The hallmark manifestation of homozygous sickle cell disease (SCD) is acute pain. The underlying etiology is unknown. It is believed that hypoxia induces changes in erythrocyte shape and produces microvasculature occlusion by sickled red cells. Vascular occlusion is believed to represent the event inducing tissue hypoxia, reperfusion injury and pain. Studies have only recently characterized pain responses to experimental stimuli in rodents and humans with SCD using quantitative sensory testing (QST). SCD is characterized by thermal and mechanical sensitivity, and there is evidence of central sensitization (heightened sensitivity to pain) from QST, temporal summation and functional MRI studies. However, the effect of hypoxia upon nociception has not been studied despite the need for hypoxia to induce sickle hemoglobin polymerization. The ischemic tourniquet pain test is a QST used to investigate nociception. It was the first QST to demonstrate opioid analgesia. While it is assumed that the resulting pain is due to hypoxia, no studies have demonstrated the degree of hypoxia needed to produce pain. Methods: Thirty adults with SCD and 30 age and sex matched 30 controls underwent the ischemic pain test. A pneumatic cuff was inflated around the upper arm to induce forearm hypoxia, and the time from cuff inflation to first reported pain (pain threshold) and until pain became intolerable (pain tolerance) was measured. Pain was quantified on a 20 point scale. Time to pain threshold and tolerance were the primary end points. Testing was repeated after a washout period in a subset of the initial subjects: 18 SCD patients and 22 controls. Repeat testing proceeded with a 15 minute observation period followed by the ischemic pain test with the time and pain score recorded at threshold and tolerance. Subjects were monitored after cuff deflation during recovery with pain scores obtained at 30 seconds, then every minute for 5 minutes and finally every 3 minutes over a total recovery period of 20 minutes. Skeletal muscle tissue oxygenation at the thenar eminence was measured continuously with a near infrared spectroscopy (NIRS) monitor (OxiplexTS; ISS, Champaign, IL). Results: SCD subjects reached the pain threshold at a mean of 6.44 versus 11.57 minutes in controls (p=0.07). Time to pain tolerance was significantly different (SS 11.29 versus controls 19.59 minutes; p=0.004). Both groups reported identical pain scores. By stepwise linear regression, SCD (p=0.002) and gender (p=0.0008) were associated with time to pain tolerance (r2=0.29), while recent opioid use and pain crisis frequency were not. Because these results demonstrated that SCD adults reach tolerance more rapidly than controls, we sought to determine if this difference was due to tissue hypoxia. Pain scores with repeat testing were not significantly different at threshold or tolerance. However, pain score curves over testing and recovery were significantly different (p=0.003, Fig 1A). SCA had pain above baseline after 11 minutes of recovery (p=0.02) suggesting a persistent pain response compared to controls. Oxyhemoglobin and deoxyhemoglobin from NIRS were not different between groups at the primary endpoints (Fig 1B and 1C). StO2 (% tissue oxygenation, Fig 1D) at both threshold and tolerance was not different between SCD and controls, suggesting that the onset and maximal level of pain during this QST is defined an StO2 thresholds 40% common to sickle cell patients and controls. However, oxyhemoglobin, deoxyhemoglobin and StO2 had already recovered to baseline by the time the pain was evident (Fig 1B, 1C and 1D). Conclusions: Adults with SCD reach hypoxia induced, experimental pain earlier than NVs. Time to maximal pain is associated with SCD and sex. NIRS showed that pain tolerance occurred at a uniform tissue oxygenation threshold indicating hypoxia is the primary determinant for sensing acute pain. However, persistent SCD pain was independent of tissue oxygenation, and could be explained by the presence of peripheral or central sensitization. These data suggest that SCD pain treatment may require improved oxygen delivery to affected tissues and analgesics. Figure 1. Nociceptive and NIRS responses to ischemic pain testing in adults with sickle cell anemia. Figure 1. Nociceptive and NIRS responses to ischemic pain testing in adults with sickle cell anemia. Disclosures No relevant conflicts of interest to declare.
The clinical hallmark of sickle cell anemia is the vaso-occlusive pain crisis. Although the exact cause for severe vaso-occlusive painful events is unknown, sickle cell microvasculature occlusion is thought to be the proximate cause producing tissue hypoxia, reperfusion injury and acute pain. Endothelial dysfunction is a prominent characteristic of sickle cell anemia, and it is unclear to what extent this abnormal vascular response contributes to vaso-occlusion and pain. We sought to evaluate the effects of hypoxia on sickle cell pain by performing a forearm ischemic pain test as a potential in vivo model for vaso-occlusion. We hypothesized that sickle cell anemia patients would tolerate a shorter period of ischemia before reaching pain tolerance. We further hypothesized that sickle patients would show more hypoxia and increased vasodilation. Thirty adults with sickle cell anemia were recruited and matched by age and sex to 30 normal volunteers. We first performed a timed ischemic pain test with brachial artery occlusion until subjects first reported pain (pain threshold) and until maximum pain tolerated (pain tolerance). Sickle cell subjects first reported pain at 411 vs. 589 s for normal volunteers (mean, p=0.07). Occlusion time to pain tolerance was significantly shorter for sickle cell patients (637 vs. 918 s, mean, p=0.004). Despite this difference, both groups reported nearly identical pain scores at threshold and tolerance. Stepwise linear regression for all subjects against 8 variables likely to influence pain showed sickle status (p=0.002) and gender (p=0.0008) were independently associated with time to tolerance, supporting our initial hypothesis. Testing with continuous physiological monitoring was next repeated in sub-groups of 7 sickle cell and 9 normal subjects in an effort to understand the association between ischemia and pain progression. Before, during, and after brachial artery occlusion, oxygenated/deoxygenated hemoglobin concentration and tissue oxygen saturation were continuously monitored with near-infrared spectroscopy at the thenar eminence. We also recorded cutaneous blood flow with a Laser Speckle Contrast Imager (FLPI-2) in the volar aspect of forearm and continuous blood pressure and pulse in the contralateral arm. Monitoring was performed during steady state prior to occlusion (15 min), during occlusion until pain tolerance, and during recovery (20 min). At steady state, sickle cell subjects had higher median heart rate (68 vs. 62 bpm, p=0.05) and cutaneous blood flow (81.8 vs. 46.8 a.u., p<0.0001). They also had lower median oxygenated hemoglobin (51.3 vs. 68 μM, p<0.0001), tissue oxygen saturation (62 vs. 68%, p<0.0001) and blood pressure (110/75 vs. 126/80, p<0.0001). During occlusion, the absolute decline in blood flow, calculated as a difference between median steady state flow and flow at 2 min of occlusion, was greater with sickle group (40.8 vs. 20.63 a.u., p=0.05). However, sickle cell oxygenated hemoglobin decreased at a slower rate (-0.12 vs. -0.15, median, p<0.0001). As before, time to pain tolerance was shorter with sickle cell (566 vs. 1460 sec., median, p=0.009). Surprisingly, sickle subjects had higher median tissue oxygen saturation (28.9 vs. 25.7%, p=0.005) and oxygenated hemoglobin (22.9 vs. 20.0 μM, p=0.006) at pain tolerance, but blood flow was not different. Consistent with this pattern, recovery of oxygenated hemoglobin occurred at a slower rate in the sickle group (0.61 vs. 0.84, median, p<0.0001). Sickle subjects had a brief hyperemic recovery period during which they returned to lower baseline levels of tissue oxygen saturation and oxygenated hemoglobin, and the duration of this hyperemic recovery was the same in normal volunteers. Overall, sickle cell subjects have significantly lower steady state tissue oxygenation, but they are less tolerant of hypoxia and develop pain at higher oxygenated hemoglobin levels during ischemia. Despite higher oxygenated hemoglobin during ischemia, sickle cell subjects have a significantly higher absolute decline in blood flow during occlusion, suggesting an altered hypoxic response compared to controls. This might suggest a hypersensitive hypoxic pain response, possibly due to the presence of chronic pain, and altered oxygen sensing. The ischemic pain test is a potential in vivo model for early stage trials of drugs that alter either acute pain transmission or oxygen delivery to tissues. Disclosures No relevant conflicts of interest to declare.
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