Sickle Cell Disease Pain Research Articles

The Impact of Socio-Economic Determinants of Health on PedsQL and Pain Outcomes Among Individuals with Sickle Cell Disease

Background: Pain in sickle cell disease (SCD) is the most visible symptom in patients. Many recent studies have shown that socio-economic status such as low income, educational achievement or even less affluent neighborhoods may contribute to the pain experience, with those of lower socioeconomic status (SES) reporting both acute and chronic pain more frequently. Furthermore, living in a less affluent area was associated with frequent use of analgesics after adjustment for pain intensity. The relationships between SES variables, pain-related anxiety, frequency of vaso-occlusive crises and/or acute care utilization have been explored; nevertheless, the relationship between SES and quality of life pain-related measures (pain hurt, pain interference, etc.) has yet to be reported. Methods: The St. Jude Children's Research Hospital Sickle Cell Clinical Research and Intervention Program (SCCRIP) is an observation cohort study of clinical outcomes in patients with SCD. Patients enrolled in SCCRIP were retrospectively evaluated based on various SES measurements. Household SES was evaluated using the Barratt Simplified Measure of Social Status (BSMSS), a composite index of parent education and occupation. The Social Vulnerability Index (SVI) was used to classify individuals based on social vulnerabilities at the neighborhood level. The area deprivation index (ADI) ranks neighborhood in a region of interest based on social risk factors that may predispose individuals to worse clinical outcomes Quality of life measures, Pain Hurt, Pain Impact, and Pain Management/Control, were extracted from the PedsQL SCD Module. High scores on the SVI and ADI are associated with low SES and high scores on the PedsQL indicate better SCD related quality of life (QoL) with lower burden and impact of pain on function. Multivariate linear regression models were used to evaluate the associations of SES with QoL pain-related outcomes, based on a stepwise model selection strategy, with potential covariates including age, gender, disease-modifying therapy (e.g., Hydroxyurea and chronic transfusions), hemoglobin, hemoglobin F (HbF)%, and each SES variable. Results: 944 patients between the ages of 5-61 (Mean=13.75, Standard Deviation=7.57) years diagnosed with SCD completed PedsQL testing and were assessed for SVI and ADI. Multivariate models demonstrated that patients with lower SVI (i.e., higher neighborhood SES) at the neighborhood level displayed higher scores with regards to Pain Hurt (est=-7.44, standard error (SE)=2.84, p=0.01), Pain Impact (est=-9.56, SE=3.18, p=0.003) and Pain Management/Control (est=-9.35, SE=3.81, p=0.01). Similar relationships were observed for patients with lower ADI. Additionally, there was a significant association between pain impact and BSMSS (est=0.20, SE=0.10, p=0.04), suggesting that individuals with higher BSMSS (higher household SES) also had higher pain impact scores (better quality of life). Conclusions: This study demonstrated that neighborhood and household SES have an impact on pain experience in youth with SCD. Patients with increased social vulnerability and area deprivation experienced lower health-related quality of life-related to SCD pain. Increased household SES was associated with greater SCD pain impact independent of the effects of patient age, gender, SCD therapy, and HbF. Our study suggests that social determinants of health, such as SES, play a role in pain experience and QOL related to SCD pain and should be explored further.

Mechanism(s)-of-Action for Arginine Therapy in Children with Sickle Cell Disease and Vaso-Occlusive Pain: Results of a Pharmacokinetics/Pharmacodynamics Study

Introduction: Low L-Arginine (Arg) bioavailability is associated with sickle cell disease (SCD) mortality and morbidity, including acute pain severity. Multiple phase 2 trials support the safety and efficacy of Arg therapy in children with SCD experiencing vaso-occlusive pain. Nitric oxide (NO) is a potent vasodilator depleted in SCD due to hemolysis. As the obligate substrate for NO production, Arg's mechanism-of-action is unknown but thought to be related in part to NO production. Kyotorphin (KTP) is an endogenous opioid analgesic composed of the amino acids tyrosine and Arg. Its nociceptive effects are through induction of Met-enkephalins release in the brain. Oral administration of Arg in wild-type mice increases the levels of KTP centrally. We have previously shown that Arg supplementation increases NO metabolites (NOx), improves mitochondrial function, decreases oxidative stress, and has opioid sparing effects in children with SCD. The association between IV Arg supplementation as a precursor to KTP in SCD is unknown and may represent a novel mechanism by which Arg decreases pain in patients with SCD. Objective: To analyze the results of a pharmacokinetics/pharmacodynamics study, evaluating the association between Arg supplementation and plasma levels of KTP and other potential mechanisms-of-action related to Arg in children with SCD and vaso-occlusive pain episodes (VOE). Methods: We conducted a pharmacokinetics/pharmacodynamics study of children aged 7-21 years with SCD hospitalized for VOE and randomized to treatment utilizing one of 3 dosing arms of Arg: 1) 100mg/kg IV three times/day, standard dose (n=4); 2) loading dose (200mg/kg) followed by standard dose (n=5); or 3) loading dose (200mg/kg) followed by continuous infusion (300mg/kg/day) until discharge (n=4). Plasma amino acids (arginine, ornithine, citrulline), global arginine bioavailability ratio (GABR; Arginine/[Citrulline+Ornithine]), KTP, NOx, exhaled NO, plasma arginase activity, and arginase-1 and -2 were measured. Mean±SD, paired t-tests, and Pearson correlation analyses between groups were performed where appropriate. Results: A total of 13 patients (age 13±3 years, 56% male, 88% Hb-SS, 85% on hydroxyurea) were enrolled. Statistically significant increases in plasma arginine levels (Fig1A), plasma KTP levels (Fig1B), and GABR from pre-dose (0 hour) to 1, 1.5, and 2 hours after arginine infusion were observed, with a return to baseline 8 hours after Arg administration. Arg and KTP levels peaked between 60-90 minutes after arginine infusion in all study arms (p<0.001, p=0.004 respectively). There were no significant differences in peak concentration across all study arm doses. Rise in KTP levels strongly correlated with changes in plasma Arg concentration ( r=0.72, p<0.0001). Plasma NOx levels significantly increased from pre-dose to Tmax (Tmax= 1-2 hours; mean percent change 156±313%, p=0.02), as did exhaled NO (mean percent change 31±27%, p=0.02). Arginase activity also increased significantly after IV Arg infusion peaking at approximately 90 minutes (mean percent change 137±183%, p= 0.03) with return to baseline at 8 hours, while there was no significant change in arginase-1 or -2 concentrations over time. Conclusion: IV Arg therapy increased plasma arginine concentration 2-5 times above baseline at presentation for VOE, and GABR also increased as expected in this pharmacokinetics study with both reaching a maximum concentration within 1 hour of infusion initiation in all dosing schemes. IV Arg supplementation increases plasma NOx levels suggesting a role for vasodilation as a potential mechanism-of-action during SCD-VOE. Exhaled NO also increased significantly, consistent with previous reports. Interestingly, IV Arg supplementation acutely increased arginase activity without a significant change in arginase concentration. Most notably, we report for the first time the impact of IV Arg therapy on plasma levels of KTP in SCD. As KTP is an endogenous opioid analgesic, this may represent a novel mechanism-of-action of Arg therapy that warrants further investigation. This observation may also have implications for the potential use of arginine supplementation in pain syndromes beyond sickle cell disease.

Observed Variability in Gene Expression in Individuals with Sickle Cell Disease during Baseline Health and Acute Pain

Background: Acute pain episodes are the most common complication of sickle cell disease (SCD). There is wide variability in frequency and presentation of pain between patients despite inheritance of the same genetic defect. The underlying biology that accounts for this variability is still unknown. Prior data support cytokine profiles change in individuals with SCD during acute pain as opposed to baseline health and may contribute to SCD pain biology. We therefore hypothesized that there would be differences in gene expression profiles within a patient between baseline health and acute pain ( intraindividual variability). Further, due to the variability in pain expression between individuals with SCD, we also hypothesized that gene expression profiles would show interindividual variability between patients with SCD. Methods: Our study included a convenience sample of individuals with SCD and healthy Black controls recruited from tertiary care facilities. Paired plasma samples were collected from individuals with SCD during baseline health and acute pain. We conducted a cross-sectional analysis in 2 independent datasets (i.e., one single center, one multicenter - “The Magnesium for Children in Crisis trial”) of these paired samples. We used a novel plasma-based transcription bioassay to assess gene transcription in a peripheral blood mononuclear cell (PBMC) that served as a sensor to plasma-borne factors. Patient plasma was co-cultured with cryopreserved PBMCs from a healthy donor to induce transcription. We identified informative transcripts that differentiated individuals with SCD from healthy controls thereby defining the disease-specific plasma-induced signature and retained transcripts differentially expressed between individuals with SCD and controls that exhibit a fold change >1.4, ANOVA p-value of <0.05 and an FDR <10%. For further data reduction, we also retained the top 25% of transcripts with the highest intensity signals and retained the top 5000 genes with the highest mean absolute deviation (MAD) in both analyses. The intersection of genes identified by these two analyses (i.e., top 25% and MAD) was used as an input gene list for Weighted Gene Correlation Network Analysis (WGCNA). WGCNA was used to extract the genes that were most closely associated with pain. To this end, we retained all genes that had a correlation of ≥0.3 and p-value of <0.05 between the gene and the number of acute care visits for pain in the prior 3 years. This gene list was designated as the final SCD pain-specific list. Heatmaps of gene expression of those in the SCD pain-specific list were created using Genesis. Results: We analyzed paired samples from 149 individuals with SCD (median age 13.6, IQR 9.3-17.1) during baseline health and acute pain (27 from single center cohort, 122 from multicenter cohort). The data reduction filtering analyses identified 1177 genes of interest. Figure 1 shows both mean gene expression in the single center cohort and paired gene expression for each individual. As depicted, overall mean gene expression does not appear to differ between baseline health and acute pain. When evaluating each individual as a paired set we observe that in the majority of individuals gene expression does not change substantially between the two states of health, suggesting minimal intraindividual variability. However, a minority of individuals do exhibit more substantial changes between states of health. When considering the same state of health, wide interindividual variability among patients is observed. These findings were reproducible in a larger, multicenter cohort, as shown in Figure 2. Conclusion: Our findings suggest low intraindividual variability in most individuals with SCD, signifying fixed gene expression that may not change within an individual between baseline health and acute pain. Wide interindividual variability in gene expression was observed which might be responsible for the differences in phenotypic pain expression despite inheritance of the same hemoglobin S mutation. These data suggest pain endotypes within SCD may exist that need further investigation. If identified, these SCD pain endotypes could be leveraged for tailored analgesia or early intervention with higher risk treatments such as curative therapy. Further investigation of groups of genes that show the most variability could be investigated as potential targets for pain treatment.

A Retrospective Study Evaluating the Association of Qualitative and Quantitative Aspects of Vaso-Occlusive Crises (VOC) with Length of Hospital Stay in Children with Sickle Cell Disease Hospitalized for a VOC

Background: Children with sickle cell disease (SCD) are at risk for developing a vaso-occlusive pain crisis (VOC) due to sickled red blood cells causing turbulent blood flow and obstruction within the vasculature, leading to local tissue infarcts and subsequently pain. A VOC can often be managed with analgesics and supportive care either at home or in the emergency room. However, sometimes the pain is not adequately controlled in those settings, so children require hospitalization for further management of their VOC. There exists a high degree of variability in length of hospital stay (LOS) among children who are admitted for VOCs. The purpose of this study is to determine which factors are associated with decreased or increased length of hospital stay (LOS). By identifying these factors, it will allow for a more targeted approach to VOC management with the goal of improving overall pain and reducing LOS. Methods: This 3 year (2019 - 2022) retrospective cohort study includes 88 patients (5 years to 27 years of age) with sickle cell disease (HbSS, HbSB0, HbSB+, HbSC) who were hospitalized for VOC management. Several variables were analyzed to determine if they correlated with LOS. These variables included SCD genotype, age, sex, pain scores, average hemoglobin and reticulocyte levels during hospitalization, pain medication dosage and frequency, blood transfusions and complications during hospitalization. The statistical analysis of these variables was conducted across all VOCs of all patients. Results: There were 289 hospital admissions for VOCs with a mean of 3.55 hospital admissions per patient among the 88 patients with SCD during study duration. LOS for these VOC hospital admissions ranged from 1 day to 10 days with an overall mean of 3.81 days per hospital admission. LOS was independently highest in females (mean LOS = 4.123 days, F (1, 287) = 6.415, p = .012) and patients who developed acute chest syndrome (mean LOS = 6.333 days, F (9, 277) = 4.771, p < .001). LOS positively correlated with pain scores (r 2 = .272, p = .002), number of blood transfusions (r 2 = .229, p < .001) and total units of blood transfused during admission (r 2 = .230, p < .001) and negatively correlated with morphine frequency (r 2 = -.125, p = .042) and average hemoglobin during admission (r 2 = -.142, p = .016). SCD genotype, age, reticulocyte levels and medication dosage were not found to have a statistically significant association with LOS. Conclusion: Our study showed that factors such as higher average pain scores, number of blood transfusions, total units of blood transfused, females and acute chest syndrome were associated with longer LOS. Other factors such as more frequent morphine administration and higher average hemoglobin levels were associated with shorter LOS. While this study provides initial insight into some of the factors that are associated with LOS in children with SCD admitted for a VOC, further studies are warranted to determine if these factors can be used to risk stratify patients in terms of severity of VOC and thereby better optimize and individualize their pain management.

Elevated Heme Drives Evoked and Ongoing Pain Behaviors in WT Mice By Sensitization of Dorsal Root Ganglia Neurons

Individuals with sickle cell disease (SCD) suffer from complex stimulus-evoked and ongoing pain that is mediated in part by the hyperexcitability of their peripheral sensory neurons. However, it is unclear whether acute or chronic elevation of cell free heme, a key pathological feature of SCD, contributes to the aberrant activity of sensory neurons. Thus, determining whether heme drives pain behavior and enhanced excitability of dorsal root ganglia (DRG) primary sensory neurons involved in pain signal transduction is critical for the development of targeted pain therapies for SCD. In the current experiments, we use evoked and ongoing pain behavior assays and in vitro calcium imaging to evaluate the hypothesis that acute increases in heme causes direct sensitization of nociceptive DRG neurons in wildtype (WT) mice. Our preliminary data reveal that similar to pain behaviors in the mouse model of SCD, hind paw injection of heme into WT mice induces mechanical hypersensitivity (Figure 1). We also observed increased aversive responses to dynamic paintbrush and noxious needle stimulation as well as the onset of paw licking behavior suggesting that heme also drives ongoing, non-evoked pain. These data suggest that axon terminals in the skin become rapidly sensitized when exposed to elevated heme. We next administered heme to primary cultured DRG neurons in vitro and observed calcium flux across the neuronal cell membrane that was dependent on extracellular calcium. To determine if heme directly triggers action potentials or enhances spontaneous activity of sensory neurons, we conducted electrophysiological recordings of neuronal activity in neurons held at resting membrane potential at physiological temperature. Our preliminary data indicate that exposure to heme may directly enhance neuronal action potential firing frequency (Figure 2). Together, these data suggest that heme opens calcium channels on sensory neurons to initiate pain signal transduction and drive acute pain behaviors. We plan to conduct additional non-evoked pain behavior assays including facial grimace analysis and conditioned place aversion to determine whether heme injection is sufficient to drive ongoing pain. We will further determine whether exposure to heme enhances the intrinsic excitability of mechanical and cold sensitive neurons as heme-dependent hyperactivity of these neurons may lead to our observed acute onset mechanical and cold hypersensitivity in heme-injected mice. Completion of these experiments will shed light on the contributions of cell free heme to SCD pain and illuminate downstream effectors that may be targeted to provide analgesic relief for this historically understudied and debilitating disease.

Agreement between youth and caregiver report of pain and functioning in pediatric sickle cell disease: PedsQL sickle cell disease module.

Pain is a primary symptom of sickle cell disease (SCD) and is often severe and chronic. To treat SCD-related pain, proper assessment of SCD pain among youth, including the degree of concordance or agreement between youth and caregiver reports of pain, is essential but has not yet been adequately evaluated. In this study, 525 youth with SCD and their parents were evaluated as part of the Sickle Cell Clinical Research and Intervention Program (SCCRIP) to examine pain rating concordance and predictors of concordance. Youth and parents completed the Pediatric Quality of Life Inventory Sickle Cell Disease module (PedsQL-SCD) to measure pain, pain interference, and pain-related constructs. Disease, clinical, and demographic variables were obtained from the SCCRIP database. Intraclass correlations demonstrated moderate-to-poor consistency between youth and caregiver reports of pain and pain interference (ICCs range from 0.17 to 0.54). Analysis of covariance and regression models found that patient age, frequency of hospitalizations and emergency department (ED) visits, economic hardship, and fetal hemoglobin levels were significantly associated with varying pain-rating agreement levels among parent proxy and child self-report pain. Concordance of pain assessments among youth with SCD and their caregivers using the PedsQL-SCD Module was moderate at best, corroborating prior research. Youth factors predicting discordance among pain-related factors included increased ED visits, older age, and female sex. Collectively, these results bolster the use of integrated pain assessments to reduce parent-child discrepancies, thereby improving the adequacy of SCD-related pain assessment and treatment.

Monitoring and responding to signals of suicidal ideation in pragmatic clinical trials: Lessons from the GRACE trial for Chronic Sickle Cell Disease Pain

Sickle cell disease (SCD) is a hemoglobin disorder and the most common genetic disorder that affects 100,000 Americans and millions worldwide. Adults living with SCD have pain so severe that it often requires opioids to keep it in control. Depression is a major global public health concern associated with an increased risk in chronic medical disorders, including in adults living with sickle cell disease (SCD). A strong relationship exists between suicidal ideation, suicide attempts, and depression. Researchers enrolling adults living with SCD in pragmatic clinical trials are obligated to design their methods to deliberately monitor and respond to symptoms related to depression and suicidal ideation. This will offer increased protection for their participants and help clinical investigators meet their fiduciary duties. This article presents a review of this sociotechnical milieu that highlights, analyzes, and offers recommendations to address ethical considerations in the development of protocols, procedures, and monitoring activities related to suicidality in depressed patients in a pragmatic clinical trial.

Gastrointestinal symptoms, diagnostic evaluations, and abdominal pathology in children with sickle cell disease.

Children with sickle cell disease (SCD) frequently present with acute pain. The abdomen, a common site of acute SCD-related pain, may be present in a variety of gastrointestinal (GI) pathologies. Limited data exist on prevalence and workup of abdominal pain in patients with SCD during acute pain events. Determine prevalence of GI symptoms, GI-specific evaluation and risks of hospitalization in children with SCD presenting to the emergency department (ED) or hospitalized with abdominal pain. Retrospective study of children less than 21years presenting to the ED or hospitalized with pain in our center over 2years. Descriptive statistics were used to report clinical characteristics, frequency of GI symptoms, workup by age (<5 vs. ≥5years), and genotype (sickle cell anemia [SCA] vs. non-SCA). Logistic regression models were used to identify risks associated with hospitalization. A total of 1279 encounters in 378 patients were analyzed; 23% (n=291) encounters were associated with abdominal pain. More abdominal pain-associated hospitalizations occurred in older children, SCA, children with lower mean hemoglobin (8.7±1.9 vs. 9.6±1.6g/dL, p<.001) and higher mean white blood cell (WBC) count (14.9±6.6 vs. 13.2±5.3×103 /μL, p=.02). We identified that less than 50% of patients presenting to the ED with abdominal pain received a GI-specific evaluation. Children with SCD frequently present with abdominal pain and other GI symptoms, with limited GI evaluations performed. GI-specific evaluation may increase diagnosis of GI pathologies, rule out GI pathologies, and contribute to the limited knowledge of the abdomen as a primary site of SCD pain.

Gut microbiota dysbiosis alters chronic pain behaviors in a humanized transgenic mouse model of sickle cell disease.

Pain is the most common symptom experienced by patients with sickle cell disease (SCD) throughout their lives and is the main cause of hospitalization. Despite the progress that has been made towards understanding the disease pathophysiology, major gaps remain in the knowledge of SCD pain, the transition to chronic pain, and effective pain management. Recent evidence has demonstrated a vital role of gut microbiota in pathophysiological features of SCD. However, the role of gut microbiota in SCD pain is yet to be explored. We sought to evaluate the compositional differences in the gut microbiota of transgenic mice with SCD and nonsickle control mice and investigate the role of gut microbiota in SCD pain by using antibiotic-mediated gut microbiota depletion and fecal material transplantation (FMT). The antibiotic-mediated gut microbiota depletion did not affect evoked pain but significantly attenuated ongoing spontaneous pain in mice with SCD. Fecal material transplantation from mice with SCD to wild-type mice resulted in tactile allodynia (0.95 ± 0.17 g vs 0.08 ± 0.02 g, von Frey test, P < 0.001), heat hyperalgesia (15.10 ± 0.79 seconds vs 8.68 ± 1.17 seconds, radiant heat, P < 0.01), cold allodynia (2.75 ± 0.26 seconds vs 1.68 ± 0.08 seconds, dry ice test, P < 0.01), and anxiety-like behaviors (Elevated Plus Maze Test, Open Field Test). On the contrary, reshaping gut microbiota of mice with SCD with FMT from WT mice resulted in reduced tactile allodynia (0.05 ± 0.01 g vs 0.25 ± 0.03 g, P < 0.001), heat hyperalgesia (5.89 ± 0.67 seconds vs 12.25 ± 0.76 seconds, P < 0.001), and anxiety-like behaviors. These findings provide insights into the relationship between gut microbiota dysbiosis and pain in SCD, highlighting the importance of gut microbial communities that may serve as potential targets for novel pain interventions.

Feasibility and preliminary efficacy of the Balance Program to reduce pain-related disability in pediatric sickle cell disease.

Sickle cell disease (SCD) pain is associated with functional impairment, and treatment is often limited to pharmacological approaches with unwanted side effects. Although behavioral interventions exist for non-SCD pain populations, interventions designed to address pain-related impairment in SCD are lacking. Twenty youth (9-17 years) with SCD completed a four-week telemedicine pain intervention (NCT04388241). Participants and caregivers completed baseline and post-intervention PROMIS pain measures and the Treatment Evaluation Inventory-Short Form (TEI-SF). Descriptive analyses assessed feasibility and acceptability. Reliable Change Index analyses assessed for significant post-intervention changes in pain functioning. Paired t test analyses compared baseline and post-intervention opioid prescription fills. All participants completed at least one treatment session. Eighteen (90%) youth completed all sessions. Youth (100%) and caregivers (94%) rated the intervention as moderately or highly acceptable on the TEI-SF. Forty-seven percent of caregivers and 44% of youth reported reliably significant improvements in pain interference after the intervention (median T-score differences: 24.8 and 23.5, respectively). Sixty-five percent of caregivers (T-score improvement difference: 19.3) and 31% of youth (T-score improvement difference: 32) reported improvements in pain behaviors. There was no significant difference in opioid prescription fills pre- and post-intervention (P>0.05). The Balance Program is feasible, highly acceptable, and can be delivered remotely to reduce barriers to care. Approximately half of youth and caregivers reported significant declines in pain interference following the intervention, with substantial improvements in functioning for treatment responders. Behavioral pain interventions are important adjunctive treatments to uniquely address functional impairment associated with acute and chronic pain in SCD.

“Buprenorphine, It Works so Differently”: Adults with Sickle Cell Disease Describe Transitioning to Buprenorphine for Treatment of Chronic Pain

A growing body of literature describes the use of buprenorphine for the treatment of chronic pain in people with sickle cell disease. The experiences of people with sickle cell disease who have tried buprenorphine have not yet reported. This qualitative descriptive study was conducted to explore perspectives on buprenorphine for chronic pain in sickle cell disease. We interviewed 13 participants with sickle cell disease who had been prescribed buprenorphine and had a clinic visit between December 1, 2020, and April 2022 in our Sickle Cell Center for Adults. Interviews were recorded, transcribed, and analyzed using thematic analysis. Eleven out of 13 participants were taking buprenorphine at the time of the interview, with a mean treatment duration of 33 months (SD 18, range 7–78 months). Five major themes were identified: 1) dissatisfaction with full agonist opioids; 2) navigating uncertainty with autonomy in deciding to try buprenorphine; 3) functional and relational changes after starting buprenorphine, 4) enduring systemic barriers to pain treatment, and 5) trusting treatment relationships are necessary when approaching patients about buprenorphine. The experience of adulthood living with sickle cell disease before and after starting buprenorphine is qualitatively different with significant improvements in social functioning. PerspectiveThis study examined the experience of adults with sickle cell disease and chronic pain transitioning from full agonist opioids to buprenorphine. It is the first qualitative study of buprenorphine in people with sickle cell disease, contributing to a small but growing literature about buprenorphine and sickle cell disease.

Hematologists' Attitudes Toward Sickle Cell Disease Pain Management

Sickle cell disease causes pain that can manifest in chronic or acute crises. In addition to other possible complications, this pain can frequently place sickle cell patients in the emergency room and hospital. The high volume of patient visits requires an analysis of the quality of care for this group and a conscious effort to improve the care from providers. This study aims to evaluate the attitudes of United States hematologists toward current SCD management guidelines established by the American Society of Hematology (ASH). No statistically convincing evidence was found to support the hypothesis that not all United States hematologists agree with each ASH sickle cell treatment guideline. However, there is a deeper level of contextual understanding and discussion necessary to confidently make this conclusion.

Nurses’ Attitudes Concerning Analgesia Administration for Pediatric Patients with Sickle Cell Disease in Jordan: A Cross-Sectional Study

BackgroundPain management of vaso-occlusive crises is a fundamental priority in the lifelong care of children and adolescents with sickle cell disease. AimThis study examined nurses' attitudes towards caring for children with sickle cell disease (SCD) and SCD pain management in those with vaso-occlusive pain. MethodA structured, self-reporting survey was provided to a convenience sample of 298 nurses across 10 hospitals serving Jordan's northern and middle regions. Descriptive and inferential statistics were applied for data analysis. ResultsMost nurses (77%) perceived their experience caring for children with SCD as positive. Many nurses (65%) felt frustrated about caring for these children during painful episodes. Participants identified workload and inadequate time as limiting their ability to address the analgesic needs of children with SCD. Receiving structured education specialized in pain management and more years of experience in nursing significantly predicted less hesitancy in administering opioid-based analgesia. ConclusionsThe results of this study provided further insight into factors that potentially contribute to vaso-occlusive pain crises frequently being poorly managed and inadequately addressed among pediatric patients. Nurses' attitudes and understanding of SCD pain management must be addressed to advance the clinical practice of managing pain in children with SCD.

Biopsychosocial Factors Associated With Pain and Pain-Related Outcomes in Adults and Children With Sickle Cell Disease: A Multivariable Analysis of the GRNDaD Multicenter Registry

Pain is the primary symptomatic manifestation of sickle cell disease (SCD), an inherited hemoglobinopathy. The characteristics that influence pain experiences and outcomes in SCD are not fully understood. The primary objective of this study was to use multivariable modeling to examine associations of biopsychosocial variables with a disease-specific measure of pain interference known as pain impact. We conducted a secondary analysis of data from the Global Research Network for Data and Discovery national SCD registry. A total of 657 children and adults with SCD were included in the analysis. This sample was 60% female with a median age of 34 (interquartile range 26–42 years) and a chronic pain prevalence of 64%. The model accounted for 58% of the variance in pain impact. Low social (P < .001) and emotional (P < .001) functioning, increasing age (P = .004), low income (P < .001), and high acute painful episodes (P = .007) were most strongly associated with high pain impact in our multivariable model. Additionally, multivariable modeling of pain severity and physical function in 2 comparable samples of registry participants revealed that increasing age and low social functioning were also strongly associated with higher pain severity and low physical functioning. Overall, the results suggest that social and emotional functioning are more strongly associated with pain impact in individuals with SCD than previously studied biological modifiers such as SCD genotype, hemoglobin, and percentage fetal hemoglobin. Future research using longitudinally collected data is needed to confirm these findings. PerspectiveThis study reveals that psychosocial (ie, social and emotional functioning) and demographic (ie, age) variables may play an important role in predicting pain and pain-related outcomes in SCD. Our findings can inform future multicenter prospective longitudinal studies aimed at identifying modifiable psychosocial predictors of adverse pain outcomes in SCD.

Knowledge, attitude, and practice of physicians regarding pain management in patients with Sickle cell disease

Sickle cell disease (SCD) is a hemoglobin disorder inherited in an autosomal recessive pattern. Pain from vaso-occlusive crises (VOCs) is the most common symptom experienced by patients with SCD; thus, pain management constitutes a significant role in this patient population. We hypothesized that physicians with less favorable attitudes toward SCD patients are less likely to follow pain management guidelines. In this cross-sectional convenience sample survey, we aimed to assess the adherence of physicians in our institute to guidelines for the management of SCD pain crises and study the factors that are associated with non-adherence to these guidelines. Most surveyed physicians were early in their career and were found to adhere to the recommendations of using opioids and NSAIDs as a first-line therapy and avoiding using meperidine. On the other hand, some analgesic practices deviated from the recommendations, including less frequent assessment and reassessment of pain and response to pain medications and less frequent use of opioid patient-controlled analgesia (PCA). It is noteworthy that the frequency and severity of untreated pain in patients with SCD are associated with higher mortality, thus appropriate comprehensive care for such a vulnerable population should be prioritized and optimized. Although we did not find an association between the providers’ attitudes toward SCD patients and their pain management practices, improving these attitudes will promote the provider–patient relationship and its therapeutic outcomes. We conclude that the physicians taking care of SCD patients in our institute adhere to some of the guidelines in the field more than others. We also conclude that they have negative attitudes toward SCD patients; nevertheless, these did not affect their pain management practices.

An alcohol dehydrogenase 7 gene polymorphism associates with both acute and chronic pain in sickle cell disease.

Introduction: As the most distressing complication of sickle cell disease (SCD), pain is marked by considerable heterogenicity. In this study we explored the potential association of alcohol dehydrogenase 7 gene (ADH7) polymorphismrs971074 with sickle cell pain. Methods: We analyzed clinical phenotypes and thers971074 single-nucleotide polymorphismin ADH7 by MassARRAY-iPlex analysis in a cohort of SCD patients. Results: The synonymous rs971074 wassignificantly associated with both acute and chronic pain in SCD. Patients withthe minor T allele(s) recorded significantly more crisis episodes and severe chronic pain symptoms. Conclusion: Our study has identified the rs971074 minor T allele as a genetic biomarker potentially influencing acute and chronic pain. These findings may ultimately help inform strategies to develop precision pain therapies in SCD.

Preliminary construct validity of patient-reported outcomes to assess chronic pain in adults with sickle cell disease.

Chronic pain affects 30% to 40% of individuals with sickle cell disease (SCD) and impairs patient functioning. Clinically meaningful, practical, and valid assessment tools for investigation, evaluation, and management of chronic pain are limited, representing a barrier for advancing SCD care. We sought to determine whether patient-reported outcomes (PROs) show preliminary construct validity in identifying individuals with SCD who were a priori defined as suggestive of having chronic pain based on previously published criteria. All individuals completed the Patient-Reported Outcomes Measurement Information System (PROMIS) domains: pain interference, pain behavior, pain quality (nociceptive, neuropathic), fatigue, sleep disturbance, depression, and anxiety; the Adult Sickle Cell Quality of Life Measurement Information System (ASCQ-Me) domains: pain impact and emotional impact; and the painDETECT questionnaire. Thirty-three adults living with SCD were enrolled, and 42.4% had chronic pain. Pain-related PROs scores distinctly differentiated individuals with chronic pain from those without. Individuals with chronic pain had significantly worse pain-related PROs scores: PROMIS pain interference (64.2 vs 54.3), PROMIS pain behavior (63.2 vs 50), and ASCQ-Me pain impact (42.9 vs 53.2). According to published PROMIS clinical cut scores for the pain-related domains, individuals with chronic pain were categorized as having moderate impairment, whereas those without chronic pain had mild or no impairment. Individuals with chronic pain had PRO pain features consistent with neuropathic pain and worse scores in fatigue, depression, sleep disturbance, and emotional impact. Pain-related PROs show preliminary construct validity in differentiating individuals with and without chronic SCD pain and could be used as valuable tools for research and clinical monitoring of chronic pain.

Examining Mental Health, Education, Employment, and Pain in Sickle Cell Disease

Pain related to sickle cell disease (SCD) is complex and associated with social determinants of health. Emotional and stress-related effects of SCD impact daily quality of life and the frequency and severity of pain. To explore the association of educational attainment, employment status, and mental health with pain episode frequency and severity among individuals with SCD. This is a cross-sectional analysis of patient registry data collected at baseline (2017-2018) from patients treated at 8 sites of the US Sickle Cell Disease Implementation Consortium. Data analysis was performed from September 2020 to March 2022. Electronic medical record abstraction and a participant survey provided demographic data, mental health diagnosis, and Adult Sickle Cell Quality of Life Measurement Information System pain scores. Multivariable regression was used to examine the associations of education, employment, and mental health with the main outcomes (pain frequency and pain severity). The study enrolled a total of 2264 participants aged 15 to 45 years (mean [SD] age, 27.9 [7.9] years; 1272 female participants [56.2%]) with SCD. Nearly one-half of the participant sample reported taking daily pain medication (1057 participants [47.0%]) and/or hydroxyurea use (1091 participants [49.2%]), 627 participants (28.0%) received regular blood transfusion, 457 (20.0%) had a depression diagnosis confirmed by medical record abstraction, 1789 (79.8%) reported severe pain (rated most recent pain crises as ≥7 out of 10), and 1078 (47.8%) reported more than 4 pain episodes in the prior 12 months. The mean (SD) pain frequency and severity t scores for the sample were 48.6 (11.4) and 50.3 (10.1), respectively. Educational attainment and income were not associated with increased pain frequency or severity. Unemployment (β, 2.13; 95% CI, 0.99 to 3.23; P < .001) and female sex (β, 1.78; 95% CI, 0.80 to 2.76; P < .001) were associated with increased pain frequency. Age younger than 18 years was inversely associated with pain frequency (β, -5.72; 95% CI, -7.72 to -3.72; P < .001) and pain severity (β, 5.10; 95% CI, -6.70 to -3.51; P < .001). Depression was associated with increased pain frequency (β, 2.18; 95% CI, 1.04 to 3.31; P < .001) but not pain severity. Hydroxyurea use was associated with increased pain severity (β, 1.36; 95% CI, 0.47 to 2.24; P = .003), and daily use of pain medication was associated with both increased pain frequency (β, 6.29; 95% CI, 5.28 to 7.31; P < .001) and pain severity (β, 2.87; 95% CI, 1.95 to 3.80; P < .001). These findings suggest that employment status, sex, age, and depression are associated with pain frequency among patients with SCD. Depression screening for these patients is warranted, especially among those experiencing higher pain frequency and severity. Comprehensive treatment and pain reduction must consider the full experiences of patients with SCD, including impacts on mental health.

Developing an Implementation Blueprint for the NIH HEAL Initiative GRACE Trial: Perspectives on Acupuncture and Guided Relaxation for Chronic Sickle Cell Disease Pain.

Objective: This study aimed to explore perspectives of people living with sickle cell disease (SCD) and SCD clinic providers and staff about the use of acupuncture and guided relaxation for treating chronic SCD pain. Data obtained were to inform an implementation blueprint for an effectiveness implementation clinical trial (GRACE Trial) testing whether acupuncture or guided relaxation reduces chronic pain when compared with usual care. Design: Qualitative research design. Methods: We conducted 33 semistructured interviews with people with SCD and SCD clinic providers and staff. Interviews were transcribed and coded. A deductive content analysis process was used to identify themes. Results: Four themes were identified: Receptivity to Acupuncture and Guided Relaxation, Limited Awareness, Complementary and Integrative Health (CIH) Therapy Preference, and Access Barriers. Both patients and clinic providers and staff were open to the use of acupuncture and guided relaxation for chronic pain treatment. After learning about these CIH therapies, some patients expressed a preference for one therapy over the other. They also discussed their ability to successfully engage with each therapy. There is a need to dispel misconceptions about the therapies by increasing understanding of how each therapy is implemented and functions to reduce pain. We identified several potential barriers that might affect the success of the trial and future health system integration, including time, transportation, and technology. Conclusion: This study is one of the first to present perspectives of both patients with SCD and clinic providers and staff on the use of acupuncture and guided relaxation for chronic SCD pain. Stakeholders' early input and perspectives highlighted that they welcome nonpharmacological CIH therapies. Implementation of a clinical trial and future health system integration will require the addressing misinformation and identifying strategies to overcome access barriers. Clinical trial registration number: NCT04906447.

The influence of child pain catastrophizing and parent behavior on health-related quality of life in pediatric sickle cell disease.

Literature suggests that a child's appraisal of pain and parent responses to pain are critical in predicting health-related outcomes. In youth with sickle cell disease (SCD), few investigations have examined child pain catastrophizing, and even fewer have examined the role that parents play in responding to SCD pain within the family context. The purpose of the current study was to examine the relationship between pain catastrophizing, parent response to child SCD pain, and health-related quality of life (HRQoL). The sample (N=100) included youth with SCD (ages 8-18) and their parent. Parents completed a demographic questionnaire and the Adult Responses to Child Pain Symptoms; youth completed the Pain Catastrophizing Scale and Pediatric Quality of Life Inventory-SCD Module. Findings indicated that pain catastrophizing, parent minimization, and parent encouragement/monitoring significantly predicted HRQoL. Minimizing and encouragement/monitoring parent responses moderated the relationship between pain catastrophizing and HRQoL, such that parent minimizing weakened the relationship and parent encouragement/monitoring strengthened the relationship. Paralleling pediatric chronic pain literature, findings suggest that pain catastrophizing predicts HRQoL in youth with SCD. However, findings from moderation analyses diverge from the chronic pain literature; data suggest that encouragement/monitoring responses strengthen the negative relationship between child pain catastrophizing and HRQoL. Child pain catastrophizing and parent response to SCD pain may be appropriate targets for clinical intervention to improve HRQoL. Future studies should strive to better understand parent responses to SCD pain.