Quantitative sensory testing and pain-evoked cytokine reactivity

Abstract

Sickle cell disease (SCD) is an inherited blood disorder associated with significant morbidity, which includes severe episodic pain, and, often, chronic pain. Compared to healthy individuals, patients with SCD report enhanced sensitivity to thermal detection and pain thresholds and have altered inflammatory profiles, yet no studies to date have examined biomarker reactivity following laboratory-induced pain. We sought to examine this relationship in SCD patients compared to healthy control participants. We completed quantitative sensory testing (QST) in 83 patients with SCD and sequential blood sampling in 27 of them, whom we matched (sex, age, race, BMI, education) to 27 healthy controls. Surprisingly, few QST differences emerged between groups. Heat pain tolerance, pressure pain threshold at the trapezius, thumb and quadriceps, and thermal temporal summation at 45°C differed between groups in the expected direction, while conditioned pain modulation and pain ratings to hot water hand immersion were counterintuitive, possibly due to tailoring the water temperature to a perceptual level; SCD patients received milder temperatures. In the matched subsample, group differences and group by time interactions were observed in biomarkers including TNFα, IL-1β, IL-4, and NPY. These findings highlight the utility of laboratory pain testing methods for understanding individual differences in inflammatory cytokines. Our findings suggest amplified pain-evoked pro-inflammatory cytokine reactivity among patients with SCD relative to carefully matched controls. Future research is warranted to evaluate the impact of enhanced pain-related cytokine response and whether it is predictive of clinical characteristics and the frequency/severity of pain crises in SCD patients.

Central sensitization associated with low fetal hemoglobin levels in adults with sickle cell anemia

“…These results are in contrast with the heat pain hyperalgesia and light touch allodynia reported in SCD mice and heat pain hyperalgesia in children with SCD [12, 18, 21, 30, 31]. However, our results are similar to another QST study of adults with SCD, which likewise did not show increased heat pain thresholds [13]. We speculate that these inconsistent findings might be explained by different physiologic effects in children versus adults [13, 18].…”

“…However, our results are similar to another QST study of adults with SCD, which likewise did not show increased heat pain thresholds [13]. We speculate that these inconsistent findings might be explained by different physiologic effects in children versus adults [13, 18]. Our sites for heat pain testing were also different than those used in the pediatric study (forearm versus hand) and may reflect site specific sensitivity [18].…”

“…Perhaps testing different sensory afferents together (e.g. heat/cold or heat/mechanical) will produce the expected inhibition as was observed in 2 other studies of adults with SCD [13, 14]. Determining CPM responses is critical for further understanding descending modulation of pain transmission within the central nervous system in SCD [13, 14, 25, 41].…”

“…Previous SCD studies have not controlled for genotype effects on experimental or clinical pain [13, 14, 18, 20, 27, 28]. Furthermore, we were likely only able to detect the HbF association because its expression is significantly higher in SCA compared to hemoglobin SC 34,36 , another common genotype present in prior QST studies [13, 14, 18, 20, 27, 28, 49, 50]. The association was similarly not detected in studies of the S-Berk mouse, which does not express HbF [19].…”

“…While SCD studies have demonstrated increased sensitivity by static QST methods, the magnitude of these differences were significantly smaller than in fibromyalgia, [14, 18, 27, 28, 32]. Recent QST studies exploring central sensitization in SCD are promising [14], however its relationship with known disease modifiers has not been evaluated [4, 13, 14, 19, 20]. Indeed, recent resting state functional MRI showed a significant correlation between anti-nociceptive brain connectivity and fetal hemoglobin in low pain burden SCD patients [15].…”