Severe acute and chronic pain are the most common complications of sickle cell disease (SCD). Pain results in disability, psychosocial distress, repeated clinic visits/hospitalizations, and significant healthcare costs. Psychosocial pain interventions that teach cognitive and behavioral strategies for managing pain have been effective in other adolescent populations when delivered in person or through digital technologies. Our aim was to conduct a multisite, randomized, controlled trial to improve pain and coping in youth aged 12 to 18 years with SCD using a digital cognitive–behavioral therapy program (iCanCope with Sickle Cell Disease; iCC-SCD) vs Education control. We enrolled 137 participants (ages 12-18 years, 59% female) and analyzed 111 adolescents (107 caregivers), 54 randomized to Education control and 57 randomized to iCC-SCD. Ninety-two percent of youth completed posttreatment assessments and 88% completed 6-month follow-up. There was a significant effect of treatment group (iCC-SCD vs Education) on reduction in average pain intensity from baseline to 6-month follow-up (b = −1.32, P = 0.009, 95% CI [−2.29, −0.34], d = 0.50), and for the number of days with pain, adolescents in the iCC-SCD group demonstrated fewer pain days compared with the Education group at 6-month follow-up (incident rate ratio = 0.63, P = 0.006, 95% CI [0.30, 0.95], d = 0.53). Treatment effects were also found for coping attempts, momentary mood, and fatigue. Several secondary outcomes did not change with intervention, including anxiety, depression, pain interference, and global impression of change. Future studies are needed to identify effective implementation strategies to bring evidence-based cognitive–behavioral therapy for sickle cell pain to SCD clinics and communities.

Patients with sickle cell disease (SCD) commonly experience vaso-occlusive pain episodes (VOE), which accounts for 78% of all emergency department (ED) visits among patients with SCD.1 SCD-VOE pain is often under-, and inconsistently, treated in the ED.2 In 2014, the National Heart, Lung, and Blood Institute (NHLBI) put forth guidelines to direct the care of patients presenting with VOE.3 Key guideline recommendations include: 1) triage as high priority with rapid evaluation of patients presenting with VOE, 2) use of parenteral opioids for moderate-to-severe pain with administration ≤30 minutes after ED triage or ≤60 minutes after registration, 3) pain reassessment and subsequent parenteral opioid dosing every 15–30 minutes until pain is controlled, 4) the administration of non-steroidal anti-inflammatory drugs (NSAIDS) as an analgesic adjuvant (if no contraindications exist), and 5) in euvolemic patients with SCD-VOE who are unable to drink fluids, intravenous hydration at no more than maintenance rate to avoid over-hydration. Our objective was to assess adherence to all NHLBI recommendations and the impact of timely opioid administration on hospital admission in a study of 20 academic pediatric EDs in the United States and Canada.

Patient reported outcomes (PROs) provide multidimensional perspectives on the impact of pain1, 2, 3, 4, 5 and have been assessed using the Patient Reported Outcomes Measurement Information System (PROMIS) in children with sickle cell disease (SCD) during outpatient visits,3,4 acute care utilization for pain,4,6 and in clinical trials to measure the effect of interventions.7, 8, 9 Here, we report the feasibility of collection of PROs of pain interference and fatigue at enrollment (baseline) from participants 3 to 21 years of age enrolled in a phase 2 randomized double-blind placebo-controlled trial of intravenous arginine therapy for acute SCD pain (NCT02536170),10 and examine the impact of an acute pain episode on these PROs.

Introduction/Objective:Acute pain episodes are a major cause of health care utilization (HCU) in sickle cell disease (SCD), and adolescence is associated with increased pain frequency. We sought to determine whether there were differences in acute pain trajectories by sex and frequency of pain episodes among adolescents with SCD who presented to the emergency department (ED).Methods:Retrospective review of electronic health records from a large, multicampus, pediatric SCD program.Results:Of the 113 adolescents included, the mean age was 16.6 (SD 0.9), 41.6% (n = 47) were female, 77.9% (n = 88) had HbSS or a similarly severe genotype, and 43.4% (n = 49) had ≥3 episodes of HCU for pain, which we defined as having history of high HCU for pain. Those with a history of high HCU for pain had higher mean pain intensity scores at presentation, were more likely to receive either intravenous or intranasal opioids, and were more likely to be hospitalized. In a model considering the 3-way interaction between sex, history of high HCU for pain, and follow-up time from the initial pain intensity score, adjusted for opioid per kilogram body weight, and prescription of hydroxyurea, adolescent female patients with high HCU for pain had the slowest decline in pain intensity during treatment for acute pain in the ED.Conclusion:Sex and history of high HCU for pain are associated with acute pain trajectories in adolescents with SCD presenting to the ED. These novel findings should be confirmed in future prospective studies.

Sickle cell disease (SCD) is the most common hemoglobinopathy in the US, affecting approximately 100,000 individuals in the US and millions worldwide. Pain is the hallmark of SCD, and a subset of patients experience pain virtually all of the time. Of interest, the arginine metabolome is associated with several pain mechanisms highlighted in this review. Since SCD is an arginine deficiency syndrome, the contribution of the arginine metabolome to acute and chronic pain in SCD is a topic in need of further attention. Normal arginine metabolism is impaired in SCD through various mechanisms that contribute to endothelial dysfunction, vaso-occlusion, pulmonary complications, risk of leg ulcers, and early mortality. Arginine is a semiessential amino acid that serves as a substrate for protein synthesis and is the precursor to nitric oxide (NO), polyamines, proline, glutamate, creatine, and agmatine. Since arginine is involved in multiple metabolic processes, a deficiency of this amino acid has the potential to disrupt many cellular and organ functions. NO is a potent vasodilator that is depleted in SCD and may contribute to vaso-occlusive pain. As the obligate substrate for NO production, arginine also plays a mechanistic role in SCD-related pain, although its contribution to pain pathways likely extends beyond NO. Low global arginine bioavailability is associated with pain severity in both adults and children with SCD as well as other non-SCD pain syndromes. Preliminary clinical studies of arginine therapy in SCD demonstrate efficacy in treating acute vaso-occlusive pain, as well as leg ulcers and pulmonary hypertension. Restoration of arginine bioavailability through exogenous supplementation of arginine is, therefore, a promising therapeutic target. Phase II clinical trials of arginine therapy for sickle-related pain are underway and a Phase III randomized controlled trial is anticipated in the near future.

We conducted a multicenter pilot investigation of the safety and feasibility of bone marrow transplantation (BMT) in adults with severe sickle cell disease (SCD) (NCT 01565616) using a reduced toxicity preparative regimen of busulfan (13.2 mg/kg), fludarabine (175 mg/m 2 ) and thymoglobulin (6 mg/kg) and cyclosporine or tacrolimus and methotrexate for graft-vs-host disease (GVHD) prophylaxis. Twenty-two patients (median age 22 years; range 17-36) were enrolled at eight centers. Seventeen patients received marrow from an HLA-identical sibling donor and five patients received marrow from an 8/8 HLA-allele matched unrelated donor. Before BMT, patients had stroke, acute chest syndrome, recurrent pain events, were receiving regular red blood cell transfusions, or had an elevated tricuspid regurgitant jet (TRJ) velocity, which fulfilled eligibility criteria. Four patients developed grades II-III acute GVHD (18%) and six developed chronic GVHD (27%) that was moderate in two and severe in one patient. One patient died of intracranial hemorrhage and one of GVHD. Nineteen patients had stable donor chimerism, 1-year post-transplant. One patient who developed secondary graft failure survives disease-free after a second BMT. The one-year overall survival and event-free survival (EFS) are 91% (95% CI 68%-98%) and 86% (95% CI, 63%-95%), respectively, and 3-year EFS is 82%. Statistically significant improvements in the pain interference and physical function domains of health-related quality of life were observed. The study satisfied the primary endpoint of 1-year EFS ≥70%. This regimen is being studied in a prospective clinical trial comparing HLA-matched donor BMT with standard of care in adults with severe SCD (NCT02766465).

Background: There is a limited understanding of the patient and family experience of Chronic Transfusion Therapy (CTT) for prevention of complications of Sickle Cell Disease (SCD). We sought to understand patient and family experience with CTT using qualitative methods. Methods: Fifteen parents of children < 18 years old and nine children 12-18 years old with SCD who were receiving CTT for > 1 year were interviewed using a semi-structured interview format, and interviews were analyzed using open coding methods. Results: Four themes created a narrative of the patient and family experience of CTT: 1) Burden of CTT, 2) Coping with CTT, 3) Perceived benefits and risks of CTT, and 4) Decision making regarding CTT. Participants reported substantial burden of CTT, including the impact of CTT on daily life and family, distress about venous access, burden of chelation therapy, and anxiety about CTT complications. Participants described how they coped with CTT. Participants reported increased energy, decreased pain, fewer hospitalizations, and stroke prevention with CTT, but also recognized complications of CTT, though awareness was limited in adolescents. Parents described sharing in the informed decision-making process with their healthcare provider about CTT, but adolescent patient participants reported that they were not involved in this process. Conclusions: CTT is associated with significant patient and family burden. Support from family, healthcare providers and school may help individuals cope with some of this burden. These findings provide the basis for future studies to identify strategies to mitigate the burden of CTT and improve the patient experience with this therapy. Future studies should also systematically assess patient knowledge about the key components of CTT and chelation using quantitative assessments.

Acute, intermittent vaso-occlusive pain is the hallmark of sickle cell disease (SCD) and is associated with substantial morbidity and impaired quality of life (QOL). The subgroup of adults with SCD who transition from recurrent, acute pain to chronic, persistent pain have even greater QOL impairment and higher rates of healthcare utilization. Self-management is central to SCD management; however, its role in chronic pain management is not established. This qualitative study was conducted to answer the following research questions: (1) What is the chronic pain experience of adults with SCD? (2) What self-management strategies do adults with SCD use for chronic pain? and (3) Do adults with SCD have any needs in the self-management of chronic pain? Eighteen Black adults with SCD completed a demographics questionnaire and an interview. The majority of the participants were 21–30 years of age (mean 33.5, SD 7.6), female (61.1%), employed at least part-time (61.1%), single/never married (72.2%), and had a SCD type of sickle cell anemia (55.5%). Interview analysis revealed three major themes: (1) the chronic pain experience; (2) strategies for managing chronic pain; and (3) challenges and needs in managing chronic pain. Study findings can be used to support chronic pain management among adults with SCD. Further research is needed to devise and implement effective strategies for the prevention and management of chronic SCD pain.

Background: Hydroxyurea, chronic blood transfusions, and bone marrow transplantation are efficacious, disease-modifying therapies for sickle cell disease but involve complex risk-benefit trade-offs and decisional dilemma compounded by the lack of comparative studies. A patient decision aid can inform patients about their treatment options, the associated risks and benefits, help them clarify their values, and allow them to participate in medical decision making. Objective: The objective of this study was to develop a literacy-sensitive Web-based patient decision aid based on the Ottawa decision support framework, and through a randomized clinical trial estimate the effectiveness of the patient decision aid in improving patient knowledge and their involvement in decision making. Methods: We conducted population decisional needs assessments in a nationwide sample of patients, caregivers, community advocates, policy makers, and health care providers using qualitative interviews to identify decisional conflict, knowledge and expectations, values, support and resources, decision types, timing, stages and learning, and personal clinical characteristics. Interview transcripts were coded using QSR NVivo 10. Alpha testing of the patient decision aid prototype was done to establish usability and the accuracy of the information it conveyed, and then was followed by iterative cycles of beta testing. We conducted a randomized clinical trial of adults and of caregivers of pediatric patients to evaluate the efficacy of the patient decision aid. Results: In a decisional needs assessment, 223 stakeholders described their preferences, helping to guide the development of the patient decision aid, which then underwent alpha testing by 30 patients and 38 health care providers and iterative cycles of beta testing by 87 stakeholders. In a randomized clinical trial, 120 participants were assigned to either the patient decision aid or standard care (SC) arm. Qualitative interviews revealed high levels of usability, acceptability, and utility of the patient decision aid in education, values clarification, and preparation for decision making. On the acceptability survey, 72% (86/120) of participants rated the patient decision aid as good or excellent. Participants on the patient decision aid arm compared to the SC arm demonstrated a statistically significant improvement in decisional self-efficacy (P=.05) and a reduction in the informed sub-score of decisional conflict (P=.003) at 3 months, with an improvement in preparation for decision making (P<.001) at 6 months. However, there was no improvement in terms of the change in knowledge, the total or other domain scores of decisional conflicts, or decisional self-efficacies at 6 months. The large amount of missing data from survey completion limited our ability to draw conclusions about the effectiveness of the patient decision aid. The patient decision aid met 61 of 62 benchmarks of the international patient decision aid collaboration standards for content, development process, and efficacy. Conclusions: We have developed a patient decision aid for sickle cell disease with extensive input from stakeholders and in a randomized clinical trial demonstrated its acceptability and utility in education and decision making. We were unable to demonstrate its effectiveness in improving patient knowledge and involvement in decision making.

Despite its efficacy, the uptake of HU in adults with sickle cell disease (SCD) is poor likely due to a combination of system, provider, and patient-related factors. We investigated attitudes of adult patients towards HU by conducting qualitative interviews with 95 adult SCD patients (age 18 to 67 years old, 71 were female). While 53% of all participants reported that they were currently taking HU, patients ranging in age 18–30 years (Group 1) were more likely to report current HU use as compared to those (Group 2) ranging in age 31–67 years (65% vs. 41% P = 0.01). Most Group 1 participants who reported currently taking HU indicated that the decision to start HU was made by a parent, though some made the decision themselves as a young adult. Group 1 participants expressed trust in the efficacy of HU as well as trust that their physician adequately shared risks and benefits for the medication. The Group 2 participants, who were not currently on HU, were skeptical that all the risks and benefits of HU were known, were concerned that the efficacy of HU was not proven, and that they were not receiving complete information about its potential side effects. Of Group 2 participants who reported currently being on HU, 25% were concerned about the side effects and efficacy of HU and reported continuing HU because of a lack of effective alternatives. These data suggest that there are significant differences by age in adult SCD patients’ attitudes towards, utilization and understanding of the risks and benefits of HU.