Discussion
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INFLAMMATION, MINOR
In this study, we comprehensively evaluated the immediate systemic neuroimmune responses following spinal mobilisation/manipulation in people with non-specific neck pain. Although there were meaningful differences in the effect of spinal mobilisation/manipulation on clinical outcomes such as pain intensity and cervical range of motion, we did not identify differences in neuroimmune responses at a systemic level between the experimental and placebo intervention, nor between those with a good outcome versus a poor outcome in the experimental group, nor meaningful associations with pain reduction. Although we found some significant differences for the clinical outcomes, some findings may be related to type 1 errors due to multiple testing, suggesting some of the significant findings may be due to chance or random variation rather than a true effect. There is an increasing volume of literature regarding the effects of joint mobilisation/manipulation on neuroimmune responses in musculoskeletal conditionsEx-vivo inflammatory markers are easy to measure, and therefore attractive to investigate in pain researchOne important issue in determining the in-vitro responsivity of whole blood cells is to control for the number of cytokine producing cells and the number of cells culturedSeveral considerations should be noted when interpreting the findings. First, due to the non-linearity of the neuroimmune responses, Ln-transformation was necessary which makes the interpretation of the data more complicated. Second, we opted for unequal sample sizes. As we also wanted to compare people with a good versus poor outcome within the experimental group, the experimental group needed to be larger than the control group at baseline. However, we incorporated unequal group sizes in our a priori sample size estimation, thereby limiting a type 2 error. Thirdly, the effects of only a single sessions of joint mobilisation/manipulation on immediate neuroimmune responses were examined. This could seem to limit the clinical relevance but gives a better insight into the true effect of mobilisation/manipulation on neuroimmune outcomes by limiting the effects of contextual factors. Moreover, our aim was to understand the biological mechanisms behind pain reduction and not the clinical efficacy of mobilisation/manipulation. Also, a longer follow-up period might complicate establishing a cause-effect relationship between the intervention and systemic neuroimmune responses due to confounding factors which may introduce biasFinally, two minor protocol deviations are needed to be mentioned. First, we changed the label ‘short term effects’ to ‘immediate effects’ as we believe 2 h post intervention is better described still as ‘immediate’ rather than ‘short term’, which may reflect days or weeks. Secondly, due to an omission, pain intensity after two days was not recorded.To conclude, we found that joint mobilisations/manipulation did not affect immediate systemic neuroimmune responses and no associations were found between neuroimmune responses and pain reduction. Having revealed that joint mobilisations/manipulation had no effect on systemic levels of inflammation, future research may focus on more localised neuroimmune responses (e.g., at the level of the dorsal root ganglion, spinal cord and brain