Using Mediation Analysis to Understand How Treatments for Paediatric Pain Work: A Systematic Review and Recommendations for Future Research

Children (Basel). 2021 Feb 16;8(2):147. doi: 10.3390/children8020147.

Hayley B Leake 1 2, G Lorimer Moseley 1, Tasha R Stanton 1, Lauren C Heathcote 3, Joshua W Pate 4, Michael A Wewege 2 5, Hopin Lee 6 7


Author information

  • 1IIMPACT in Health, University of South Australia, Adelaide, SA 5000, Australia.
  • 2Centre for Pain IMPACT, Neuroscience Research Australia, Sydney, NSW 2031, Australia.
  • 3Department of Anaesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Palo Alto, CA 94304, USA.
  • 4Department of Physiotherapy, Graduate School of Health, University of Technology Sydney, Sydney, NSW 2008, Australia.
  • 5Department of Exercise Physiology, School of Medical Sciences, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW 2052, Australia.
  • 6Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford OX3 7LD, UK.
  • 7School of Medicine and Public Health, University of Newcastle, NSW 2308, Australia.


Clinicians have an increasing number of evidence-based interventions to treat pain in youth. Mediation analysis offers a way of investigating how interventions work, by examining the extent to which an intermediate variable, or mediator, explains the effect of an intervention. This systematic review examined studies that used mediation analysis to investigate mechanisms of interventions on pain-relevant outcomes for youth (3-18 years) with acute or chronic pain, and provides recommendations for future mediation research in this field. We searched five electronic databases for clinical trials or observational longitudinal studies that included a comparison group and conducted mediation analyses of interventions on youth and assessed pain outcomes. We found six studies (N = 635), which included a total of 53 mediation models examining how interventions affect pain-relevant outcomes for youth. Five studies were secondary analyses of randomized controlled trials of psychological interventions for chronic pain; one was a longitudinal observational study of morphine for acute pain. The pain conditions studied were irritable bowel syndrome, functional abdominal pain, juvenile fibromyalgia, mixed chronic pain, and post-operative pain. Fourteen putative mediators were tested, of which three partially mediated treatment effect; seven did not significantly mediate treatment effect and four had mixed results. Methodological and reporting limitations were common. There are substantial gaps in the field with respect to investigating, and therefore understanding, how paediatric interventions work.

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