly Prince of Wales Children's Hospital), Sydney.Honorary/Visiting Consultant Physician in Rheumatology (Paediatric) (1974-2013). , also Honorary/Visiting Physician in Pain Medicine (2008-2013).

Founder, Director, Pain Research Unit (1990-2012). Currently Honorary Associate, Pain Research Unit, Department of Anaesthesia and Pain Medicine, SCH. The Pain Research Unit from 2001 was incorporated into the Department of Anaesthesia and Pain Medicine.Sydney Children`s Hospital Pain Research Unit website:http://www.schn.health.nsw.gov.au/search/site?query=pain+research

Conjoint Associate Professor, UNSW School of Women’s and Children’s Health (2003).

PREVIOUS HOSPITAL APPOINTMENTS IN PAEDIATRIC RHEUMATOLOGY

1969-69 Research Fellow, Medical Research Council Rheumatism Unit, Canadian Red Cross Memorial Hospital, Taplow, England.

1970-71 Research Fellow, Division of Rheumatology, Department of Medicine, University of California at Los Angeles, USA.

1975-2012 Visiting Physician in Paediatric Rheumatology, Prince of Wales Childrens Hospital/Sydney Children`s Hospital. Increasing focus on pain medicine within the Paediatric Rheumatology Clinic from 1990.

TEACHING

Medical Undergraduate: In recent years to the present supervision of UNSW students for BSc Med Honours and Independent Learning projects.

Post-graduate: Presentations and lectures at National and International conferences and to numerous other organisations from 1987.

MEDICAL AND SCIENTIFIC ORGANISATIONS RE PAEDIATRIC PAIN MEDICINE

Membership, and offices held:

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Faculty of Pain Medicine, Australian and New Zealand College of AnaesthetistsFellow, Foundation Diplomate (1999-)

International Association for the Study of Pain (IASP)Member, Scientific Program Committee for World Pain Congress representing paediatric pain and rheumatology (1993-1996)Member, Special Interest Group on Pain in Rheumatic Disease (1997-2005), Musculoskeletal pain (2013- ), genetics and Pain (2012- )Member, Special Interest Group on Pain in ChildhoodCouncillor (1990-1994)

Member, Scientific Program Committee, Third International Symposium on Paediatric Pain, Philadelphia (1994)Convenor, Chairman of Scientific Program Committee, Member Local Arrangements Committee, Sixth International Symposium on Paediatric Pain, (Sydney 2003)

American Pain SocietyMember (1998-)

The Australian Pain SocietyMember (circa 1980)

EDITORIAL BOARD IN PEDIATRIC PAIN

Paediatric Pain LetterEditorial Board member (1996-2003)

RESEARCH GRANT REVIEW APPOINTMENTS

National Health and Medical Research Council:Member, Panel of Independent Assessors (1981-2012)

NATIONAL HEALTH AND MEDICAL RESEARCH COUNCIL GRANTS PAEDIATRIC

1982 Champion GD, Reeve R. Concepts and measurement of pain in children. $6,665.

1997-8. Champion GD, Goodenough B, Zeigler J, Taplin JE. Pain in children: age-related effects on measures of intensity, unpleasantness and coping. $127,950.

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PRESENTATIONS AT SCIENTIFIC MEETINGS

In the past 4 years I have been author or co-author of 30+ presentations at national and international conferences, particularly in paediatric pain medicine. A presentation at the International Pain Genetics Conference in Miami, February 2012, was awarded the best clinical presentation. The presentation to the ASM of the Faculty of Pain Medicine, ANZCA May 2013 was awarded the best free paper presentation. The papers presented in 2015 and accepted for presentation in March 2016 for the ASM of the Australian Pain Society are listed at the end of this document.

SUPERVISION OF STUDENT RESEARCH PROJECTS

I have in recent years supervised or co-supervised University of NSW medical students in an honorary

capacity, averaging 3/year for Independent Learning Projects and two BSc (Med) Hons degrees (first class).

This supervision is reflected in the publications and research presentations listed below.

I have also formally supervised numerous Dutch student elective research projects, principally in recent

years in association with the University of Groningen.

All personal research activities since 1975 have been self-funded except for sessional payments 2009-April 2012 from a Sydney Children`s Hospital Foundation grant.

PUBLICATIONS IN OR RELEVANT TO PAEDIATRIC PAIN

Publications of original research and clinical studies and commentaries in or relevant to paediatric pain medicine in refereed journals (34 of 133 total publications):

1. Champion GD. Growing pains. Limb pains in children with no organic disease. Patient Management. 1985; 14:117-121.

2. Lee EJD, Williams KM, Day RO, Graham GG, Champion GD. Stereoselective disposition of ibuprofen enantiomers in man. Br J Clin Pharmacol 1985; 19:669-674.(274 citations. This paper has been deemed a Citation Classic by

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the British Journal of Pharmacology and reprinted with commentaries in a Special Issue of the Journal: Volume 58, Issue 7, December 2004, S759-767).

3. Ungerer JA, Horgan B, Chaitow J, Champion GD. Psychosocial functioning in children and young adults with juvenile arthritis. Pediatrics 1988; 81:195-202.

4. Bieri D, Reeve RA, Champion GD, Addicoat L, Ziegler JB. 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 1990; 41:139-150. (839 citations. Third most cited publication in paediatric pain 1975-2010. Also 956 citations of the derivative paper: Hicks CL, von Bayer CL, Spafford PA, von Korlaar I, Goodenough B. The Faces Pain Scale – Revised: toward a common metric in pain measurement. Pain 2001; 93:173-183).

5. Arts SE, Abu-Saad HH, Champion GD, Crawford MR, Fisher RJ, Juniper KH, Ziegler JB. Age-related response to lignocaine-prilocaine (EMLA) emulsion and effect of music distraction on the pain of intravenous cannulation. Pediatrics 1994; 93:797-801.

6. Johnston R, Spence SH, Champion GD, Ziegler JB. Pain, affect, and cognition in children: 1. The influence of affective state on pain in children. Proceedings of the 7th World Congress on Pain. Progress in Pain Research and Management, Vol 2, ed. Gebhart GF, Hammond DL, Jensen TS. Seattle, IASP Press, 1994:869-875

7. Goodenough B, Addicoat L, Champion GD, McInerney M, Young B, Juniper K, Ziegler JB. Pain in 4 to 6 year old children receiving intramuscular injections: a comparison of the Faces Pain Scale with other self-report and behavioural measures. Clinical Journal of Pain 1997; 13:60-73.

8. Goodenough B, Kampel L, Champion GD, Nicholas MK, Laubreaux L, Ziegler JB, McInerney M. An investigation of the placebo effect and other factors in the report of pain severity during venipunctur in children. Pain 1997; 72:383-391.

9. Goodenough B, Champion GD, Laubreaux L, Tabah L, Kampel L. Needle pain severity in children: does the relationship between self-report and observed beha- viour vary as a function of age?Australian Journal of Psychology 1998; 50:1-9.

10. Champion GD, Goodenough B, von Baeyer CL, Thomas W. Self-report measures of pain in children. In: McGrath PJ, Finley GA eds. Measurement of Pain in Infants and Children. Progress in Pain Research and Management. Volume 10. IASP Press (International Association for the Study of Pain). 1998: 10;123-160

11. Champion GD, Kong JHN, Goodenough B. medical considerations in the management of chronic pain in children. Pain 1999. An Updated Review. Refresher Course Syllabus, 9th World Pain Congress, International Association for the Study of Pain. Seattle: IASP Press 1999:245-251.

12. Goodenough B, Thomas W, Champion GD, Perrott D, Taplin JE, von Baeyer CL, Ziegler JB. Unravelling age effects and sex differences in needle pain: ratings of sensory intensity and unpleasantness of venipuncture pain by children and their parents. Pain 1999; 80:179-190.

13. Goodenough B, van Dongen K, Brouwer N, Abu-Saad HH, Champion GD. A comparison of the Faces Pain Scale and the Facial Affective Scale for

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children’s estimate of the intensity and unpleasantness of needle pain during blood sampling. European Journal of Pain 1999; 3:301-315.

14. Goodenough B, Perrott D, van Dongen K, Brouwer N, Champion GD. Children’s response to vaccine fluid injection versus needle puncture pain during routine immunisation. Ambulatory Child Health 2000; 6:91-100.

15. Anand KS and The International Consensus Group for Neonatal Pain. Consensus statement for the prevention and management of pain in the newborn infant. Archives of Pediatrics and Adolescent Medicine 2000; 155:179-180. (This was one of the 20 most frequently cited publications in paediatric pain 1975-2010)

16. Goodenough B, Perrott D, Champion GD, Thomas W. Painful pricks and prickle pains: is there a relationship between children’s rating of venipuncture pain and parental assessments of usual reaction to other pains? The Clinical Journal of pain 2000; 16:135-143.

17. Goodenough B, von Baeyer CL, Champion GD. Facial expression and the self-report of pain in children. In: Katsikitis M (ed). The Human Face: Measurement and Meaning. The Netherlands, Kluwer Academic Publishers 2002 (copyright 2003): 189-214.

18. Perrott DA, Goodenough B, Champion GD. Children’s ratings of the intensity and unpleasantness of post-operative pain using facial expression scales. European Journal of Pain 2004; 8:119-127.

19. Perrott DA, Piira T, Goodenough B, Champion GD. Efficacy and safety of acetaminophen vs ibuprofen for treating children’s pain or fever: a meta-analysis. Archives of Pediatrics and Adolescent Medicine 2004; 158:521-526.

20. Piira T, Sugiura T, Champion GD, Donnelly N, Cole ASJ. The role of parental presence in the context of children’s medical procedures: a systematic review. Child: Care, Health & Development 2005; 31:233-243.

21. Goodenough B, Piira T, von Baeyer CL, Chua K, Wu E, Trieu JDH, Champion GD. Comparing six self-report measures of pain intensity in children. The Suffering Child 2005; 8:19 June. http://www.usask.ca/childpain/research/6scales/6scales.pdf

22. Piira T, Champion GD, Bustos T, Donnelly N, Lui K. Factors associated with infant pain response following an immunization injection. Early Human Development 2007; 83:319-326.

23. Bustos T, JaanisteT, Salmon K, Champion GD. Evaluation of a Brief Parent Intervention teaching coping-promoting behaviour for the infant immunization context: a randomised controlled trial. Behav Modif. 2008 Jul;32(4):450-67. doi: 10.1177/0145445507309031.

24. Du S, Champion GD, Yap CSL. Theories of fear acquisition: the development of needle phobia in children. Pediatric Pain Letter 2008; 10 (2): 13-17.

25. Balendran J, Champion D, Jaaniste T, Welsh A. A common sleep disorder in pregnancy: restless legs syndrome and its predictors. Aust N Z J Obstet Gynaecol. 2011 Jun;51(3):262-4

26. von Baeyer CL, Champion GD. Commentary: Multiple pains as functional pain syndromes. J Pediatr Psychol. 2011 May;36(4):433-7.

27. Pathirana S, Champion D, Jaaniste T, Yee A, Chapman C. Somatosensory test responses in children with growing pains. J Pain Res. 2011; 4: 393–400.

28. Champion D, Pathirana S, Flynn C, Taylor A, Hopper JL, Berkovic SF,

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Jaaniste T, Qiu W. Growing pains: twin family study evidence for genetic susceptibility and a genetic relationship with restless legs syndrome. Eur J Pain. 2012 Oct;16(9):1224-31.

29. Jaaniste T, Phipps E, Lang T, Champion GD. Impact of pediatric chronic pain on siblings: evidence and theory. Pediatric Pain Letter 2013; 15: 34-37.

30. Coenders A, Chapman C, Jaaniste T, Qiu W, Anderson D, Glogauer M, Goodison-Farnsworth E, McCormick M, Champion D. In search of risk factors for chronic pain in adolescents: a case-control study of childhood and parental associations. J Pain Res 2014; Mar 27; 7: 175-183.

31. Wong MW, Williamson BD, Qiu W, Champion D, Teng A. Growing pains and periodic limb movements of sleep in children. J Paed Child Health 2014; 50 (6): 455-460.

32. Crawford M, Lang T, Lao A, Champion D. Pain in Children and Adolescents. In: Pain: The person, the Science, and the Clinical Interface. Chapter 11, Armati P and Chow R, eds. IP Communications Pty Ltd, Lane Cove, NSW. 2015.

33. Hoogwout SJ, Paananen MV, Smith AJ, Beales DJ, O'Sullivan PB, Straker LM, Eastwood PR, McArdle N, Champion D. Musculoskeletal pain is associated with restless legs syndrome in young adults. BMC Musculoskelet Disord. 2015 Oct 14;16:294.

34. Lim SW, Gunaratne Y, Jaaniste T, McCormick M, Champion GD. Somatosensory Test Responses and Physical and Psychological Functioning of Children and Adolescents with Chronic Somatic Pain: An Exploratory Study. Clin J Pain 2016 (accepted for publication after minor revision).

Manuscripts for the first six substudies from our twin family case-control study are in preparation for submission in 2016 for publication (see Highlights and also selected abstracts below).

ACKNOWLEDGEMENTS

The research output has been modest by the standards of many full time academics, but would not have been possible at all for a physician in private practice unfunded (except for a period 2009-April 2012 when supported by the Sydney Children`s Hospital Foundation) were it not for the patient support of my wife Caroline (Tommie) and the remarkable collaboration, guidance and assistance of medical colleagues, research scientists and students. From my schooldays, I have been highly conscious of the value of teamwork and collaboration.A/Professor John Ziegler facilitated my initial appointment as a rheumatologist and was very helpful in getting the first major study, The Faces Pain Scale, funded by the NH&MRC and ultimately published. Daiva Bieri, physiotherapist, gave me lessons in determinately meticulous attention to research detail in that study. Dr Matthew Crawford, Director, Department of Anaesthesia and Pain Medicine at SCH has been wonderfully effective in enabling the Pain Research Unit to be an integral part of the Department and in supporting and collaborating in our research in many ways. Professor Carl von Baeyer, currently President of the Pain in Childhood Special Interest Group of the International Association for the Study of Pain, has a special

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place in the history of our Pain Research Unit. In the course of his initial sabbatical visit, subsequent visits and long-range communication, he has been a general mentor and in particular has taken us along on his journey to being the foremost authority on measurement and assessment of pain in childhood. Professor John Hopper, Director (Research) of the Centre for Molecular, Environmental, Genetic and Analytic (MEGA) Epidemiology at The University of Melbourne, is our principal mentor and co-author for the twin studies. Dr Minh Bui is our statistician co-author with the Australian Twin Registry (ATR). The staff of the ATR and responding twin families have been invaluable. Professor Sam Berkovic, Director, Comprehensive Epilepsy Program, Austin Health, Melbourne, has also been a very helpful mentor for the twin studies.There have been wonderful Hospital Research Scientists in the Pain Research Unit. Particular mention must be made of the two longest standing research collaborators Dr Tiina Jaaniste (current) and Dr Belinda Goodenough (previous), both of whom have been inspirational research guides and facilitators, and kept my romantic research ideas grounded in reality. The others have all been a great pleasure to work with and learn from, going back in time: Theresa Donnelly, Aneeka Bott, Cindy Chapman, Wen Qiu, Carol Yap, Louise Addicoat and Kate Juniper.We have benefited from the input of a number of overseas medical postgraduates, notably Amy Lao from Taiwan.The clinical team members of the Chronic Pain Clinic at SCH have collaborated and facilitated much of our clinical research and have been co-authors on several publications.The students from the University of NSW and from the Netherlands have helped me maintain some insight into the minds and behaviour of the young, have impressed by their computer skills and general capability which has far exceeded student capability when I was a medical student.Sydney Children`s Hospital Administration and The School of Women`s and Children`s Health, University of NSW have been supportive beyond reasonable expectations.Mention was made of donors, notably including the late Jim Fay and Ruth Fay, Denis Ashton, and of our remarkable fund raising team of friends chaired by Mrs Gay Windeyer in the Pain Research Unit section above. The other donors who have provided vital support over the years and to whom we have been hugely indepted are BBM Ltd through their support for young people.

CURRENT RESEARCH: ABSTRACTS OF PRESENTATIONS

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GIVEN 2015, ACCEPTED FOR 2016, NATIONAL AND INTERNATIONAL CONFERENCES

There were 10 studies from research directed or co-directed by GDC presented at national and international conferences 2015, and 3 so far for 2016. A selection is shown here:

PRIMARY DYSMENORRHOEA IN ADOLESCENTS AND YOUNG WOMEN: HERITABILITY AND ASSOCIATIONSYuxi Chen1, Theresa Donnelly 1 , Minh Bui2, Aneeka Bott1, Tiina Janiiste1, John Eden3, John Hopper2, Matthew Crawford1, David Champion1,3.1. Department of Pain and Palliative Care, Sydney Children’s Hospital, Randwick, NSW, Australia; 2. School of Population Health, University of Melbourne, Carlton, Victoria, Australia; 3. School of Women’s and Children’s Health, University of New South Wales, Kensington, NSW, Australia.

Background and Aims: Primary Dysmenorrhea (PDM) commonly affects adolescents and is relatively severe for 10-20% of sufferers. Onset is typically as a recurrent acute pain, 6-12 months after menarche. The experience of PDM is associated with characteristics of chronic pain conditions, demonstrating central sensitisation of nociception and abnormal brain imaging (1). PDM is familial and characteristically presents with somatic and psychological symptoms which can be considered as a PDM symptom complex. PDM has been found to co-occur with other pain disorders, but the extent to which this occurs in adolescents is not known. Utilising a twin family case-control design, our aims were to investigate genetic influence and to determine associations between PDM and primary pain disorders. Methods: The study sample consisted of 203 twin individuals from a subset of a continuing twin family study conducted with the Australian Twin Registry, who met inclusion criteria (female only twin pairs aged >11years), their mothers and oldest siblings. Twins were aged between 11-22years (M=17.4, SD=2.76) and monozygous (MZ) twin pairs comprised 54.5% of the sample. Structural Equation (ACE) Modelling was applied to estimate genetic and environmental influences on lifetime prevalence of menstrual pain and the dysmenorrhea symptom complex, and current menstrual pain (highest and average). Generalised Estimating Equation Regression models were fitted to test associations between PMD variables and common childhood pain disorders whilst controlling for within twin correlations. Results: Co-twin intra-class correlation for lifetime prevalence of menstrual pain severity for MZ twins was 0.50 (95%CI 0.35-0.674) and for dizygous (DZ) twins was 0.30 (08-0.51), additive genetic influence estimate 0.53. For the lifetime prevalence of PMD symptom complex, MZ correlation was 0.62 (0.50-0.74) and for DZ twins 0.32 (0.12-0.53), additive genetic influence estimate 0.60. For average current menstrual pain MZ twin correlation was 0.71 (0.61-0.81) and for DZ twins correlation was 0.15 (0.00-0.43), genetic influence estimate 0.69. Multivariate associations were observed between lifetime prevalence of menstrual pain and low back pain (β=0.77, p<0.01) and restless legs syndrome (RLS) (β=1.01, p<0.01). Lifetime prevalence of PMD symptom complex was multivariately associated with recurrent abdominal pain (β=2.61, p<0.05) and RLS (β=4.35, p<0.05). There were statistically significant independent associations between current PMD pain measures with iron deficiency

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and RLS.Conclusions: Analyses suggest that PMD, past and current, in adolescents and young women is likely to be moderately genetically influenced. The association profile for PMD demonstrated some similarities with previously studied primary pain disorders in having associations with RLS and iron deficiency, but differed in having fewer pain associations.

(1) Vincent, K. et al (2011). Dysmenorrhoea is associated with central changes in otherwise healthy women. Pain, 152, 1966-1975.

Australian Pain Society ASM Perth March 2016 (accepted)

CHRONIC PAEDIATRIC PAIN: INSIGHTS FROM A TWIN FAMILY CASE-CONTROL STUDYT. J. Donnelly 1 , M. Bui2, A. Bott1, S. Goh1, T. Jaaniste1, C. Chapman1, M. Crawford1, J. Hopper2, D. Champion1. 1. Department of Pain and Palliative Care, Sydney Children’s Hospital, Randwick, NSW, Australia; 2. School of Population Health, University of Melbourne, Carlton, Victoria, Australia.

Background and Aims: Chronic pain is associated with significant personal and social costs and experienced by approximately 20% of the population (1). In a previous case-control study, a personal history of childhood migraine, non-migraine headache and recurrent abdominal pain (RAP), as well as parental history of RAP and self-reported depression or anxiety were found to be multivariately associated with adolescent chronic pain compared with controls (2). Our aim in this study was to further explore childhood and parental associations as potential risk factors for paediatric chronic pain utilising a twin family case-control design.Methods: Via the Australian Twin Registry, questionnaires, validated where available, were mailed to 3909 randomly selected twin families asking about the presence of chronic pain, common primary pain conditions (headache, migraine, RAP, growing pains (GP), low back pain) and non-pain conditions demonstrated to be relevant (restless legs syndrome (RLS), iron deficiency, anxiety and depression). Of the 1189 evaluable family responses, 51.2% of twins were female, with an average age of 10.4 (SD=5.02). Casewise concordance analyses were utilised to assess the likelihood of genetic influences for each of the conditions. Random effects logistic regression analyses were used to generate univariate and multivariate associations between pain conditions in twin individuals and between twins and parents’ conditions. Results: Chronic musculoskeletal pain accounted for 50.9% of the chronic pain cases, followed by chronic visceral pain (34.2%) and chronic pain including fibromyalgia (6.1%). In analyses of twin individuals with chronic pain and their own other conditions, multivariate associations were shown with migraine (OR=3.61, p<0.001), headache (OR=2.36, p<0.01), RAP (OR=6.15, p<0.001), RLS (OR=2.01, p<0.05) and iron deficiency (OR=3.70, p<0.001). Casewise concordance rates for chronic pain were significantly higher in monozygous compared with dizygous twins (p<0.05) consistent with probable genetic influence. The results of random effects logistic

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regression showed significant associations between mother’s life prevalence of GP (OR=2.05, p<0.05), RAP (OR=3.32, p<0.001), chronic pain (OR=3.90, p<0.001) and iron deficiency (OR=2.04, p<0.05) with twin individual’s chronic pain. Similarly, father’s life prevalence of GP (OR=2.84, p<0.01), headache (OR=2.33, p<0.05), RAP (OR=4.40, p<0.001) and chronic pain (OR=3.06, p<0.01) were associated with twin individual’s chronic pain.Conclusions: The extent to which these associations individually and collectively represent significant risk factors for chronic pain in later life requires further investigation. The important associations with chronic pain common to both the current twin study and the previous case-control study (2) were individual’s migraine, non-migraine headache and RAP, and parental RAP. (1) Treede, R. et al (2015) A classification of chronic pain for ICD-11. Pain, 156, 1003-1007. (2) Coenders, A. et al (2014) In search of risk factors for chronic pain in adolescents: a case-control study of childhood and parental associations. Journal of Pain Research, 7, 175-183.

Australian Pain Society ASM Perth March 2016 (accepted)

MUSCULOSKELETAL PAIN IS ASSOCIATED WITH RESTLESS LEGS SYNDROME IN YOUNG ADULTS.Stijn J Hoogwout1, Markus V Paananen2, Anne J Smith3, Darren J Beales3, Peter B O’Sullivan3, Leon M Straker3, Peter R Eastwood4, Nigel McArdle4, David Champion 5 1.Faculty of Medical Sciences, University of Groningen, Groningen, The Netherlands, 2. Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Finland, 3. School of Physiotherapy and Exercise Science, Curtin University, Perth, Western Australia 6845, Australia, 4. Centre for Sleep Science, School of Anatomy, Physiology & Human Biology, University of Western Australia, Crawley WA 6009, Australia, 5. Department of Anaesthesia and Pain Medicine, Sydney Children’s Hospital, Randwick, NSW 2031, Australia.

Background and Aims: In recent years, there has been considerable evidence of a relationship between the sensorimotor disorder restless legs syndrome (RLS) and pain disorders, including migraine and fibromyalgia. An association between multi-site pain and RLS has been reported in adult women. In the current study, we explored the association between musculoskeletal (MSK) pain and RLS in a large cohort of young adults.Methods: Twenty two year olds (n=1072), followed since birth as part of the Western Australian Pregnancy Cohort (Raine) Study, provided data on MSK pain (duration, severity, frequency, number of pain sites). RLS was considered present when 4 diagnostic criteria recommended by the International Restless Legs Syndrome Study Group were met (urge to move, dysaesthesia, relief by movement, worsening symptoms during the evening/night) and participants had these symptoms at least 5 times per month. Associations between MSK pain and RLS were analyzed by multivariable logistic regression with bias-corrected bootstrapped confidence intervals, and with final models adjusted for sex, psychological distress and sleep quality.

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Results: The prevalence of RLS was 3.0% and MSK pain was reported by 37.4% of the participants. In multivariable logistic regression models, strong associations were found between RLS-diagnosis and long duration (three months or more) of MSK pain (odds ratio 3.6, 95% confidence interval 1.4-9.2) and reporting three or more pain sites (4.9, 1.6-14.6).Conclusions: Different dimensions of MSK pain were associated with RLS in young adults, suggestive of shared pathophysiological mechanisms. Overlap between these conditions requires more clinical and research attention.

Australian Pain Society ASM Perth March 2016 (accepted)

SENSITIVITY TO MULTIPLE SENSORY EXPERIENCES IN PRIMARY PAIN DISORDERS AND IN CHRONIC PAIN: A TWIN FAMILY STUDYAneeka Bott1, Minh Bui2, Cindy Chapman1, Tiina Jaaniste1, Matthew Crawford1, John L. Hopper2, David Champion 1 ,3.1. Department of Pain and Palliative Care, Sydney Children’s Hospital, Randwick, Australia. 2. Melbourne School of Population and Global Health, The University of Melbourne, Carlton, Australia, 3. Faculty of Medicine, University of New South Wales, Kensington, Australia.

Background and Aims: Increased sensitivities to multiple cutaneous stimuli are common in pain contexts, but additional sensitivity to light, sound, smell and taste has not been extensively tested beyond primary headaches and fibromyalgia. Our aims were to investigate whether multiple sensory sensitivity (MSS) had a component of genetic risk and whether it was associated more widely with primary pain disorders, and with conditions associated with the pain disorders, anxious depression (AD), restless legs syndrome (RLS) and iron deficiency (ID).

Methods: Questionnaires were mailed to 3,909 twin families (twins aged 3 to 18 years, parents and siblings) through the Australian Twin Registry to assess three-month lifetime prevalence of the primary pain disorders and associated conditions (RLS, parent-reported doctor confirmed ID and anxious depression (AD)). The questionnaires for categorisation of the pain disorders and RLS and AD were all validated or widely used. AD was assessed by the ASEBA Behavioural Checklists. The MSS questionnaire (scored 0-35) was derived from the Short Sensory Profile of W. Dunn and involved 5 point Likert scales for 7 sensations (pain, touch, thermal, light, sound smell and taste). Familial and other associations were estimated as odds ratios (ORs) for risk associated with having an affected relative or trait of interest.

Results: There were 1017 evaluable family responses (26%). The mean MSS responses were 10.2 for twins, 12.5 for mothers, 10.1 for fathers and 9.0 for first siblings. The unadjusted intra-class correlation for MSS in monozygous (MZ) twins was 0.79 and for dizygous (DZ) twins was 0.71 (p=0.004). MSS in mothers (β=0.57), fathers (β=0.33) and first siblings (β=0.57) was associated with MSS in twin individuals (all p<0.001). These associations remained in multivariate analysis. MSS in twins was associated with increased risk of migraine (OR=1.08), recurrent abdominal pain (OR=1.04), RLS (OR=1.04) and AD (β=0.40) (all p<0.01). MSS in

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mothers was associated with migraine (OR=1.05), low back pain (OR=1.05) and AD (β=0.17) in twin individuals (all p<0.05). ID in mothers was associated with MSS in twins (β=0.19, p<0.05). MSS in fathers was associated with recurrent abdominal pain (OR=1.04) and AD (β=0.11) in twins (p<0.05). MSS in siblings was associated with AD in twins (β=0.24, p<0.001). After controlling for clinical AD the association between MSS and migraine in twin individuals held.

Conclusions: The self-reported sensory response to multiple everyday sensory experiences (MSS) was at most associated with a weak genetic component of risk. The strongest association between MSS and primary pain disorders was with migraine which held in multivariate analyses controlling for clinical anxious depression. Whether there is a causal direction for this association merits further analysis and research.

Abstracts of the Australian Pain Society ASM Brisbane 2015

Parental factors which affect child and adolescent post-operative pain outcomes: systematic review

A Powell1 *, D Chan1, T Jaaniste1,2, D Champion1,2, J Wood1,2

1 Faculty of Medicine, The University of New South Wales2 Department of Anaesthesia and Pain Medicine, Sydney Children’s Hospital

Introduction:Parents play a prominent role in the management of their child’s postoperative pain, and can have a substantial influence over their child’s pain outcomes. The nature of this parental influence may be related to factors such as (i) parental cognitions or emotions and (ii) parental behaviours.

Aims:To examine the existing literature investigating the impact of parental factors on the postoperative pain outcomes of their children.

Methods:The Medline, Embase and PsychINFO databases were searched from their inceptions up to March 17th, 2014 for the following terms: “parent”, “belief”, “factor”, “attitude”, “association”, “influence”, “psychology”, “affect”, “character”, “behaviour”, “conduct”, “trait”, “state”, “child”, “adolescent”, “postoperative”, “postsurgical”, “postdischarge”, “pain”, “medicine”, and “analgesia”. Reference lists of relevant articles were also hand searched. Coding was carried out by 2 coders. Inter-rater reliability was established on 200 abstracts and found to be good. Articles were considered thematically as two groups; (i) studies on parents’ cognitive and emotional factors, and (ii) studies on parents’ behavioural factors.

Results: A total of 1592 potentially relevant abstracts were identified through the search strategy and evaluated. Duplicates were removed. The remaining

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1225 references were reviewed by two of the authors. A total of 31 full articles and conference abstracts were relevant and were included for final review.

There was strong evidence that elevated parental anxiety is correlated with increased postoperative pain in their child or adolescent. Evidence addressing other parental factors was limited, and thus only tentative conclusions could be drawn. Parental cognitive and emotional factors identified in the literature included beliefs and misconceptions about analgesics, anxiety, pain catastrophizing, and stress. Behavioural factors identified included analgesic provision, and the use of non-pharmacological methods to relieve pain (such as distraction, positive reinforcement, thermal regulation, massage, positioning, reassurance, and emotional support).

Conclusion:Research needs to further identify and explore the parental factors that may influence children’s postoperative pain outcomes. Clarification is needed regarding the interrelationships between these factors and outcomes. Brief interventions for parents at risk of experiencing heightened anxiety, such as appropriate information provision, may be useful in improving their child’s postoperative pain outcomes.

New Zealand Pain Society ASM 2015

Post-discharge pain outcomes and child-related risk factors following paediatric short-stay tonsillectomy and appendicectomy: a prospective observational study

Background: Published literature suggests that pain following paediatric short-stay surgery may be problematic, particularly following from hospital. Potential child-related risk factors for increased pain include pain catastrophising, anxious depression, and negative attitudes towards medication.

Objectives: The objectives of this study were twofold. First; to investigate paediatric post-discharge pain outcomes. Second; to examine the child-related risk factors which may predict increased post-discharge pain.

Methods: This prospective observational study surveyed children aged 3-14 undergoing short-stay tonsillectomy or appendicectomy, and their primary caretakers. Parents and children completed a pre-discharge questionnaire assessing pain catastrophising, anxious depression, and negative attitudes to medication. Participants were then surveyed for ten-days post-discharge using electronic questionnaires loaded on iPod Touch™ devices, examining pain outcomes, functional limitation, and medication behaviours.

Results: This report presents an interim analysis of an ongoing study. Children (n = 26) experienced moderate peak pain intensities in hospital and at time of discharge. Post-discharge, it took a median of nine days until patients reported no pain. Tonsillectomy patients experienced higher post-discharge pain than appendicectomy patients (t(24) = 2.545, p < .05), and anxious depression was strongly correlated with a longer recovery period

(r = .702, p < .05); other analyses did not reach statistical significance due to low power.

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Conclusions: Post-discharge pain in children is problematic. Future research needs to further examine risk factors and use a specific model to frame hypotheses. Targeted interventions to reduce unhelpful pain catastrophising, anxious depression and negative attitudes towards medication utilization may be beneficial in the short-stay surgical context.

David Chan co-supervised ILP student UNSW presented at New Zealand Pain Society ASM 2015 .Familial influences in recurrent and chronic pain: insights into genetic risk and associations from a twin family studyA. Bott1, M. Bui2, T. Jaaniste 1 ,3, T. Lang1,3, C. Chapman1, M. Crawford1, J.L. Hopper2, D. Champion1,3

1. Department of Anaesthesia and Pain Medicine, Sydney Children’s Hospital, Randwick, Australia, 2. Melbourne School of Population and Global Health, The University of Melbourne, Carlton, Australia, 3. School of Women’s and Children’s Health, Faculty of Medicine, University of New South Wales, Kensington, Australia.

Aim of investigation: Research into the role of the family in pain disorders has largely been psychosocial, including inferences about causation. We investigated genetic risk and associations of the common primary pain disorders of childhood (growing pains, migraine, non-migraine headaches, recurrent abdominal pain (RAP), low back pain) and other chronic pain conditions, and their associations with restless legs syndrome (RLS), iron deficiency (ID) and anxious depression (AD).

Methods: Validated (or widely used) questionnaires were mailed to 3,909 twin families (twins aged 3 to 18 years, parents and siblings) through the Australian Twin Registry to assess three-month lifetime prevalence of the primary pain disorders and RLS, parent-reported doctor confirmed ID, and AD. Using a twin family case-control design, familial and other associations were estimated as odds ratios (ORs) for risk associated with having an affected relative or trait of interest. Analyses also included multivariate models and structural equation modelling (ACE).

Results: For each of the primary pain disorders, and for RLS, ID and AD, ORs for MZ twins, DZ twins, first siblings, mothers and fathers were consistent with genetic risk, an interpretation supported by casewise concordance and ACE model analyses. There were multiple associations among the pain disorders in family members and between the pain disorders and RLS, ID and AD in twin individuals. For example, a twin child had increased risk for migraine when mother had migraine (OR=3.84), RAP (OR=2.54), chronic pain (OR=1.82) or AD (OR=1.06), all p’s<0.01. Mothers’ pain disorders and associated conditions tended to be the strongest predictors of disorders in twin individuals, followed by conditions in the siblings. Fathers’ disorders were only weakly associated with traits in twin children.

Conclusions: The familial role in the occurrence of the common primary pain disorders and the associated conditions RLS, ID and AD included an important genetic component of risk.

Abstracts of the 10th International Symposium on Pediatric Pain Seattle May-June

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2015.

PAEDIATRIC RESTLESS LEGS SYNDROME WITH OR WITHOUT GROWING PAINS: NOVEL INSIGHTS FROM A TWIN FAMILY STUDY.

M. Bui1, A. Bott2 C. Chapman2, T. Jaaniste2,3, M. Crawford2, S. Berkovic4, J.L. Hopper1, D. Champion2, 3.1. Melbourne School of Population and Global Health, The University of Melbourne, Carlton, Australia, 2. Department of Anaesthesia and Pain Medicine, Sydney Children’s Hospital, Randwick, Australia, 3. Faculty of Medicine, University of New South Wales, Kensington, Australia, 4. Department of Medicine, University of Melbourne, Carlton, Australia.

Paediatric restless legs syndrome (RLS) and growing pains (GP) have clinical similarities and a possible common genetic cause. We conducted a twin family case-control study considering three mutually exclusive traits: having RLS with GP, having RLS without GP, and having GP without RLS.

Questionnaires were mailed to 3,909 twin families (twins 3-18 years, parents, siblings) through the Australian Twin Registry to assess three-month lifetime prevalence of the primary pain disorders of childhood and RLS, iron deficiency (ID), anxious depression (AD) and sensory sensitivity. RLS criteria were derived from Allen et al (2003) and GP from Peterson (1986). Familial and other associations were estimated as odds ratios (ORs) for risk associated with having an affected relative or trait of interest.

Evaluable responses were obtained from 1017 twin families (26%). For having RLS with GP, casewise concordance for monozygous (MZ) twins was 0.54 and 0.22 for dizygous (DZ) twins (p<0.01). The ORs were 38.9 (p<0.001) and 6.5 (p=0.001) for MZ and DZ twins respectively. Twin individuals had increased risk for having RLS and GP when mothers (OR=6.4), fathers (OR= 5.0) and oldest siblings (OR=6.7) were affected (all p<0.001). Low back pain, RAP, headache and ID (OR=2.1) were also associated with this trait in twin individuals (all p<0.05). For having RLS without GP, casewise concordance for MZ twins was 0.33 and 0.26 for DZ twins (p=0.54). The ORs were 10.5 and 8.1 for MZ and DZ twins respectively (both p<0.001). Twin individuals had increased risk for this trait when mothers (OR=2.5, p<0.001) and oldest siblings (OR=2.9, p<0.01) had RLS without GP. Fathers having RLS without GP was not associated with twins having the condition (OR=1.7, p=0.1). Recurrent abdominal pain, chronic pain, ID (OR=5.8), AD and sensory sensitivity were associated with this trait in twin individuals (all p<0.01). For having GP without

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RLS, casewise concordance was 0.52 for MZ twins and 0.38 for DZ twins (p=0.05). The OR for MZ pairs was 13.7 (p<0.001) and 6.0 for DZ pairs (p<0.001). Twin individuals had increased risk of the trait when mothers (OR=3.0), fathers (OR=3.5) and oldest siblings (OR=5.0) were affected. Headache was the only pain disorder associated with this trait in twin individuals (OR=2.1, p<0.001).

For having both RLS and GP, there was strong evidence consistent with genetic factors being associated with substantial gradient of risk, and this trait had only a weak association with ID. For RLS without GP, evidence for genetic factors was weak, shared environmental factors were prominent, and there was a strong association with ID, which is known to have causal implications. For GP without RLS, there was evidence for weak genetic risk and there were no associations with ID.

Abstracts of the 10th International Symposium on Pediatric Pain, Seattle June 2015.

PARENT-REPORTED IRON DEFICIENCY: GENETIC RISK AND ASSOCIATIONS WITH THE COMMON PRIMARY PAIN DISORDERS OF CHILDHOOD

D. Champion 1, 2, M. Bui3, A. Bott2, H. Vo1, T. Jaaniste1, 2, J.L. Hopper 3, M. Crawford 2

1. Faculty of Medicine, University of New South Wales, Kensington, Australia, 2. Department of Anaesthesia and Pain Medicine, Sydney Children’s Hospital, Randwick, Australia, 3. Melbourne School of Population and Global Health, The University of Melbourne, Carlton, Australia.

Several genome wide association studies have identified genetic markers associated with measures of human iron stores. Iron deficiency (ID) has a causal association with restless legs syndrome (RLS) which in turn is associated with several primary pain disorders. Studies have also shown that ID has potential for multifactorial influences on emotion. We conducted a twin family study of the genetic and environmental risk factors for paediatric iron deficiency (ID) and its relationship with RLS, anxious depression (AD), and with the common primary pain disorders of childhood.

Questionnaires were sent to 3,909 twin families (twins aged 3 to 18 years, parents and siblings) through the Australian Twin Registry to assess lifetime prevalence of the primary pain disorders of childhood as well ID and RLS. Validated questionnaires were used for probable diagnostic categorisation of the pain disorders and RLS. For ID, lifetime prevalence was assessed by parental-report where doctor confirmation was stated.

There were 1,017 evaluable responses in which 87 twin families (8.6%) had at least one twin with a history of ID. Casewise concordance was 0.60 for monozygous (MZ) and 0.34 for dizygous (DZ) twin pairs (p=0.02). Odd ratios (OR) were 48.8 (p<0.001) for MZ, and 15.8 (p<0.001) for DZ pairs. Risk of ID in twin individuals was increased

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when mother (OR=2.4), and oldest sibling (OR=5.4) had ID (both p<0.001). After adjusting for age, ID was associated with migraine (OR=2.20), recurrent abdominal pain (OR=2.30), chronic pain (OR=4.51), RLS (OR=4.03), and AD (OR=2.6) (all p<0.05). Having a mother with ID (35%) was also associated with risk of recurrent abdominal pain (OR=1.74), chronic pain (OR=1.70), RLS (OR=1.72) and AD (OR=1.7) in twin individuals (all p<0.05).

Under the assumptions of the classic twin model, there was evidence for a genetic component of risk for parent-reported lifetime prevalence of paediatric ID. Our results are consistent with findings from genome wide association studies reporting genetic influence on iron parameters. Childhood and maternal ID were associated with RLS and with the primary pain disorders. Additionally, the maternal and co-twin associations between ID and AD suggests possible developmental influences by ID on AD. We propose that ID is a risk factor for the primary pain disorders, acting through dopaminergic dysfunction and/or neurodevelopmental influences.

Abstracts of the 10th International Symposium on Pediatric Pain, Seattle June 2015.

PAEDIATRIC ANXIOUS DEPRESSION: GENETIC RISK AND ASSOCIATIONS WITH THE PRIMARY PAIN DISORDERS AND RESTLESS LEGS SYNDROME

A. Bott1, M. Bui2, C. Chapman1, A. Curran3, T. Jaaniste1, 4, M. Crawford1, J.L. Hopper2, D. Champion1,4. 1. Department of Anaesthesia and Pain Medicine, Sydney Children’s Hospital, Randwick, Australia, 2. School of Population and Global Health, The University of Melbourne, Carlton, Australia, 3. Faculty of Medicine, University College Cork, Cork, Ireland, 4. Faculty of Medicine, University of New South Wales, Kensington, Australia.

Anxiety and depression are distinct conditions that are thought to have genetic risk factors in common and are often co-morbid with different pain conditions. The principal aim of this study was to investigate evidence for a genetic component to risk of paediatric anxious depression (AD) and estimate associations with the primary pain disorders of childhood and with restless legs syndrome (RLS).

Questionnaires were sent to 3,909 twin families (twins aged 3 to 18 years, parents and siblings) through the Australian Twin Registry to assess three-month life prevalence of the primary pain disorders and RLS, iron deficiency (ID) and AD. The questionnaires used for probable diagnostic categorisation of the pain disorders and RLS had been validated or were widely used. AD was assessed by a subscale of the ASEBA Behavioural Checklist.

There were 1,017 evaluable responses from twin families (26%). Clinical AD (as a binary trait) was reported for 108 twins (5.3%) and the casewise concordance was 0.47 for monozygous (MZ) and 0.19 for dizygous (DZ) twin pairs (p<0.001). The within twin pairs ORs were 28.5 (p<0.001) and 5.0 (p<0.001) for MZ and DZ twin

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pairs respectively. Risk of AD was associated with AD in mothers (OR 6.3), fathers (OR 4.7) and oldest siblings (OR 7.3) (all p<0.01). After adjusting for age, risk of AD in twin individuals was associated with having migraine (OR 3.4), recurrent abdominal pain (OR 2.8), chronic pain (OR 2.9), RLS (OR 2.1) and ID (OR 2.4) (all p<0.01).

MZ twin concordances, and parental and sibling associations with AD in twin individuals support an interpretation of a genetic component to risk of AD. AD was also associated with ID and RLS, all 3 of which involve dopamine dysfunction. We hypothesise common dopaminergic mechanisms between the primary pain disorders, AD, RLS and ID. The relationship between AD and ID is interesting, given that ID, especially in early development, might have long lasting effects on behavioural functions (Kim & Wessling-Resnick, 2014). The extent to which the association between AD and the pain disorders, RLS and ID is causal, consequential or involves pleiotropy will be further discussed.

Abstracts of the 10th International Symposium on Pediatric Pain Seattle May-June 2015.

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