A Systematic Review and Meta-Analysis of Conditioned Pain Modulation in Children and Young People with Chronic Pain

Abstract

Background/objectives: Conditioned pain modulation (CPM) is a psychophysical experimental measure of the endogenous pain inhibitory pathway in humans, wherein one pain stimulus (the conditioning stimulus) is used to inhibit an individual's perception of a second painful (test) stimulus. Research provides evidence of impaired endogenous inhibitory pain responses in adults with chronic pain. CPM is now increasingly applied in paediatric research and clinical practice. The primary aim of this systematic review was to examine the efficacy of CPM in paediatric chronic pain populations (6-24-year-olds) compared to pain-free children and young people (CYP).

Methods: The protocol was registered on PROSPERO (CRD42020221927). A systematic search of seven databases was conducted from database inception to 20th June 2024. Study inclusion criteria were as follows: (i) recruited a sample of CYP aged 6 to 24 (inclusive) with chronic pain or who were pain-free; and (ii) applied a CPM paradigm comprising both a painful test and conditioning stimuli that were sufficiently detailed to allow for replication,(iii) adhered to a study design of randomised control trial, case control or cohort study, including cross-sectional or longitudinal; (iv) available in the English language. Study exclusion criteria were: (i) The CPM paradigm used a non-painful test or conditioning stimulus only; and (ii) was only available as an abstract, letter, poster, editorial, case report, or review with or without meta-analyses. Risk of bias was assessed using the Appraisal Tool for Cross Sectional Studies (AXIS). Meta-analyses were conducted in Comprehensive Meta Analysis 3.0 using random effects models to compare the overall CPM responses in CYP with chronic pain conditions to healthy control CYP.

Results: Thirty-two studies were eligible for inclusion, six of which were included in one or more meta-analysis (n = 407 chronic pain, n = 205 control). Meta-analysis revealed significantly weaker CPM responses in CYP with a variety of chronic pain conditions compared to healthy controls (standardized mean difference (SMD) = 0.352), and significantly weaker CPM responses in CYP with abdominal pain conditions compared to healthy controls (SMD = 0.685). No significant difference in CPM response was found between CYP with migraine and healthy controls (SMD = -0.201).

Conclusions: Variable results were found across individual studies, and the meta-analysis of the small number of eligible studies provides tentative evidence for impaired CPM in CYP with chronic pain compared to healthy controls. Further research is clearly needed. In particular, studies should present CPM results separately for different age groups, ethnic groups, and sexes, as these variables shape clinical pain responses.

Keywords: conditioned pain modulation; meta-analysis; paediatric chronic pain; quantitative sensory testing; systematic review.

Figure 1

Graphical depiction of a typical conditioned pain modulation experimental paradigm using heat pain as test stimulus (administered to participant’s left forearm) and cold pain as conditioning stimulus (administered to participant’s right hand and wrist). From left to right: (i) participant is seated comfortably in a temperature- and sound-controlled environment; (ii) heat pain test stimulus is administered via thermode alone and heat pain threshold is recorded; (iii) heat pain test stimulus is administered again in the presence of the conditioning pain stimulus (cold water administered via the cold pressor test) and the heat pain threshold is recorded again. Figure created by an independent artist with the assistance of Midjourney version 5.

Figure 2

PRISMA 2020 flow of records for inclusion in the systematic review and meta-analysis of conditioned pain modulation in children and young people with chronic pain.

Figure 3

AXIS assessments for all eligible studies included in a systematic review and meta-analysis of conditioned pain modulation in children and adolescents. Note 1. Numbered items are as follows: 1. Were the aims/objectives of the study clear? 2. Was the study design appropriate for the stated aim(s)? 3. Was the sample size justified, with evidence of adequate statistical power? 4. Was the target/reference population clearly defined? (Is it clear who the research was about?) 5. Was the sample frame taken from an appropriate population base so that it closely represented the target/reference population under investigation? 6. Was the selection process likely to select subjects/participants that were representative of the target/reference population under investigation? 7. Were measures undertaken to address and categorise non-responders? (i.e., potential participants not responding to study invitation) 8. Were the risk factor and outcome variables measured appropriate to the aims of the study? 9. Were the CPM outcome variables measured correctly using instruments/measurements that had been trialled, piloted, or published previously in an equivalent paediatric sample? 10. Is it clear what was used to determine statistical significance and/or precision estimates? (e.g., p-values, confidence intervals). 11. Were the methods (including statistical methods) sufficiently described to enable them to be repeated? 12. Were the basic data adequately described? 13. Does the response rate raise concerns about non-response bias? 14. If appropriate, was information about non-responders described? 15. Were the results internally consistent? 16. Were the results presented for all the analyses described in the methods? 17. Were the authors’ discussions and conclusions justified by the results? 18. Were the limitations of the study discussed? 19. Were there any funding sources or conflicts of interest that may have affected the authors’ interpretation of the results? 20. Was ethical approval granted and consent/assent of participants attained? Note 2. Green signifies a favourable assessment, red signifies an unfavourable assessment, orange signifies the answer is unclear from the information provided in the study article, and blue signifies the item is not applicable (NA).