Sickle cell disease iPSC-derived sensory neurons exhibit increased excitability and sensitization to patient plasma.

ABSTRACT: Individuals living with sickle cell disease (SCD) experience severe recurrent acute and chronic pain. Challenges to gaining mechanistic insight into pathogenic SCD pain processes include differential gene expression and function of sensory neurons between humans and mice with SCD, and extremely limited availability of neuronal tissues from patients with SCD. Here, we used induced pluripotent stem cells (iPSCs), derived from patients with SCD, differentiated into sensory neurons (SCD iSNs) to begin to overcome these challenges. We characterize key gene expression and function of SCD iSNs to establish a model to investigate intrinsic and extrinsic factors that may contribute to SCD pain. Despite similarities in receptor gene expression, SCD iSNs show pronounced excitability using patch clamp electrophysiology. Furthermore, we find that plasma taken from patients with SCD during acute pain associated with a vaso-occlusive event increases the calcium responses to the nociceptive stimulus capsaicin in SCD iSNs compared with those treated with paired plasma from patients with SCD at steady state baseline or healthy control plasma samples. We identified high levels of the polyamine spermine in baseline and acute pain states of plasma from patients with SCD, which sensitizes SCD iSNs to subthreshold concentrations of capsaicin. Together, these data identify potential intrinsic mechanisms within SCD iSNs that may extend beyond a blood-based pathology.

Return visit rates after an emergency department discharge for children with sickle cell pain episodes.

BACKGROUND: High return visit rates after hospitalization for people with sickle cell disease (SCD) have been previously established. Due to a lack of multicenter emergency department (ED) return visit rate data, the return visit rate following ED discharge for pediatric SCD pain treatment is currently unknown. PROCEDURE: A seven-site retrospective cohort study of discharged ED visits for pain by children with SCD was conducted using the Pediatric Emergency Care Applied Research Network Registry. Visits between January 2017 and November 2021 were identified using previously validated criteria. The primary outcome was the 14-day return visit rate, with 3- and 7-day rates also calculated. Modified Poisson regression was used to analyze associations for age, sex, initial hospitalization rate, and a visit during the COVID-19 pandemic with return visit rates. RESULTS: Of 2548 eligible ED visits, approximately 52% were patients less than 12 years old, 50% were female, and over 95% were non-Hispanic Black. The overall 14-day return visit rate was 29.1% (95% confidence interval [CI]: 27.4%-30.9%; site range 22.7%-31.7%); the 7- and 3-day return visit rates were 23.0% (95% CI: 21.3%-24.6%) and 16.7% (95% CI: 15.3%-18.2%), respectively. Younger children had slightly lower 14-day return visit rates (27.3% vs. 31.1%); there were no associations for site hospitalization rate, sex, and a visit occurring during the pandemic with 14-day returns. CONCLUSION: Nearly 30% of ED discharged visits after SCD pain treatment had a return visit within 14 days. Increased efforts are needed to identify causes for high ED return visit rates and ensure optimal ED and post-ED care.

Non-crisis related pain occurs in adult patients with sickle cell disease despite chronic red blood cell exchange transfusion therapy.

BACKGROUND: Chronic red blood cell transfusions reduce acute care utilization for sickle cell disease (SCD) pain. However, little is known about whether chronic transfusions treat or prevent the development of non-crisis pain. We investigated patient-report of pain in adults with SCD receiving chronic exchange transfusions (CET) compared to adults not on CET with similar disease characteristics. STUDY METHOD AND DESIGN: Eleven participants receiving chronic exchange transfusion (CET) for at least one year were compared to 33 participants not receiving CET. Participants completed validated patient-reported outcomes regarding pain impact and quality of life at regularly scheduled visits or before CET. One year of health care utilization and opioid prescriptions were examined. RESULTS: After 1:1 propensity matching was performed for age, genotype, WBC and neutrophil counts, patients on CET had lower Pain Impact scores (-5.1, p = 0.03) and higher Neuropathic (7.4, p < 0.001) and Nociceptive Pain Quality (3.7, p < 0.001) scores, all indicating worse pain. However, CET was associated with a reduction in annual all cause admissions (-3.1, p < 0.001), length of stay (-2.1 days, p < 0.001) and ED visits (-2.7, p < 0.001). CET was not associated with differences in opioids dispensed. CONCLUSIONS: After adjusting for disease characteristics, CET was associated with worse pain impact and neuropathic and nociceptive pain quality, lower health care utilization and with similar levels of opioids dispensed. This data suggest that CET may reduce hospitalizations for acute pain but may not adequately treat nociceptive or neuropathic pain in SCD.

Recommendation to reality: Closing the transcranial Doppler screening gap for children with sickle cell anemia.

BACKGROUND: Although annual transcranial Doppler (TCD) screening is recommended for children with sickle cell anemia (SCA), compliance is low and variable. Our objective was to utilize an electronic health record (EHR)-based registry to improve TCD adherence among children with SCA, 2-16 years of age, at our institution. METHODS: We developed an in-EPIC real time registry for children with sickle cell disease in year 2016. Since end of year 2016, we have been extracting data quarterly to examine TCD rates and share the list of children who have not received a TCD screen in the past 18 months with the clinical team. The registry also includes a TCD risk score to enhance point of care. We also added Child Life support to increase TCD compliance among children <7 years. Control charts are used to examine TCD rates. RESULTS: At baseline, prior to and start of quarterly data audit and feedback, 63% of children received the recommended annual TCD screen. TCD rates steadily increased to 80% by the third quarter of 2017. We observed a dip in TCD rates, driven by failure of screening young children. Since the initiation of Child Life support for children <7 years, we have sustained TCD screen rates >70%. Overall, our data meet criteria for special cause variation, indicating improvement in TCD rates since 2015. CONCLUSIONS: Regular tracking and identification of patients overdue for a TCD screen using an EHR-based registry resulted in sustained improvement in TCD screening rates. Involvement of Child Life support further improved TCD rates.

Neuropathic pain is associated with poor health-related quality of life in adolescents with sickle cell disease: A preliminary report.

BACKGROUND: Neuropathic pain is associated with poor health-related quality of life (HRQL) in pain conditions other than sickle cell disease (SCD); this relationship in SCD is unknown. We investigated this relationship and hypothesized neuropathic pain is associated with poor HRQL in adolescents with SCD. METHODS: We conducted a cross-sectional study of patients with SCD ages 13-18 years during baseline health. Primary outcome was HRQL, assessed by the PedsQL SCD Module (child self-report, parent proxy report). PedsQL is scored from 0 to 100, with higher scores indicating better HRQL. Neuropathic pain was assessed using the painDETECT questionnaire (scored 0-38); higher scores indicated greater likelihood of neuropathic pain. All completed both PedsQL SCD Module and painDETECT questionnaire. Descriptive statistics were used and associations between painDETECT and PedsQL Total Score, Pain Impact, Pain and Hurt, and Pain Management and Control Scores were determined via Pearson correlation. Significance was P < .05. RESULTS: Twelve patients were enrolled. Median (interquartile range [IQR]) age was 15 (14-16.5) years, 75% were female, and 83% were on hydroxyurea. Higher painDETECT scores were significantly associated with lower PedsQL SCD Module child self-report Pain and Hurt Scores (r = -0.68, P = .01). Higher painDETECT scores were also significantly associated with lower PedsQL parent proxy-report Total Scores (r = -0.64, P = .03) and Pain and Hurt Scores (r = -0.67, P = .02). CONCLUSIONS: These data suggest that adolescents with SCD and neuropathic pain have poor HRQL even in their baseline state of health. Prospective, larger studies are needed to confirm this preliminary finding and explore a multimodal approach for pain assessment in SCD.

Gabapentin alleviates chronic spontaneous pain and acute hypoxia-related pain in a mouse model of sickle cell disease.

Pain is the main complication of sickle cell disease (SCD). Individuals with SCD experience acute pain episodes and chronic daily pain, both of which are managed with opioids. Opioids have deleterious side effects and use-associated stigma that make them less than ideal for SCD pain management. After recognizing the neuropathic qualities of SCD pain, clinically-approved therapies for neuropathic pain, including gabapentin, now present unique non-opioid based therapies for SCD pain management. These experiments explored the efficacy of gabapentin in relieving evoked and spontaneous chronic pain, and hypoxia/reoxygenation (H/R)-induced acute pain in mouse models of SCD. When administered following H/R, a single dose of gabapentin alleviated mechanical hypersensitivity in SCD mice by decreasing peripheral fibre activity. Gabapentin treatment also alleviated spontaneous ongoing pain in SCD mice. Longitudinal daily administration of gabapentin failed to alleviate H/R-induced pain or chronic evoked mechanical, cold or deep tissue hypersensitivity in SCD mice. Consistent with this observation, voltage-gated calcium channel (VGCC) α2 δ1 subunit expression was similar in sciatic nerve, dorsal root ganglia and lumbar spinal cord tissue from SCD and control mice. Based on these data, gabapentin may be an effective opioid alternative for the treatment of chronic spontaneous and acute H/R pain in SCD.

Longitudinal Trend in Emergency Department Reliance for Pain Among Sickle Cell Disease Patients in Wisconsin.

Patients with sickle cell disease frequently visit the emergency department for pain. The metric of emergency department reliance (EDR) describes emergency department utilization in relation to all ambulatory visits and serves as a quality of care indicator. This study uses Wisconsin Medicaid data from 2011 to 2015 to examine trend of EDR for pain over the period of 5 years. We stratified our cohort (N=750) by patient ages into 4 groups: (1) children; (2) transition group; (3) young adults; and (4) adults. Using a linear mixed model, we estimated longitudinal trends adjusting for age group and hydroxyurea possession calculated as medication possession ratio. Results show that EDR for pain has distinct temporal patterns for each group. EDR for pediatrics continually remained less than the established threshold of 0.33. The EDR for transition group significantly increased over time; however, the EDR for young adults has significantly decreased since 2011. There were no significant differences in EDR over time for adults older than 30 years. Overall, increase in medication possession ratio was associated with lower EDR. The low EDR for pain among children and the improvements among adults indicate the success of efforts for sickle cell disease patients. However, further interventions are needed for the transition age group.

Interventions for treating neuropathic pain in people with sickle cell disease.

BACKGROUND: Pain is the hallmark of sickle cell disease (SCD) and it can be severe, frequent and unpredictable. Although nociceptive pain is more common, at times, people with SCD may have neuropathic pain. The latter can occur due to peripheral or central nerve injury. This review is focused on identifying treatment of only painful sensory neuropathy in people with SCD. OBJECTIVES: To determine the effectiveness and safety of any pharmacological or non-pharmacological therapies for treating neuropathic pain in people with SCD. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched trial registries, the reference lists of relevant articles and reviews and contacted experts in the field.Date of last search: 31 January 2019. SELECTION CRITERIA: Randomised controlled trials (RCTs) (parallel or cross-over in design), quasi-RCTs of pharmacological or non-pharmacological therapies for treating neuropathic pain in people with SCD compared to placebo or another intervention in any category (i.e. pharmacological or non-pharmacological). DATA COLLECTION AND ANALYSIS: Two review authors independently assessed all trials identified by the searches and extracted relevant data. Two authors independently assessed the risk of bias in the selected trials using the Cochrane risk of bias tool. Two review authors independently rated the quality of the evidence for each outcome using the GRADE guidelines. MAIN RESULTS: One RCT of 22 participants with SCD, conducted in the USA was included in this review. Participants were randomly assigned to either pregabalin (n = 11) or placebo (n = 11). Oral pregabalin was administered at an initial dose of 75 mg twice daily. The drug was titrated at increments of 75 mg to a maximum of 600 mg daily or decreased by 75 mg per day if necessary, based on clinical presentation and pain level. Neuropathic pain was assessed using self-reports on the Leeds Assessment of Neuropathic Symptoms and Signs (S-LANNS) scale and the Neuropathic Pain Symptom Inventory (NPSI), where higher scores were indicative of more pain. Outcomes included self-reported pain, quality of life and withdrawal due to adverse effects measured at baseline and monthly for three months post-intervention. The overall risk of bias was low with a high risk of bias due to attrition.In relation to this reviews primary outcomes, for self-reported neuropathic pain relief, given the paucity of data, we are very uncertain whether there is a difference between the pregabalin and placebo groups at the end of three months as measured by the S-LANSS scale, mean difference (MD) -2.00 (95% confidence interval (CI) -9.18 to 5.18), or the NPSI scale, MD -11.10 (95% CI -33.97 to 11.77) (very low-quality evidence). There was no report of 'Patient Global Impression of Change' in the included trial.Although the mean quality of life scores (Short Form-36) at three months showed small increases in seven of the eight domains post-intervention in the pregabalin group as compared to the placebo group, this was very low-quality evidence and we are very uncertain whether pregabalin increases quality of life. Neither of our pre-defined outcomes of 'time to improvement of symptoms' or 'changes in sleep quality', were measured in the included trial.While treatment-related adverse effects appeared higher in pregabalin group than the placebo group at three months, this was very low-quality evidence and we are very uncertain whether there is a difference, RR 1.33 (95% CI 0.39 to 4.62) (very low-quality evidence). There was one withdrawal for adverse effects in the pregabalin group while three people withdrew or dropped out from the placebo group due to adverse effects and complications and hospitalisation related to SCD. AUTHORS' CONCLUSIONS: The included trial provided very low-quality evidence. Self-reported pain relief was greater in the pregabalin group compared to the placebo control group but only using the S-LANSS scale and we are very unsure whether there is a difference. While the pregabalin group tended to have improved quality of life over the duration of the trial, this was very low-quality evidence and we are uncertain whether there is a difference. Adverse effects and withdrawals were similar across the treatment and placebo control group in trial. There are both insufficient trials addressing this review question and insufficient outcomes addressed in the single included RCT. Therefore, there is still a significant gap in evidence on interventions for neuropathic pain in people with SCD.

Sickle Cell Clinical Research and Intervention Program (SCCRIP): A lifespan cohort study for sickle cell disease progression from the pediatric stage into adulthood.

BACKGROUND: Previous natural history studies have advanced the understanding of sickle cell disease (SCD), but generally have not included sufficient lifespan data or investigation of the role of genetics in clinical outcomes, and have often occurred before the widespread use of disease-modifying therapies, such as hydroxyurea and chronic erythrocyte transfusions. To further advance knowledge of SCD, St. Jude Children's Research Hospital established the Sickle Cell Clinical Research and Intervention Program (SCCRIP), to conduct research in a clinically evaluated cohort of individuals with SCD across their lifetime. PROCEDURES: Initiated in 2014, the SCCRIP study prospectively recruits patients diagnosed with SCD and includes retrospective and longitudinal collection of clinical, neurocognitive, geospatial, psychosocial, and health outcomes data. Biological samples are banked for future genomics and proteomics studies. The organizational structure of SCCRIP is based upon organ/system-specific working groups and is opened to the research community for partnerships. RESULTS: As of August 2017, 1,044 (92.3% of eligible) patients with SCD have enrolled in the study (860 children and 184 adults), with 11,915 person-years of observation. Population demographics included mean age at last visit of 11.3 years (range 0.7-30.1), 49.8% females, 57.7% treated with hydroxyurea, 8.5% treated with monthly transfusions, and 62.9% hemoglobin (Hb) SS or HbSB0 -thalassemia, 25.7% HbSC, 8.4% HbsB+ -Thalassemia, 1.7% HbS/HPFH, and 1.2% other. CONCLUSIONS: The SCCRIP cohort will provide a rich resource for the conduct of high impact multidisciplinary research in SCD.

Patient-reported neuropathic pain in adolescent and young adult cancer patients.

BACKGROUND: Neuropathic pain, a known complication of cancer and its treatments, negatively impacts quality of life. There are limited data using screening tools to aid in the diagnosis of neuropathic pain in cancer patients. Our primary objective was to determine the proportion of adolescent and young adult cancer patients reporting neuropathic pain on a patient-completed, neuropathic pain screening tool. PROCEDURES: This prospective, cohort study enrolled patients 14-39 years of age who were receiving therapy for primary cancer diagnosis, cancer relapse, or had recently completed treatment. The painDETECT, a patient-completed, neuropathic pain screening tool used down to age 14, was administered a maximum of three times in on-therapy patients and once in off-therapy patients. Provider documentation of neuropathic pain at the corresponding visit was abstracted from the medical record. RESULTS: Seventy-eight patients participated. Median (interquartile range) age at study enrollment was 18.1 (16-19.4) years and 47% were female. Cancer diagnoses included 41% leukemia, 26% solid tumor, 23% lymphoma, and 10% central nervous system tumor. The proportion of patients reporting neuropathic pain was 26% (95% confidence interval [CI] 16-40%) in on-therapy patients and 11% (95% CI 3-27%) in off-therapy patients. In patients reporting neuropathic pain, only 26% had a clinical diagnosis of neuropathic pain documented in the medical record at the corresponding visit. CONCLUSIONS: Neuropathic pain occurs in one in four adolescents and young adults receiving cancer therapy. Use of screening tools may increase the detection of neuropathic pain in adolescents and young adults receiving cancer therapy and could ultimately improve pain treatment.

Substance P is increased in patients with sickle cell disease and associated with haemolysis and hydroxycarbamide use.

Sickle cell disease (SCD) pain transitions from acute to chronic for unknown reasons. Chronic elevation of the pain neurotransmitter substance P (SP) sensitizes pain nociceptors. We evaluated SP levels in controls and SCD patients during baseline and acute pain and investigated associations between SP and age, gender, pain history, haemolysis and hydroxycarbamide (also termed hydroxyurea) use. Plasma SP levels were measured using enzyme-linked immunosorbent assay. Independent samples t-test compared SP levels between: (i) SCD baseline and controls, and (ii) SCD baseline and acute pain. Multivariate linear regression determined associations between SP and age, gender, pain history and hydroxycarbamide use. Spearman correlation determined an association between SP and haemolysis. We enrolled 35 African American controls, 25 SCD baseline and 12 SCD pain patients. SCD patients were 7-19 years old. Mean ± standard deviation SP level (pg/ml) in SCD baseline was higher than controls (32·4 ± 11·6 vs. 22·9 ± 7·6, P = 0·0009). SP in SCD pain was higher than baseline (78·1 ± 43·4 vs. 32·4 ± 11·6, P = 0·004). Haemolysis correlated with increased SP: Hb (r = -0·7, P = 0·0002), reticulocyte count (r = 0·61, P = 0·0016), bilirubin (r = 0·68, P = 0·0216), lactate dehydrogenase (r = 0·62, P = 0·0332), aspartate aminotransferase (r = 0·68, P = 0·003). Patients taking hydroxycarbamide had increased SP (ß = 29·2, P = 0·007). SP could be a mediator of or marker for pain sensitization in SCD and a biomarker and/or target for novel pain treatment.

Impact of emergency department care on outcomes of acute pain events in children with sickle cell disease.

The impact of emergency department (ED) treatment on outcomes of sickle cell disease (SCD) acute pain hospitalizations is not well described. We investigated whether length of stay (LOS) and change in health-related quality of life (HRQL) are affected by initial opioid dose and time to administration. We conducted secondary analyses of data from the randomized-controlled Magnesium for children in Crisis (MAGiC) trial. The primary outcome was LOS. Secondary outcome was change in HRQL, assessed using PedsQL SCD Pain and Hurt and Pain Impact Domains measured in ED and at discharge. Independent variables were (1) time to first IV opioid, (2) total initial opioid dose (mg/kg/hr of morphine equivalents administered between ED and first study drug), and (3) Time to first oral opioid. Spearman correlations determined the associations with LOS. Using two-sample t-tests, we compared mean change in HRQL scores between IV opioid initiated within 60 and >60 min, opioid doses in the highest and lowest tertiles, and oral opioid initiated within 24 and >24 hr. Two hundred and four patients participated at 8 sites. Mean (SD) age was 13.6 (4.7) years. Earlier initiation of oral opioids was strongly correlated with shorter LOS (r = 0.61, P < 0.01). Higher initial opioid dose was weakly correlated with longer LOS (r = 0.34, P < 0.01). Higher initial opioid doses (6 vs -2.2; P = 0.01) and oral opioids initiated within 24 hr (5.7 vs -1.7, P = 0.04) were associated with larger mean change in HRQL at discharge. Prospective trials evaluating the impact of ED care on outcomes of pain hospitalizations could improve SCD pain treatment. Am. J. Hematol. 91:1175-1180, 2016. © 2016 Wiley Periodicals, Inc.

Clinical Interpretation of Quantitative Sensory Testing as a Measure of Pain Sensitivity in Patients With Sickle Cell Disease.

Patients with sickle cell disease (SCD) display significantly lower mean/median thermal and mechanical pain thresholds compared with controls. This suggests impaired pain sensitivity where stimuli produce exaggerated pain. Despite these mean/median differences, clinicians need to understand if patients meet criteria for impaired pain sensitivity. We defined thresholds for impaired cold, heat, and mechanical pain sensitivity in SCD patients. Using quantitative sensory testing (QST) we assessed cold, heat, and mechanical pain thresholds in SCD patients and African American controls aged 7 years and above. Impaired pain sensitivity was defined as: (1) cold pain threshold 1 SD above control median threshold; (2) heat pain threshold 1 SD below control median threshold; and (3) mechanical pain threshold 1 SD below control median threshold. Fifty-five SCD patients and 57 controls participated in this study. Impaired pain sensitivity thresholds were: (1) cold: 17.01°C, (2) heat: 43.91°C, and (3) mechanical: 4.42 g. Impaired cold pain sensitivity was the most common finding (63.6%), then heat (60%), and mechanical (38.2%). Impaired pain sensitivity to ≥1 testing modalities occurred in 81.8% of SCD patients. Determining impaired pain sensitivity thresholds increases clinical utility of QST. QST could be a screening tool to phenotype SCD pain, an outcome for pain interventional trials, or guide pain neurobiology investigations.

Early insights into the neurobiology of pain in sickle cell disease: A systematic review of the literature.

Novel insights into the neurobiology of sickle cell disease (SCD) pain have recently been discovered. We systematically reviewed the literature focusing on original research that examined the biology of pain in SCD and/or addressed assessment or treatment of neuropathic pain in SCD. This review of 15 articles that met inclusion criteria provides epidemiological, basic, and clinical data that support central and/or peripheral nervous system abnormalities likely contribute to sickle cell pain. Continued basic and clinical investigation into pain neurobiology is imperative to translate these discoveries into novel ways to assess and treat neuropathic pain and decrease patient suffering.

The use of neuropathic pain drugs in children with sickle cell disease is associated with older age, female sex, and longer length of hospital stay.

Although neuropathic pain is increasingly recognized in sickle cell disease (SCD), it is unknown how neuropathic pain drugs are used in children with SCD. Thus, we investigated use of these drugs and hypothesized older age and female sex are associated with increased neuropathic drug use and the use of these drugs is associated with longer length of stay. We analyzed the Pediatric Health Information System (2004 to 2009) including all inpatient visits aged 0 to 18 years with any SCD-related (all genotypes) discharge diagnosis. To limit confounding we excluded psychiatric and seizure visits. Antiepileptics, tricyclic antidepressants, and selective serotonin reuptake inhibitors were drugs of interest. Generalized Estimating Equations determined the impact of age and sex on neuropathic drug use and the impact of neuropathic drug use on length of stay. We analyzed 53,557 visits; 2.9% received≥1 neuropathic drugs. The odds of receiving a neuropathic drug increased significantly with age (reference group, 0 to 4 y: 5 to 10, odds ratio [OR], 5.7; 11 to 14: OR, 12.5; 15 to 18: OR, 22.8; all P<0.0001] and female sex (OR, 1.5; P=0.001). Neuropathic drug use was associated with longer length of stay (risk ratio, 8.3; P<0.0001). Neuropathic drug use in children with SCD was associated with older age, female sex, and longer length of stay.

A Comparison of Pain Assessment Measures in Pediatric Sickle Cell Disease: Visual Analog Scale Versus Numeric Rating Scale.

Given the availability of various pain severity scales, greater understanding of the agreement between pain scales is warranted. We compared Visual Analog Scale (VAS) and Numeric Rating Scale (NRS) pain severity ratings in children with sickle cell disease (SCD) to identify the relationship and agreement between pain scale ratings. Twenty-eight patients (mean ± SD age, 14.65 ± 3.12 y, 50% female) receiving pain interventions within the emergency department completed serial VAS and NRS pain severity ratings every 30 minutes. Data were used to calculate the relationship (Spearman correlation) and agreement (Bland-Altman approach) between the VAS and NRS. One hundred twenty-eight paired VAS-NRS measurements were obtained. VAS and NRS ratings were significantly correlated for the initial assessment (rs = 0.88, P < 0.001) and all assessments (rs = 0.87, P < 0.001). Differences between VAS and NRS means were -0.52 (P = 0.006) for the initial assessment and -0.86 (P < 0.001) across all assessments. The difference between VAS and NRS ratings decreased as pain severity increased across all assessments (P = 0.027), but not the initial assessment. Within pediatric patients with SCD, VAS and NRS ratings were found to trend together; however, VAS scores were found to be significantly lower than NRS scores across assessments. The agreement between the 2 measures improved at increasing levels of pain severity. These findings demonstrate that the VAS and NRS are similar, but cannot be used interchangeably when assessing self-reported pain in SCD.

Neuropathic pain in patients with sickle cell disease.

BACKGROUND: Despite the suggestion of a neuropathic component to sickle cell disease (SCD) pain, there are minimal data on the systematic assessment of neuropathic pain in patients with SCD. Neuropathic pain is defined as pain primarily initiated by dysfunction of the peripheral or central nervous system. PROCEDURE: In a cross-sectional study, we used the painDETECT questionnaire, a one-page validated neuropathic pain screening tool, to determine the presence of neuropathic pain in patients with SCD and to evaluate the relationship between neuropathic pain, age, and gender. We hypothesized that 20% of patients with SCD will experience neuropathic pain and that neuropathic pain will be associated with older age and female gender. The completed painDETECT questionnaire yields a total score between 0 and 38 (≥ 19 = definite neuropathic pain, 13-18 = probable neuropathic pain, ≤ 12 = no neuropathic pain). Scores ≥ 13 were designated as having evidence of neuropathic pain. RESULTS: A total of 56 patients participated. Median age was 20.3 years and 77% were female. We found 37% of patients had evidence of neuropathic pain. Age was positively correlated with total score (r = 0.43; P = 0.001) suggesting older patients experience more neuropathic pain. Females had higher mean total scores (13 vs. 8.4; P = 0.04). Significantly more patients with neuropathic pain were taking hydroxyurea (90% vs. 59%; P = 0.015). Despite 37% of patients experiencing neuropathic pain, only 5% were taking a neuropathic pain drug. CONCLUSIONS: Neuropathic pain exists in SCD. Valid screening tools can identify patients that would benefit from existing and future neuropathic pain therapies and could determine the impact of these therapies.

Do difficulties in swallowing medication impede the use of hydroxyurea in children?

BACKGROUND: Use of hydroxyurea (HU) in children with sickle cell disease (SCD) may be hampered by its formulation as a capsule and the limited availability of liquid HU. PROCEDURE: At four Pediatric SCD clinics, parents of children with SCD ages 5-17 years were surveyed about their children's medication use and ability to swallow medication. Data were stratified by HU therapy and analyzed using descriptive statistics, Chi square tests, Fisher exact tests and univariate analysis. RESULTS: Of the 116 parents surveyed, 97% were the primary caregiver. One fourth (26%) of parents reported that their child's difficulty swallowing medication interfered with daily medication use. Age-related differences were found in ability to swallow medication, but not by HU use. Children taking HU were more likely to take multiple daily medications, with more frequent dosing schedules. Among 65 HU users, children using the liquid formulation (28%, n = 18) were younger than capsule users (P < 0.0001). Nonetheless, half of liquid HU users were aged 8-13. Children using liquid HU were more likely to have difficulties swallowing medication than those who use HU capsules (OR 4.29, 95% CI 1.14-16.18, P = 0.032). Few had received training for swallowing medication. CONCLUSIONS: One fourth of surveyed parents viewed swallowing as challenging to daily medication use. These findings suggest that difficulty swallowing capsules is a fairly frequent barrier to for children prescribed HU, especially for younger children. HU use appears more likely in families with daily and more complex medication schedules. Coaching for swallowing capsules may improve HU utilization and adherence.

Acute care utilization among individuals with sickle cell disease and related cardiopulmonary and renal complications.

Cardiopulmonary and renal end organ (CPR) complications are associated with early mortality among individuals with sickle cell disease (SCD). However, there is limited knowledge regarding acute care utilization for individuals with SCD and CPR complications. Our objective was to determine the prevalence of CPR complications in a state specific SCD population and compare acute care utilization among individuals with and without CPR complications. We leveraged 2017-2020 data for individuals with SCD identified by the Sickle Cell Data Collection program in Wisconsin. The prevalence of CPR complications is determined for distinct age groups. Generalized linear models adjusted for age compared the rate of acute care visits/person/year among individuals who had cardiopulmonary only, renal only, both cardiopulmonary and renal, or no CPR complications. There were 1378 individuals with SCD, 52% females, mean (SD) age 28.3 (18.5) years; 48% had at least one CPR complication during the study period. The prevalence of CPR complications was higher in adults (69%) compared to pediatric (15%) and transition (51%) groups. Individuals with SCD and cardiopulmonary complications had higher acute visit rates than those without CPR complications (5.4 (IQR 5.0-5.8) vs 2.4 (IQR 2.1-2.5), p <0.001)). Acute care visit rates were similar between individuals with SCD who had renal only complications and no CPR complications (2.7 (IQR 2.5-3.0) vs 2.4 (2.1-2.5), p = 0.24). The high acute care visit rates, especially for those with cardiopulmonary complications, warrant further investigation to understand risk factors for CPR complications, the underlying reasons and identify effective disease management strategies.