Enhanced Pain Sensitivity in Adult Sickle Cell Disease Patients: Potential Mediating Factors
Authors: Sop Daniel M , Zhang Yue May , Smith Wally R 
Published: December 2024

Background
Sickle Cell Disease (SCD) is a genetic disorder characterized by chronic anemia, recurrent painful vaso-occlusive crises, and multiple systemic complications. Among these, silent cerebral ischemia (SCI) is a prevalent yet often unnoticed complication that significantly impacts neurological function. SCI in SCD patients is linked to cognitive deficits and increased pain sensitivity, but the underlying mechanisms remain poorly understood. This study aims to investigate the impact of potential mediators on pain sensitivity in adult SCD patients.
Methods
The study analyzed data from nine SCD patients. Two patients with brain damage were excluded to focus on those without brain injury. The final sample included seven patients with various SCD genotypes to account for differences in disease severity. Pearson correlation examined the linear relationship between each mediator and the exposure, each mediator and the outcome, and the exposure and the outcome. ANOVA tested reported pain sensitivity differences across genotypes.
Mediation analysis investigated the pathways through which cerebral blood flow (CBF) impacts pain cognition, defined as the total score on the Pain Sensitivity Questionnaire (PSQ_Total). The analysis considered cognitive functions (cognitive flexibility, executive function, and processing speed), hemoglobin levels, and heart rate as mediators, with CBF as the exposure, genotype as a confounder, and PSQ_Total as the outcome. Regression analysis examined the relationship between each mediator and the exposure, each mediator and the outcome, and the exposure and the outcome. Anova tested reported pain sensitivity differences across genotypes. Mediation analysis assessed the causal effect of CBF on PSQ_total through mediators.
Results
The Pearson correlation analysis revealed a positive correlation between pain sensitivity (PSQ_Total), and hemoglobin levels (r=0.83, p=0.02) and an inverse correlation between pain sensitivity and cerebral blood flow (r=-0.74, p=0.05). Furthermore, CBF showed a significant inverse correlation with processing speed (r=-0.80, p=0.03).
ANOVA indicated that the SC genotype had the highest pain sensitivity, while the Sβ0 genotype has the lowest. However, this difference was not statistically significant. It is important to note that these findings may be influenced by the small sample size.
Mediation analysis revealed that cerebral blood flow (CBF) can influence pain cognition (PSQ_Total) with a total effect of -0.06 (p-value=0.0006) when hemoglobin is considered as a mediator. This effect includes a direct impact of -0.02 (p &lt; 0.0001) and an indirect impact through hemoglobin of -0.04 (p = 0.03). The percentage of the total effect mediated by hemoglobin was found to be 60.9% (p &lt; 0.0001).
When processing speed is considered as a mediator, independent of other mediators, mediation analysis revealed that CBF can impact pain cognition with a total effect of -0.06 (p-value=0.0006). The direct effect of this impact was -0.1 (p &lt; 0.0001), and the indirect effect was 0.04 (p = 0.01). The percentage of the total effect mediated by processing speed was -71.6%. Other tested mediators did not reach statistical significance in mediating the relationship.
Conclusion
This study sheds light on the intricate relationship between cerebral blood flow (CBF), cognitive function, hemoglobin levels, and pain sensitivity in adult SCD patients. The mediation analysis revealed that hemoglobin levels and processing speed significantly mediate the impact of CBF on pain sensitivity. Specifically, increased CBF is associated with a direct decrease in PSQ_Total (a measure of pain sensitivity), and also influences pain sensitivity through its effects on hemoglobin levels. However, the relationship with processing speed is more complex: while increased CBF directly decreases pain sensitivity, it also indirectly increases pain sensitivity by reducing processing speed. These findings suggest that interventions targeting hemoglobin levels and cognitive processing speed could be crucial in managing pain sensitivity in SCD patients. However, the small sample size limits the generalizability of these results, and further research with larger cohorts is necessary to confirm these findings and explore additional mediators.