Experimental and Psychological Pain Phenotyping In Adults With Sickle Cell Anemia and Normal Volunteers

Sickle cell anemia (SCA) is the most prevalent Mendelian disease in the U.S. and is characterized by HbS polymerization, hemolytic anemia and vaso-occlusion. The hallmark clinical manifestation of SCA is acute vaso-occlusive pain crisis (VOC) with severe episodes requiring hospitalization for pain management. Vaso-occlusion resulting in pain is believed to occur with hypoxia, intra-vascular erythrocyte sickling and ischemia reperfusion injury. Recurring episodes of VOC often have no clear causation and may have effects upon physiological pain perception and intrinsic psychological characteristics like catastrophizing. It is not presently known if physiological pain processing or psychological factors influence pain in SCA compared to normal volunteers (NV). We hypothesized that adults with SCA would experience hypersensitivity to painful stimuli compared to NV as seen in other chronic painful conditions.

18 subjects with SCA and 19 age and sex matched NV underwent quantitative sensory testing (QST) for thermal, pressure and ischemic experimental pain phenotypes. Thermal testing (cold and heat) was performed at 4 sites on the volar forearm for temperature at first detection, threshold for sensing pain, and pain tolerance. Pressure pain threshold and tolerance were measured bilaterally at the thumb, forearm, and trapezius with an algometer. Ischemic pain testing was performed on the non-dominant arm inflating a blood pressure cuff of 220 mmHg and determining time to threshold and tolerance. Subjects were also administered the Pain Catastrophizing Scale (PCS-E) which is composed of 13 questions that address 3 dimensions: rumination, magnification, and helplessness. SCA and NV subjects with chronic pain unrelated to complications of SCA were excluded. All SCA subjects tested at baseline pain levels at least 2 weeks since their last painful event requiring intravenous narcotics. Non-parametric t-tests were used to compare results between SCA subjects and NV.

The mean age of SCA subjects was 33.4 (range 21-47) and NV was 32.1 (range 18-44). The only significant difference for thermal QST was temperature at first cold detection (SCA mean 24.5±6.3 ¢ªC vs. NV mean of 26.6±4.7 ¢ªC, P=0.05). There were no other significant thermal differences between SCA subjects and NV for cold pain threshold (P=0.84), cold pain tolerance (P=0.82), first heat detection (P=0.21), heat pain threshold (P=0.68) or heat pain tolerance (P=0.38). Furthermore, there were no differences in pressure between SCA and NV for pain thresholds at the thumb (P=0.31), forearm (P=0.44) or trapezius (P=0.10), nor were there pain tolerance differences at the thumb (P=0.63), forearm (P0.98) or trapezius (P=0.44). Surprisingly, ischemic pain QST showed no differences for initial pain threshold (468.3±263.1 seconds for SCA vs. 569.6±395.8 seconds for NV, P=0.69) or pain tolerance (642.5±245.4 seconds for SCA vs. 774.4±453.5 seconds for NV). Compared to NV, SCA subjects had significantly higher total catastrophizing (SCA median 30 vs. NV median 7, P=0.0005), rumination (SCA median 12 vs. NV median 3, P=0.0038), magnification (SCA median 8 vs. NV median 3, P=0.0006), and helplessness scores (SCA median 13 vs. NV median 3, P=0.0004).

Thermal detection of cold temperature change was the only observed difference, despite our hypothesis that recurrent painful episodes from SCA would alter sensitivity to experimental stimuli. Of particular interest are the results of ischemic pain QST, where SCA subjects appear to tolerate ischemia as well as NV despite the expectation this test would promote earlier forearm hypoxia, erythrocyte sickling and potentially vaso-occlusion. No significant difference in onset of ischemic pain between SCA and NV subjects appears to contradict the predominant pain vaso-occlusion paradigm for SCA. In addition, SCA subjects report significant levels of pain castastrophizing. Catastrophizing in other pain conditions may contribute to a psychological state that increases the severity of pain perception and a fear that pain control is impossible. Thus, catastrophizing may enhance chronic pain, pain impact, and its refractory response to pharmacotherapy. Further studies are necessary to determine if experimental pain or catastrophizing are associated with acute pain or chronic pain in SCA and to further elucidate the pathophysiology of pain in SCA.

No relevant conflicts of interest to declare.