Aura and mental stress are associated with reports of pain in sickle cell disease‐a pilot study using a mobile application
Authors: Juan Espinoza, Payal Shah, Saranya Veluswamy, Lonnie Zeltzer, Michael C.K. Khoo, Thomas D. Coates, Jacquelyn Baskin
Journal: American Journal of Hematology (2020)

Sickle Cell Disease (SCD) patients frequently report severe pain from vaso-occlusive pain crisis (VOC), associated with increased morbidity and mortality. The underlying mechanisms that trigger VOC are still unknown, but recent research has suggested that autonomic dysfunction may play an important role.1-3 We have been able to quantify blood flow and autonomic mediated vasoconstriction under different stimuli such as stress and cold.1 Khaleel et al found that patients vasoconstricted in response to pain anticipation even before the actual pain stimuli.3 In fact, clinically, patients have observed subtle differences in their body with no evidence of pain in the pre-pain phase.4 They often report this as discomfort and pain anticipatory feelings or premonition of pain in the prodromal stage of VOC,4 similar to “aura” in patients with migraines,5 but the mechanism of this aura or premonition of imminent VOC in SCD is not known. To better understand the triggers of sickle-related pain, we needed to determine the frequency and magnitude of sickle-related pain episodes as well as the temporal relation between the pain and possible triggering factors. To accomplish this, we developed a minimalistic, user-friendly R-Helper mobile application to collect data on pain episodes, including pre-pain symptoms or contributing factors like stress and aura. This application allows patients to record their daily pain episodes and intensity, the patientʼs state of mind (daily stress level) and whether the patient had an aura prior to the pain episode. We present (a) the utility of using a simple mobile application to evaluate the frequency and intensity of pain in patients with SCD, and (b) the potential association between pain episodes, mental stress and presence of an aura. A total of 51 chronically transfused and non-transfused pediatric patients with SCD were enrolled from the Childrenʼs Hospital Los Angeles between October 2015 and August 2016. The consent/assent was obtained under the auspices of CHLA Institutional Review Board. Study participants were instructed to download the R-Helper application from the appropriate application store, and then were given a study ID code that activated the application. Details of R-helper application design and architecture has been described in on-line supplemental file S1, and in supplemental methods. Data was captured over 13-month period with more than 12 500 discrete data points. Descriptive statistics (frequency, percentages, mean/median and range) were used for data analyses. Each entry entered by the patient was treated individually. Linear regression was used to assess the relationship of pain with mental stress and aura. Utilization and compliance data were calculated over a 13-month time period. The details of utilization and compliance data are available in on-line supplemental file S2, supplemental results. Of the 51 patients enrolled, 39 participants had entered data and were analyzed. There were 17 (44%) males and median age was 19 years. A majority of patients (79%) were carrying Hemoglobin SS genotype. Out of 39, only 4 (10%) patients were previously diagnosed with chronic pain. Overall, females reported more frequent aura, pain, and pain medication use (P < .005). Females also reported significantly greater sickle cell pain intensity (5.5 vs 2.9) and mental stress intensity (3.4 vs 0, P < .005). Older patients reported frequent pain and aura events and greater pain intensity (6.3 vs 5.3) and stress intensity (1.7 vs 0) under “My day.” Non-transfused patients reported more frequent pain, aura before pain, higher use of pain medication, and higher stress intensity (3.8 vs 0, P < .001). Table S2 represents the total number of pain, aura and pain intensity reports over the 13-month period. A total of 59 reports of aura “In the moment” were entered by 14 patients. Out of those 59 reports for aura “In the moment,” 83% (n = 49 reports) stated that it was followed by pain and 10 reports of aura were not followed by pain (17%; P < .001). Under “My Day” reports, 26 patients reported experiencing auras, with five patients reporting more than 10 episodes. Out of 101 reports of aura under “My Day,” 78% (n = 79 reports) stated that it was followed by pain that day and 22% (n = 22 reports) of aura were not followed by pain that day (P < .001). Patients who reported having aura “in the moment” had significantly lower pain intensity (median 4.1) vs those without aura (median 6.1; P = .003). There was no association of aura and pain intensity for the day. Under “My Day,” if a patient reported having pain (n = 465), 84% (n = 390 reports) of the times they took medications. If a patient reported having aura before pain (n = 77), 92% (n = 71 reports) reported taking pain medication and 8% (n = 6 reports) did not take the pain medications (P = .03). On univariate analysis, there was a significant association between higher stress and higher pain (R2 = 0.24, P < .001, Figure 1). On multivariate analysis, greater pain intensity was significantly associated with greater stress intensity after controlling for age and gender (R2 = 0.33, Coefficient = 0.40, P < .001). In the same model, patients older than 20 years of age and females reported higher pain intensity. (Coefficient = 1.50 and 0.83 respectively, P < .001). The novel feature of this study was the identification of an aura preceding many episodes of SCD pain. While this phenomenon has been recognized for a long time, to our knowledge, its association with sickle pain has never been quantitatively evaluated. The pathophysiology of aura in the pre-pain phase is not known but these premonition feelings may reflect perceived dysautonomia-related changes in blood flow or in heart rate. Such changes may then lead to decrease in blood flow, red blood cells entrapment and sickle vaso-occlusion. Interestingly, patients who reported having aura had less pain intensity. Patients took medications 92% of time they reported having aura. Targeting these individuals with cognitive-neuromodulatory interventions in the pre-pain phase may improve neurovascular physiology in SCD.6 Although participants were instructed to enter their information when they had an aura and not wait until the onset of pain, most of the patients reported both at the same time. The next generation of mobile applications should better delineate the time interval between aura and pain to track temporal relationship. Incorporating interactive cognitive behavioral therapies in real-time could potentially mitigate the progression to VOC. One of the major findings was the strong association of mental stress and pain. Patients who reported higher stress had higher pain intensity, after controlling for age and gender. We have also demonstrated that experimental mental stress, anxiety and pain anticipation are associated with a decrease in microvascular blood flow and parasympathetic withdrawal. This is an indication that the stress induced autonomic mediated vasoconstriction can further promote VOC.2 To reduce the burden of this psychophysiological process, there is emerging need for development of integrative interventions. Available psychotherapeutic interventions such as distraction therapy, hypnosis, and biofeedback therapy will not only mitigate the stress and anxiety but also improve microvascular blood flow.6 Females reported more frequent pain, stress and aura as well as higher pain and stress intensity. The older age in our cohort includes the older patients transitioning to adult care. Compared to the patients younger than 20 years of age, older cohort frequently reported pain and stress with greater pain intensity. Transfusions are known to decrease VOC due to decrease in Hemoglobin S%. Our data showed that non-transfused patients reported more frequent pain but the pain intensity was not different between groups. However, the mental stress intensity was higher in non-transfused patients. These data are consistent with other studies supporting the validity of the application. This study showed the feasibility of using a mobile application to record pain, stress and aura in a cohort of patients with SCD. These triggering parameters could then be related to biophysical markers of vascular stability, autonomic function and blood flow. The overarching goal of this research is to evaluate the temporal relationship between VOC triggers, aura and pain events in SCD to facilitate the design of interventions that might abort VOC. We hope that the future version of this application will allow us to measure concomitant physiological data so that we can understand the physiology involved. Furthermore, this type of device may lend itself to a bio-feedback approach that may help avert the pain crisis all together. This work is supported by the Excellence in Hemoglobinopathies Research Award (EHRA) program (NIH U01-HL117718). The authors are thankful to Barry Cynamon for helping in data analysis. The authors are thankful to research coordinators Ana Munoz, Natalie Ornelas and Anna Ratiu for patient recruitment and data collection. The authors report no conflicts of interest. J.E. designed the application, interpreted data and drafted the manuscript. P.S. performed statistical analysis, data interpretation and wrote the manuscript, S.V. contributed in data interpretation and edited the manuscript, L.Z. designed the experiment and edited the manuscript, M.C.K. interpreted the data and edited the manuscript; T.D.C. designed the study, interpreted data and edited the manuscript, J.B. designed the study, supervised data collection, interpreted the data and edited the manuscript. Appendix S1. Supporting information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.