Clinically Meaningful Interpretation of Quantitative Sensory Testing As a Measure of Pain Sensitivity in Patients with Sickle Cell Disease
Authors: Brandow Amanda M , Farley Rebecca , Panepinto Julie A. 
Published: November 2019

Abstract
Patients with sickle cell disease (SCD) display hypersensitivity to thermal and/or mechanical stimuli compared to healthy controls when assessed with quantitative sensory testing (QST) suggesting impaired pain sensitivity. Impaired pain sensitivity is present when a defined stimulus (cold, heat, mechanical) produces exaggerated pain in a patient compared to healthy controls and suggests pain processing abnormalities in the peripheral and/or central nervous system. Existing studies report significant differences in mean/median thermal and/or mechanical pain thresholds between SCD patients and healthy controls. However, for clinical purposes it is important to understand if an individual patient meets criteria for impaired pain sensitivity. To date, thresholds above or below which a patient is defined as having impaired pain sensitivity have not been established in pediatric SCD patients. We sought to: 1) define thresholds for impaired cold, heat, and mechanical pain sensitivity in SCD patients ages ≥7 years and 2) determine the proportion of SCD patients meeting criteria for impaired pain sensitivity with each testing modality. Our secondary objective was to compare age, gender and prior history of pain between patients with and without impaired pain sensitivity.
We conducted a cross-sectional study of SCD patients and healthy African American controls ages ≥ 7 years. Using QST we assessed cold, heat, and mechanical pain thresholds via the method of limits on the thenar eminence of the non-dominant hand and lateral dorsum of foot (randomized). Our primary outcome was threshold for impaired pain sensitivity defined as: 1) cold pain threshold that was one standard deviation (SD) above median cold pain threshold in the control group; 2) heat pain threshold that was one SD below median heat pain threshold in the control group; 3) mechanical pain threshold that was one SD below median mechanical pain threshold in the control group. Data were skewed so bootstrap resampling was used to obtain the 95% CI for the median that is congruent with the SD of the median. Mann-Whitney Test and Pearson Chi-square were used to compare age, gender, and prior history of pain (total number of lifetime emergency department visits and/or hospitalizations) between those with and without impaired pain sensitivity.
A total of 55 SCD patients and 57 African American controls completed QST. There were no differences in mean±SD age (15.4±6.3 vs. 16.3±10.2 yrs, p=0.59) or gender (60% vs. 56% female, p=0.68) between groups. SCD genotypes were: 67% SS, 18% SC, 11% Sβ+ thal, 4% other. Table 1 displays thresholds for impaired pain sensitivity and proportions of SCD patients meeting criteria for impaired pain sensitivity. We found 21.8% (n=12) of SCD patients had impaired pain sensitivity with all 3 testing modalities and the majority (81.8%, n=45) had impaired pain sensitivity with one or more testing modalities. Only 18.2% (n=20) had no evidence of impaired pain sensitivity. There was no difference in median age, gender, or median number of pain encounters between those with and without impaired pain sensitivity (15 (IQR 10.5-19) vs. 13.5 yrs (IQR 11-21.5), p=0.939; 60% female in both groups; number of pain encounters: 9 (IQR 4-23.5) vs. 3 (IQR 0.25-19.8), p=0.132).
Determining a threshold for impaired pain sensitivity is clinically meaningful. Using QST data, we established thresholds for impaired cold, heat and mechanical pain sensitivity. Based on these thresholds, almost a quarter of SCD patients were impaired in all 3 modalities tested and the majority were impaired in at least one modality. Impaired cold pain sensitivity was the most common finding supporting epidemiological data that increased numbers of pain events are associated with colder temperatures. If used clinically, QST could serve as a screening tool to phenotype SCD pain, guide further evaluation of the etiology of pain, guide treatment decisions, or serve as an outcome for an intervention aimed at altering pain sensitivity.
Table 1. Thresholds for Impaired Pain Sensitivity and Proportion of SCD Patients with Impaired Pain Sensitivity (n=55) Threshold* Proportion Impaired Hand Cold Pain Threshold >17.01ºC 63.6% (n=35) Heat Pain Threshold <43.91ºC 60% (n=33) Mechanical Pain Threshold <4.42 g 41.8% (n=23) Foot Cold Pain Threshold >21.75ºC 58.2% (n=32) Heat Pain Threshold <42.39ºC 40% (n=22) Mechanical Pain Threshold <7.29 g 54.5% (n=30) *1 SD from Control Median

Disclosures
Brandow: NIH, ASH: Research Funding. Panepinto:HRSA, NIH: Research Funding; NKT Therapeutics, Inc: Consultancy.