Investigating home-based opioid use among youth with sickle cell disease using ecological momentary assessment.

BACKGROUND: Opioids are a common and essential treatment for acute sickle cell disease (SCD) pain. However, opioids carry well-known adverse side effects, including potential development of hyperalgesia and nociplastic pain. We characterized opioid use in youth with SCD using ecological momentary assessment (EMA) data, and investigated the relationships between home-based opioid use, pain, and a range of biopsychosocial factors. METHOD: Eighty-eight youth with SCD (aged 8-17 years) completed EMAs assessing home-based opioid use, pain, and related factors. Analyses consisted of descriptive and multilevel logistic regression to predict daily home opioid use. RESULTS: Youth averaged 3.64 weeks of EMAs. Approximately 35% of the sample (n = 31) took an opioid during the EMA period, and used them on only 24% of reported pain days. Youth who took opioids reported a higher percentage of pain days (t = -2.67, p < .05) and mean pain severity scores (t = -2.30, p < .05) than youth who did not take opioids. Multilevel logistic regression analyses indicated that high daily pain severity (odds ratio [OR] = 1.02, p < .01), older age (OR = 1.324, p < .01), and low positive affect (OR = 0.91, p < .01) were each related to an increased likelihood of opioid use. CONCLUSION: Youth with SCD take opioids appropriately in response to their pain, based on daily self-report. Beyond daily pain severity, age, and daily variation in positive affect were related to home-based opioid use. This suggests that behavioral interventions that enhance positive affect may promote reduced opioid use among youth with SCD.

High-impact chronic pain in sickle cell disease: insights from the Pain in Sickle Cell Epidemiology Study (PiSCES).

ABSTRACT: The US National Pain Strategy recommends identifying individuals with chronic pain (CP) who experience substantial restriction in work, social, or self-care activities as having high-impact chronic pain (HICP). High-impact chronic pain has not been examined among individuals with CP and sickle cell disease (SCD). We analyzed data from 63 individuals with SCD and CP who completed at least 5 months of pain diaries in the Pain in Sickle Cell Epidemiology Study (PiSCES). Forty-eight individuals met the definition for HICP, which was operationalized in this study as reporting pain interference on more than half of diary days. Compared with individuals without HICP, individuals with HICP experienced higher mean daily pain intensity, particularly on days without crises. They also experienced a greater proportion of days with pain, days with healthcare utilization, and days with home opioid use and higher levels of stress. They did not have a statistically significantly higher proportion of days with crises or experience higher mean daily pain intensity on days with crises. Individuals with HICP experienced worse physical functioning and worse physical health compared with those without HICP, controlling for mean pain intensity, age, sex, and education. The results of this study support that HICP is a severely affected subgroup of those with CP in SCD and is associated with greater pain burden and worse health outcomes. The findings from this study should be confirmed prospectively in a contemporary cohort of individuals with SCD.

Riociguat in patients with sickle cell disease and hypertension or proteinuria (STERIO-SCD): a randomised, double-blind, placebo controlled, phase 1-2 trial.

BACKGROUND: Although nitric oxide based therapeutics have been shown in preclinical models to reduce vaso-occlusive events and improve cardiovascular function, a clinical trial of a phosphodiesterase 5 inhibitor increased rates of admission to hospital for pain. We aimed to examine if riociguat, a direct stimulator of the nitric oxide receptor soluble guanylate cyclase, causes similar increases in vaso-occlusive events. METHODS: This was a phase 1-2, randomised, double blind, placebo-controlled trial. Eligible patients were 18 years or older, had confirmed sickle cell disease documented by haemoglobin electrophoresis or HPLC fractionation (haemoglobin SS, SC, Sß-thalassemia, SD, or SO-Arab), and stage 1 hypertension or proteinuria. Participants were randomly assigned 1:1 to receive either riociguat or matching placebo via a web-based system to maintain allocation concealment. Both treatments were administered orally starting at 1·0 mg three times a day up to 2·5 mg three times a day (highest tolerated dose) for 12 weeks. Dose escalation by 0·5 mg was considered every 2 weeks if systolic blood pressure was greater than 95 mm Hg and the participant had no signs of hypotension; otherwise, the last dose was maintained. The primary outcome was the proportion of participants who had at least one adjudicated treatment-emergent serious adverse event. The analysis was performed by the intention-to-treat. This trial is registered with ClinicalTrials.gov (NCT02633397) and was completed. FINDINGS: Between April 11, 2017, and Dec 31, 2021, 165 participants were screened and consented to be enrolled into the study. Of these, 130 participants were randomly assigned to either riociguat (n=66) or placebo (n=64). The proportion of participants with at least one treatment-emergent serious adverse event was 22·7% (n=15) in the riociguat group and 31·3% (n=20) in the placebo group (difference -8·5% [90% CI -21·4 to 4·5]; p=0·19). A similar pattern emerged in other key safety outcomes, sickle cell related vaso-occlusive events (16·7 [n=11] vs 21·9% [n=14]; difference -5·2% [-17·2 to 6·5]; p=0·42), mean pain severity (3·18 vs 3·32; adjusted mean difference -0·14 [-0·70 to 0·42]; p=0·69), and pain interference (3·15 vs 3·12; 0·04 [-0·62 to 0·69]; p=0·93) at 12 weeks were similar between groups. Regarding the key clinical efficacy endpoints, participants taking riociguat had a blood pressure of -8·20 mm Hg (-10·48 to -5·91) compared with -1·24 (-3·58 to 1·10) in those taking placebo (-6·96 mm Hg (90% CI -10·22 to -3·69; p<0·001). INTERPRETATION: Riociguat was safe and had a significant haemodynamic effect on systemic blood pressure. The results of this study provide measures of effect and variability that will inform power calculations for future trials. FUNDING: Bayer Pharmaceuticals.

Dysphagia in patients with sickle cell disease: An understudied problem.

Dysphagia which is defined as disordered swallowing is well known as one of the most common and dangerous symptoms of many diseases, including neurological disorders such as Parkinson's disease, amyotrophic lateral sclerosis, myasthenia gravis, and most commonly, stroke. Strokes are a potentially devastating complication of sickle cell disease (SCD), the most common genetic hemoglobinopathy worldwide, yet little is known about dysphagia as it relates to SCD. Thus, the purposes of this article are to review briefly the primary causes and health consequences of dysphagia, to highlight the relevance of dysphagia to SCD, to review what little is known about dysphagia in SCD, to recommend, based on our consensus and the available literature, when to screen, evaluate, and monitor dysphagia in patients with SCD, and to outline unanswered questions where research on dysphagia in SCD might improve health outcomes.

Impact of community health workers on quality of life in adolescents and young adults with sickle cell disease: The SHIP-HU study.

Health-related quality of life (HRQoL) is an important outcome for patients with sickle cell disease (SCD). It is often poor compared with other chronic medical conditions or measured as a multidomain disease-specific construct. We previously reported outcomes in the Start Healing in Patients with Hydroxyurea (SHIP-HU) randomized controlled trial in adolescents and adults with SCD at six clinical sites. Besides the primary outcomes, we also measured HRQoL as a secondary outcome. Patients in the intervention arm were each assigned community health workers (CHWs) who provided case management services. CHW services were independent of medical management, and medical managers were blinded to the study arm. Patients in the control arm received only standard of care. We hypothesized that having a CHW would improve HRQoL in patients enrolled in SHIP-HU. We did not find significant differences between domains of HRQoL in the two study arms. Possible explanations include selection bias of enrolled versus unenrolled patients, selection bias of sites, medical providers and medical management, enforced blinding, and a lack of cooperation between medical managers and CHWs. The importance of CHWs and HRQoL is nonetheless recognized based on the literature. Future interventions on HRQoL in SCD should consider alternative study designs and multimodal interventions.

Vaso-occlusive crisis pain intensity, frequency, and duration: which best correlates with health-related quality of life in adolescents and adults with sickle cell disease?

ABSTRACT: In a cross-sectional analysis of baseline data from a randomized clinical trial, we studied 198 adolescents and adults aged 15+ with sickle cell disease. Interest was in assessing the relative strengths of the relationship of vaso-occlusive crisis (VOC) pain domains of intensity, frequency, and duration, with health-related quality of life (HRQOL). Variation in psychosocial, physical function, and pain expression domains of HRQOL was partially explained by frequency, intensity, and duration of VOC pain, separately and together, over and above differences in age, sex, genotype, and organ system damage. However, no single domain measure accounted for more than an additional partial R2 of 12.5% alone. Vaso-occlusive crisis pain frequency explained the most variation, when simultaneously considering VOC intensity and duration, except for stiffness , where duration was most predictive. Yet VOC pain intensity, and even VOC duration, also contributed to variability in HRQOL. We recommend that for most purposes, because all 3 VOC pain domains contribute to variability in HRQOL, all 3 domains should be assessed and interventions should be targeted to improve all 3 domains to maximize HRQOL outcomes (Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT02197845 ).

Patient Motivation to Reduce or Discontinue Opioids for Chronic Pain: Self-efficacy, Barriers, and Readiness to Change.

OBJECTIVES: This study aimed to assess levels and predictors of self-efficacy and motivation to change opioid use among a community sample of patients using opioids for chronic pain, as well as patient-reported barriers to pursuing opioid discontinuation. METHODS: Participants with a variety of chronic pain conditions, recruited from ResearchMatch.org , completed a battery of electronic, self-report questionnaires assessing demographic and medical characteristics, pain treatment history, and levels of readiness, self-efficacy, and other attitudes toward reducing or discontinuing opioid use. Multiple regression analyses and analyses of variance were conducted to examine predictors of readiness and self-efficacy to change opioid use. A modified version of rapid qualitative analysis was utilized to analyze themes in participant responses to an open-ended item about "what it would take" to consider opioid discontinuation. RESULTS: The final sample included N=119 participants, the majority of whom were female (78.2%), Caucasian (77.3%), and well-educated. Readiness and self-efficacy to decrease or stop opioid use were fairly low on a 0 to 10 Visual Analog Scale (2.6 to 3.8) and significantly higher to decrease than stop ( P <0.01). Higher readiness to change was predicted by lower pain severity and higher concern about opioids, whereas higher self-efficacy was predicted by shorter pain duration. Results from the qualitative analyses revealed that the availability of an alternative treatment option was the most commonly cited requirement to consider opioid discontinuation. DISCUSSION: Patients with lower pain severity, shorter duration of pain, and higher concerns about opioids may be a prime target from a motivation standpoint for interventions addressing opioid tapering and discontinuation.

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. PERSPECTIVE: This 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.

Precision, integrative medicine for pain management in sickle cell disease.

Sickle cell disease (SCD) is a prevalent and complex inherited pain disorder that can manifest as acute vaso-occlusive crises (VOC) and/or chronic pain. Despite their known risks, opioids are often prescribed routinely and indiscriminately in managing SCD pain, because it is so often severe and debilitating. Integrative medicine strategies, particularly non-opioid therapies, hold promise in safe and effective management of SCD pain. However, the lack of evidence-based methods for managing SCD pain hinders the widespread implementation of non-opioid therapies. In this review, we acknowledge that implementing personalized pain treatment strategies in SCD, which is a guideline-recommended strategy, is currently fraught with limitations. The full implementation of pharmacological and biobehavioral pain approaches targeting mechanistic pain pathways faces challenges due to limited knowledge and limited financial and personnel support. We recommend personalized medicine, pharmacogenomics, and integrative medicine as aspirational strategies for improving pain care in SCD. As an organizing model that is a comprehensive framework for classifying pain subphenotypes and mechanisms in SCD, and for guiding selection of specific strategies, we present evidence updating pain research pioneer Richard Melzack's neuromatrix theory of pain. We advocate for using the updated neuromatrix model to subphenotype individuals with SCD, to better select personalized multimodal treatment strategies, and to identify research gaps fruitful for exploration. We present a fairly complete list of currently used pharmacologic and non-pharmacologic SCD pain therapies, classified by their mechanism of action and by their hypothesized targets in the updated neuromatrix model.

Association of Cerebral Hemodynamics and Anemia on Processing Speed in Adults with Sickle Cell Disease.

Background and Purpose: Compared to healthy controls, adult patients with Sickle Cell Disease (SCD) are anemic, and therefore have higher cardiac output and Cerebral Blood Flow (CBF) to maintain brain oxygenation. They also demonstrate comparatively more cognitive deficits due to either overt strokes or silent cerebral ischemia. However, there are few correlative studies between CBF and cognitive deficits, specifically processing speed in SCD. Such studies are important to develop biomarkers of central brain processing and ischemia for diagnosis, prognosis, and evaluating the effectiveness of potential interventions. This pilot cross-sectional study tested the hypotheses that adults with SCD and elevated CBF demonstrate lower central brain processing speed than controls on average and that CBF is inversely correlated with processing speed. Methods: We conducted a pilot cross-sectional study to assess the relation-ships between CBF, central brain processing speed, and hemoglobin levels in asymptomatic adults with SCD and controls from an urban academic medical center. MRI acquisitions at 3T consisted of 2D phase-contrast quantitative arteriograms (Qflow) of the bilateral internal carotid and vertebral arteries and 3D pseudo-continuous arterial spin labeling (pCASL) of the brain. Participants were patients with SCD (hemoglobin [Hb]SS, [Hb] SBetaThal°, or [Hb]SC) aged 22-52 years of African American descent (N=7) or community controls (Hb AA) (n=3). Processing speed was assessed as an in-direct functional marker of ischemia using a recommended test from the NIH Toolbox for Assessment of Neurological and Behavioral Function, the Pattern Comparison Processing Speed Test. t-tests were used to compare means of CBF, hemoglobin, and cognition between SCD patients and healthy controls. Among SCD patients only multivariate correla-tions were used to evaluate relationships between brain perfusion in specific brain regions vs. processing speed and CBF. The significance level was set at p≤0.05. Results: Adults with SCD reported higher CBF compared to healthy con-trols (72.15±28.90 vs. 47.23±12.30 ml/min/100g, p=0.04), and lower hemoglobin concentration (8.64±2.33 vs. 13.33±0.58, p=0.001). Heart rate in SCD patients was higher than in controls (86.29±1.37 vs. 74.00±2.10, p=0.04). Patients with SCD demonstrated lower processing speed (96.14±21.04 vs.123±13.74, p=0.02) than controls. Among adult patients with SCD, perfusion in specific regions of the brain showed an inverse relationship with processing speed, as did whole-brain CBF (p=0.0325). Conclusion: These findings, although from a small sample, lend a degree of validity to the claim that processing speed is slower in people with SCD than in controls and that CBF is significantly higher in SCD patients com-pared to controls. The results also lend credence to the finding that the degree of processing speed deficiencies among adults with SCD is correlated with the degree of elevated CBF, which is known to correspond with the degree of anemia associated with SCD.

The Lives Lost to Inequities: Avertable Deaths From Neurologic Diseases in the Past Decade.

BACKGROUND AND OBJECTIVES: Mortality rates for neurologic diseases are increasing in the United States, with large disparities across geographical areas and populations. Racial and ethnic populations, notably the non-Hispanic (NH) Black population, experience higher mortality rates for many causes of death, but the magnitude of the disparities for neurologic diseases is unclear. The objectives of this study were to calculate mortality rates for neurologic diseases by race and ethnicity and-to place this disparity in perspective-to estimate how many US deaths would have been averted in the past decade if the NH Black population experienced the same mortality rates as other groups. METHODS: Mortality rates for deaths attributed to neurologic diseases, as defined by the International Classification of Diseases, were calculated for 2010 to 2019 using death and population data obtained from the Centers for Disease Control and Prevention and the US Census Bureau. Avertable deaths were calculated by indirect standardization: For each calendar year of the decade, age-specific death rates of NH White persons in 10 age groups were multiplied by the NH Black population in each age group. A secondary analysis used Hispanic and NH Asian populations as the reference groups. RESULTS: In 2013, overall age-adjusted mortality rates for neurologic diseases began increasing, with the NH Black population experiencing higher rates than NH White, NH American Indian and Alaska Native, Hispanic, and NH Asian populations (in decreasing order). Other populations with higher mortality rates for neurologic diseases included older adults, the male population, and adults older than 25 years without a high school diploma. The gap in mortality rates for neurologic diseases between the NH Black and NH White populations widened from 4.2 individuals per 100,000 in 2011 to 7.0 per 100,000 in 2019. Over 2010 to 2019, had the NH Black population experienced the neurologic mortality rates of NH White, Hispanic, or NH Asian populations, 29,986, 88,407, or 117,519 deaths, respectively, would have been averted. DISCUSSION: Death rates for neurologic diseases are increasing. Disproportionately higher neurologic mortality rates in the NH Black population are responsible for a large number of excess deaths, making research and policy efforts to address the systemic causes increasingly urgent.

Use of Community-Engaged Research Approaches in Clinical Interventions for Neurologic Disorders in the United States: A Scoping Review and Future Directions for Improving Health Equity Research.

BACKGROUND AND OBJECTIVES: Evidence suggests a significant prevalence of race and ethnic disparities in the United States among people with neurologic conditions including stroke, Alzheimer disease and related dementia (ADRD), Parkinson disease (PD), epilepsy, spinal cord injury (SCI), and traumatic brain injury (TBI). Recent neurologic research has begun the paradigm shift from observational health disparities research to intervention research in an effort to narrow the disparities gap. There is an evidence base that suggests that community engagement is a necessary component of health equity. While the increase in disparities focused neurologic interventions is encouraging, it remains unclear whether and how community-engaged practices are integrated into intervention design and implementation. The purpose of this scoping review was to identify and synthesize intervention studies that have actively engaged with the community in the design and implementation of interventions to reduce disparities in neurologic conditions and to describe the common community engagement processes used. METHODS: Two databases, PubMed and CINAHL, were searched to identify eligible empirical studies within the United States whose focus was on neurologic interventions addressing disparities and using community engagement practices. RESULTS: We identified 392 disparity-focused interventions in stroke, ADRD, PD, epilepsy, SCI, and TBI, of which 53 studies incorporated community engagement practices: 32 stroke studies, 15 ADRD, 2 epilepsy studies, 2 PD studies, 1 SCI study, and 1 TBI study. Most of the interventions were designed as randomized controlled trials and were programmatic in nature. The interventions used a variety of community engagement practices: community partners (42%), culturally tailored materials and mobile health (40%), community health workers (32%), faith-based organizations and local businesses (28%), focus groups/health need assessments (25%), community advisory boards (19%), personnel recruited from the community/champions (19%), and caregiver/social support (15%). DISCUSSION: Our scoping review reports that the proportion of neurologic intervention studies incorporating community engagement practices is limited and that the practices used within those studies are varied. The major practices used included collaboration with community partners and utilization of culturally tailored materials. We also found inconsistent reporting and dissemination of results from studies that implemented community engagement measures in their interventions. Future directions include involving the community in research early and continuously, building curricula that address challenges to community engagement, prioritizing the inclusion of community engagement reporting in peer-reviewed journals, and prioritizing and incentivizing research of subpopulations that experience disparities in neurologic conditions.

Race, Ethnicity, and Belief in a Just World: Implications for Chronic Pain Acceptance Among Individuals with Chronic Low Back Pain.

Chronic pain acceptance is a psychological process consistently linked with improved functional outcomes. However, existing research on this construct has not considered the role of racial or ethnic background, despite growing evidence of racialized disparities in pain experience and treatment. This study aimed to examine racial differences in chronic pain acceptance, as measured by the chronic pain acceptance questionnaires (CPAQ), in a multicultural sample of individuals with chronic low back pain (N = 137-37.2% White, 31.4% Hispanic, and 31.4% Black/African American). We further sought to examine moderating effects of discrimination, pain-related perceived injustice (PI), and just world belief (JWB). Analyses consisted of cross-sectional one-way analyses of variance with Bonferroni-corrected post hoc comparisons, followed by regression models with interaction terms, main effects, and relevant covariates. Results indicated higher scores on the CPAQ for White individuals compared to Black or Hispanic individuals. Significant interactions were noted between race/ethnicity and JWB in predicting pain acceptance, after controlling for demographic and pain-related variables, such that the positive association between JWB and pain acceptance was significant for White participants only. Race/ethnicity did not show significant interactions with PI or prior racial discrimination. Findings highlight racial differences in levels of chronic pain acceptance, an adaptive pain coping response, and a stronger JWB appears to have a positive impact on pain acceptance for White individuals only. Results further confirm that members of disadvantaged racial groups may be more susceptible to poorer pain adjustment, which is the result of complex, multi-level factors. PERSPECTIVE: This study identifies racial differences in levels of pain acceptance, an adaptive psychological response to chronic pain, such that White individuals with chronic low back pain demonstrate higher levels of pain acceptance. The article further explores the impacts of intrapersonal and sociocultural variables on racial differences in pain acceptance.

Patient-Reported Experiences in Voxelotor-Treated Children and Adults with Sickle Cell Disease: A Semistructured Interview Study.

Objective: Voxelotor is a first-in-class sickle hemoglobin-polymerization inhibitor that was approved in 2019 by the US Food and Drug Administration for treatment of patients with sickle cell disease (SCD) aged ≥12 years; in 2021, the approval was extended to children with SCD aged 4 to 11 years. Additionally, both the Ministry of Health and Prevention for the United Arab Emirates and the European Commission granted marketing authorization for voxelotor in September 2021 and February 2022, respectively, for treatment of SCD in adults and pediatric patients aged ≥12 years. Thus, additional information on the patient experience with voxelotor would be useful for patients, caregivers, and healthcare professionals alike. The purpose of this study was to conduct semistructured interviews in an effort to understand the experiences and perspectives of voxelotor-treated patients with SCD. Methods: One-time semistructured interviews with adults, adolescents, and children with SCD and their primary caregivers were conducted in the United States. Twenty-three adults and adolescents were recruited across 4 clinical sites, and 10 children-caregiver dyads were recruited from a single site. The interview was designed to elicit patient perspectives on symptomatic changes with voxelotor and the impact of treatment on patients' perceived health-related quality of life. Individual interview transcripts were analyzed using a thematic analytic approach, and concept saturation was assessed in both cohorts. Results: Most patients reported improvements in their SCD symptoms with voxelotor treatment, specifically regarding pain crises, jaundice, and fatigue. Almost all patients experienced improvements in self-reported health-related quality of life with voxelotor treatment. Conclusions: This study provides patient and caregiver perspectives on the symptomatic benefits of voxelotor treatment. These findings not only highlight the benefits of voxelotor treatment in improving symptoms and increasing health-related quality of life across the entire SCD population but also can inform further research on SCD-specific patient-reported outcomes.

Intraindividual pain variability metrics for youth with sickle cell disease: Relations to health outcomes.

BACKGROUND: While the majority of pediatric sickle cell disease (SCD) research has used mean pain intensity as the only pain metric, recent evidence suggests this metric alone is inadequate in describing the intraindividual variability in SCD pain experiences and subsequent impact. There is limited information on other intraindividual pain metrics in youth with SCD, or how they relate to health outcomes in this population. The aims of this study were to describe differing patterns of intraindividual pain metrics derived from ecological momentary assessments (EMAs) of youth with SCD and to characterize the unique relationships between these metrics and health outcomes. METHODS: Eighty-eight youth with SCD, aged 8-17 (mean age = 11.6), were recruited from three regional pediatric SCD clinics in the United States. At baseline, youth and their guardians reported on demographic and disease information. Then youth completed twice daily EMAs for up to 4 weeks. Pain metrics derived from EMA data were calculated including mean daily pain intensity (DP), SD-DP (standard deviation of DP), proportion of pain days (PPD), and 90th percentile of DP (p90). Pearson correlations were calculated between pain metrics and health outcomes. RESULTS: High DP and SD-DP were correlated with more anxiety symptoms, while high SD-DP and p90 were correlated with more depression symptoms. High SD-DP was correlated with low self-esteem, and high DP and PPD were correlated with low sickle cell self-efficacy. For healthcare utilization due to pain, high p90 was correlated with more emergency department visits, while high DP, p90, and PPD were correlated with more healthcare contacts. CONCLUSION: There are distinct associations between pain variability metrics beyond DP and health outcomes. Collectively, the patterns of associations suggest the utility of these pain metrics for determining risk in relation to specific health outcomes for youth with SCD.

Structural Racism and Impact on Sickle Cell Disease: Sickle Cell Lives Matter.

Wealth begets health: the health care system in the United States is run by and benefits the groups that have traditionally held power. Systems of structural racism and health care disparities persist. Patients with sickle cell disease (SCD) remain particularly vulnerable to disparities. They suffer from stigmas, lack of well-trained providers, and from misalignment of their needs with the priorities of their health care teams. These critically important burdens may actually be worsening rather than improving mortality for individuals living with SCD. Changes must be made at the federal, state, and local levels in order to address these systems of inequity and save vulnerable lives.

Targeting TRPV1 activity via high-dose capsaicin in patients with sickle cell disease.

Evidence suggests neuropathic pain (NP) develops over time in sickle cell disease (SCD), contributing to a complex, difficult-to-treat phenotype, with management based on scant evidence. One characteristic of NP found is hyperalgesia caused by nervous system sensitization, but risk factors for this have not been identified within the SCD population, as exact mechanisms leading to its development are not well defined. The SPICE (Sickle cell Pain: Intervention with Capsaicin Exposure) trial was a pilot safety and feasibility trial of high-dose (8%) topical capsaicin for patients with SCD and recurrent/chronic pain with neuropathic features, aimed at exploring capsaicin's utility as a mechanistic probe and adjunctive pain treatment for this population. Ten participants identifying "target" sites of pain with NP-type qualities consented to treatment. The primary endpoint was safety/tolerability. The novel Localized Peripheral Hypersensitivity Relief score (LPHR) was developed to determine improvement in sensitivity attributable to TRPV1 neutralization. There were no severe treatment-related adverse events. Higher baseline pain sensitivity at a given body site was associated with self-reported history of more frequent localized vaso-occlusive pain episodes at that site. There was a statistically significant improvement in the mean LPHR, evidencing TRPV1's importance to the development of hypersensitivity and a potential therapeutic benefit of capsaicin for SCD.

Satisfaction and access to care for adults and adolescents with sickle cell disease: ASCQ-Me quality of care and the SHIP-HU study.

A lack of adult sickle cell providers has long been blamed for poor satisfaction and access to specialty care for adults with sickle cell disease (SCD). We were interested in comparing how adolescent and adult patients already in established SCD centers perceived access and quality of care. Hydroxyurea-eligible patients aged 15 years and older were enrolled in the Start Healing in Patients with Hydroxyurea trial, which required them to be affiliated with a SCD specialist. Patients were seen in one of three adult-oriented specialty clinic sites or one of three pediatric-oriented sites. At baseline, patients completed the Adult Sickle Cell Quality of Life Measurement Information System measure as part of a survey battery. Patients treated at adult clinic sites reported being less able to get timely ambulatory appointments (p = .004). They reported emergency department (ED) wait times of >1 h far more often (47.7 vs. 19.3%, p = .0048). They reported less overall satisfaction with care (7.47 vs. 8.77, p < .0001), and less satisfaction with care in the ED (2.88 vs. 3.4, p = .0068. Ambulatory satisfaction was no different between pediatric site versus adult site patients. Poorer systems of care appeared to underlie reported differences, rather than differences in biopsychosocial determinants. Even among specialty-care-affiliated SCD patients, those seen in adult clinics reported worse access to care and lower satisfaction with care than patients seen in pediatric clinics. In addition to increasing the number of adult SCD providers and better preparing pediatric SCD patients to transfer to adult programs, SCD clinical caregivers must also improve aspects of adult care quality to meet reasonable patient expectations of timeliness and interpersonal aspects of care quality.

Feasibility and Quality Validation of a Mobile Application for Enhancing Adherence to Opioids in Sickle Cell Disease.

Prescription opioid nonadherence, specifically opioid misuse, has contributed to the opioid epidemic and opioid-related mortality in the US. Popular methods to measure and control opioid adherence have limitations, but mobile health, specifically smartphone applications, offers a potentially useful technology for this purpose. We developed, tested, and validated the OpPill application using the Mobile Applications Rating Scale (MARS), a validated tool for assessing the quality of mobile health apps. The MARS contains four scales (range of each scale = 0-4) that rate Engagement, Functionality, Aesthetics, and Information Quality. It also assesses subjective quality, relevance, and overall application impact. Our application was built to be a mobile monitoring and reporting system intended to enhance opioid adherence by collecting data and providing systematic feedback on pain and opioid use. Patients (n = 28) all had one of various SCD genotypes, were ages 19 to 59 years (mean 36.56), 53.6% were female, and 39.3% had completed some college. Patients rated the OpPill application highly on all four scales: Engagement, 3.93 ± 0.73; Functionality, 4.54 ± 0.66; Aesthetics, 3.92 ± 0.81; Information, 3.91 ± 0.87. The majority of patients found the application to be relevant for their care. A total of 96% reported the information within the app was complete, while 4% estimated the information to be minimal or overwhelming. Patients (91.7%) overwhelmingly reported that the quality of information as it pertained to SCD patients was relevant; only 8.3% found the application to be poorly relevant to SCD. Similarly, patients (91.7%) overwhelmingly rated both the application's performance and ease of use positively. The large majority of participants (85.7%) found the application to be interesting to use, while 74% found it entertaining. All users found the application's navigation to be logical and accurate with consistent and intuitive gestural design. We conclude that the OpPill application, specifically targeted to monitor opioid use and pain and opioid behavior in patients with Chronic Non-Cancer Pain, was feasible and rated by SCD patients as easy-to-use using a validated rating tool.

Urgent use of voxelotor in sickle cell disease when immediate transfusion is not safe.

The use of blood transfusions to improve anemia resulting from sickle cell disease (SCD) is often limited by alloimmunization, which occurs due to exposure to incompatible antigen present on donor red blood cells (RBCs). This complication occasionally manifests as delayed hemolytic transfusion reactions (DHTRs) that cause hemolysis of the recipient's own RBCs and can lead to fatal anemia. In this case study, we report a patient with SCD who experienced a DHTR following chronic transfusion and was successfully treated with voxelotor, an orally administered sickle hemoglobin (HbS) polymerization inhibitor for the treatment of SCD. Laboratory tests following admission indicated pan-reactivity in antigens, and a rare donor registry was used to locate acceptable units. The patient experienced the DHTR 3 days after admission, which limited laboratory tests due to profound hemolysis. Alternative treatments were limited, and phenotypically matched units were incompatible, so voxelotor was selected as a last-resort treatment. Following initiation of voxelotor 1500 mg, the patient's hemoglobin levels returned to baseline (6 g/dl) within 10 days, with clinical improvements. This report provides evidence regarding the use of voxelotor in the treatment of profound anemia where other treatments could be unsafe or unavailable.