Patients with Sickle Cell Disease Have Increased Sensitivity to Cold and Heat Stimuli, 2
Authors: Brandow Amanda M , Kattappuram Robbie , Stucky Cheryl L. , Hillery Cheryl A. , Panepinto Julie A. 
Published: October 2019

Abstract
Abstract 2116
Sickle Cell Disease (SCD) pain is associated with colder temperatures, touch, and increased wind speed and barometric pressure. The specific array of associated factors suggests hypersensitivity to tactile stimuli, a characteristic of neuropathic pain. Sickle mice exhibit hypersensitivity at baseline compared to controls to cold, heat, and mechanical stimuli via a TRPV1 mediated pathway. However, it is not known whether humans experience this same hypersensitivity. Thus, the objective of this study was to quantify sensitivity differences to thermal (heat, cold) and mechanical stimuli between SCD patients and healthy African American controls. We hypothesized SCD patients will exhibit hypersensitivity to thermal and mechanical stimuli compared to controls and this hypersensitivity will worsen with age and frequency of pain.
We conducted a cross-sectional study of SCD patients in baseline health and race-matched controls age ≥ 7 yrs. Our primary outcome was detection of hypersensitivity to thermal and mechanical stimuli. We excluded those with a pain phenotype other than SCD, overt stroke, analgesics within 24 hrs of testing, or acute SCD pain event within 2 weeks of testing. Subjects underwent quantitative sensory testing (QST) to thermal and mechanical stimuli. QST evaluates the somatosensory system detecting sensory loss (hyposensitivity) or gain (hypersensitivity). Thermal stimulation was performed with a Thermal Sensory Analyzer (Medoc;Israel), an FDA approved computer-assisted device that delivers cold and warm stimuli via a thermode attached to the skin (baseline temperature, 32°C; stimulus range, 0–50°C). Mechanical testing was performed using graded vonFrey monofilaments (force range 0.255 mN to 1078.731 mN). Testing was done on the thenar eminence of the non-dominant hand. Primary outcomes included: 1) Cold Pain Threshold (°C), 2) Heat Pain Threshold (°C), 3) Mechanical Pain Threshold (mN) as reported by “method of limits” where subjects pushed a button (thermal) or spoke (mechanical) when the progressive stimulus was painful. The final outcome was the computed mean of 3 tests (thermal) and 5 tests (mechanical).
Independent samples t-tests were used to compare outcomes between SCD patients and controls. Linear regression was used to evaluate the impact of age and gender on pain thresholds in both groups and the impact of lifetime history of pain, defined as total number of emergency department visits or hospitalizations for pain, on pain thresholds in SCD patients.
55 SCD patients and 57 controls were recruited (Jan 2010-June 2011). There were no differences in mean age (15.4 yrs vs.16.3 yrs; p=0.59, t-test) or gender (SCD=60% female vs. Controls=56% female; p=0.70, Pearson Chi-Square). SCD genotypes were 67% (n=37) HbSS, 18% (n=10) HbSC, 11% (n=6), HbSβ+thal, and 4% (n=2) other. SCD patients had significantly lower cold pain thresholds (p=0.008) and heat pain thresholds (p=0.04) compared to controls (Table 1). There were no differences in mechanical pain thresholds (p=0.38) (Table 1). Older age was associated with lower cold pain thresholds (parameter estimate=0.19°C; p=0.05), lower heat pain thresholds (parameter estimate=0.13°C; p=0.0069), and lower mechanical pain thresholds (parameter estimate=0.11mN; p=0.02) in both groups. Gender had no effect on the outcomes (cold pain threshold, p=0.15; heat pain threshold, p=0.07; mechanical pain threshold, p=0.29). Total number of lifetime SCD pain events had no effect on the outcomes (cold pain threshold, p=0.91; heat pain threshold, p=0.65, mechanical pain threshold, p=0.77).
SCD patients in baseline health experience increased sensitivity to cold and heat stimuli compared to race-matched controls and this sensitivity worsens with older age. These findings suggest peripheral sensitization may exist in SCD. Further research into how cold and heat sensing receptors and pathways contribute to SCD pain is warranted. Ultimately, this may lead to the development of novel therapeutics targeted to the specific underlying neurobiology of SCD pain that aids in the treatment or prevention of SCD pain.Table 1.Pain Thresholds of SCD Patients and Healthy Controls.OutcomeSCD Patients (Mean ± SD)Controls (Mean ± SD)P-valueCold Pain Threshold (°C)18.5 (7.7)14.1 (9.4)0.008Heat Pain Threshold (°C)42.5 (4.4)44.3 (4.6)0.04Mechanical Pain Threshold (mN)303.9 (409.6)375.6 (451.2)0.38

Disclosures:
No relevant conflicts of interest to declare.