Pain Episodes In Sickle Cell Disease Research Articles

Inpatient Use of Extended-Release (ER) Opioids for Vaso-Occlusive Crisis Associated with Increased Length of Stay for ER Opioid-Naïve Patients

Background: The intermittent acute pain syndrome associated with sickle cell disease (SCD) is a poorly understood phenomenon with complex pathophysiology. Given the broad spectrum of analgesic interventions, including immediate-release (IR) and extended-release (ER) opioids, healthcare providers are challenged with the task of safely and effectively escalating inpatient opioid regimens, especially in the setting of limited guidelines outlining the combination of different opioid formulations. Despite SCD being the most common genetic disorder in the United States, more research is required to improve physician expertise with appropriate and timely pain management of vaso-occlusive crisis. Methods: This study was a retrospective chart review (n=200) of patients with known SCD requiring hospitalization for acute pain secondary to vaso-occlusive crisis without an alternative etiology of pain symptoms. The review included a patient population aged 18-67 years old with 43.5% males and 56.5% females hospitalized from 2/1/2022 to 5/6/2022. The primary outcome measure was hospital length of stay (LOS) for adequate pain control compared against varying factors of inpatient opioid-prescribing practices, including initiation or continuation (if prescribed within 6 months prior to admission encounter per PDMP review) of an ER opioid formulation, degree of morphine milligram equivalents (MME) escalation from outpatient regimen, utilization of a sickle cell analgesic order set, and initiation of patient-controlled analgesia pump (PCA). A secondary outcome measure investigated was the quantitative comparison of highest daily prescribed MME in relation to the aforementioned inpatient variables. Data analysis was completed using Wilcoxon Rank Summary analysis, with a significant p-value set to < 0.05. Results: Among the primary outcome analysis, the only significant factor affecting LOS was the introduction of an ER opioid. The results show that within the patient cohort naïve to an outpatient ER opioid (n=105), ER opioid-incorporated inpatient analgesic regimens resulted in a significantly increased mean LOS compared to IR opioid monotherapy regimens, with an average of 8.8 inpatient days as compared to 5.3 days, respectively (p-value < 0.001). For the patients prescribed an outpatient ER opioid at baseline (n=95), the continuation of an inpatient ER opioid did not result in a significant change in mean LOS, calculated as 6.7 days vs. 6.0 days in the continued and non-continued groups, respectively (p-value = 0.716). Among the secondary outcome measures, utilization of a sickle cell order set and PCA did not significantly affect degree of MME escalation. Conclusions: Limited evidence-based recommendations for the treatment of acute pain episodes in SCD has resulted in widely varying opioid regimens prescribed by inpatient providers and has created clinical challenges regarding the optimization of pain management. This study investigated inpatient opioid regimens utilized in treatment of vaso-occlusive crisis and found that the initiation of ER opioids resulted in increased length of stay for ER opioid-naïve patients as compared to treatment with IR opioids alone. These results question the benefit of inpatient ER opioids in relation to the risk of opioid dependence and MME escalation.

Cluster Analysis Reveals Distinct Subgroups with Severe Pain in Sickle Cell Disease: A Cross-Sectional Study Using the Grndad Multi-Center Registry

Introduction: Sickle cell disease (SCD) affects millions worldwide and is characterized by episodic severe pain, impacting quality of life and leading to significant healthcare utilization. Yet, clinicians face significant challenges in treating pain in individuals with SCD due to heterogeneity in pain experiences and pain impact. Improved understanding of the clinical characteristics of individuals with SCD who are at risk for developing severe pain is necessary to better manage pain and develop novel and personalized pain interventions. The objectives of this study were to (1) identify distinct pain subgroups based on demographic and psychosocial characteristics and (2) evaluate the relationship between the subgroups and pain impact. Methods: We performed a hierarchical cluster analysis on a cross-sectional sample of adults living with SCD enrolled in the Global Research Network Data and Discovery (GRNDaD) registry who had completed the Adult Sickle Cell Quality of Life Measurement Information System (ASCQ-Me) surveys. Classification variables for clustering included SCD subtype (SS/Sβ 0-thalassemia [SCA] vs SC/Sβ +-thalassemia [variant]), sex, age, presence of chronic pain, frequency of SCD pain episodes, and social and emotional functioning. Results: There were 472 adult participants included in the analysis. The overall sample was 59% female with a median age of 33 (IQR 26-42 years). Five distinct subgroups were identified: Subgroup 1 (n=117, 100% SCA subtype, 100% female, median age 33, high chronic pain and pain episodes, and poor social and emotional functioning), Subgroup 2 (n=98, 100% variant subtype, 65% female, median age 34, high chronic pain and pain episodes, poor social and emotional functioning), Subgroup 3 (n=141, 100% SCA, 100% male, median age 30, moderate chronic pain, high pain episodes, and low-normal social and emotional functioning), Subgroup 4 (n=41, 100% variant, 54% female, median age 40, low chronic pain and pain episodes, normal social and emotional functioning), and Subgroup 5 (n=75, 100% SCA, 100% female, median age 34, no chronic pain, low pain episodes, and normal social and emotional functioning). All subgroups differed significantly (p<0.05) with respect to pain impact/interference, with Subgroups 1-3 demonstrating worse pain impact. Additionally, significant differences in hospitalization, education and income, total hemoglobin and fetal hemoglobin levels were noted between the subgroups. Hydroxyurea use was similar in the three clusters with SCA (subgroups 1 and 2). Conclusion: To our knowledge, this analysis represents the largest pain subgroup analysis in SCD. Subgroups with worse pain impact were characterized by poorer social and emotional functioning, implying that psychosocial factors are strongly associated with pain outcomes in individuals with SCD. Moreover, variations in pain impact based on sex and SCD subtype suggest these factors are associated with differences in pain outcomes. Additionally, we found that the presence of chronic pain is associated with higher pain impact, increased healthcare utilization, and more frequent pain episodes. The study should be interpreted with consideration of the following limitations: (1) cross-sectional design, which limits the ability to establish causality or directionality between the various associations, and (2) reliance on self-reported measures that may be subject to recall and reporting biases. Nevertheless, these findings highlight the heterogeneity in pain experiences and suggest that multimodal interventions may be critical in addressing the pain and psychosocial burden for individuals with SCD. Longitudinal studies are needed to further validate these findings and explore how pain profiles may change over time in individuals with SCD.

Pklr Variants Associated with Acute Pain in Sickle Cell Disease Influence ATP Concentrations in Red Blood Cells

Background: We previously demonstrated association of PKLR intron 2 variants with hospitalization rate for acute pain in people with sickle cell disease (SCD) and utilized allele-specific expression analysis to show that these variants influence PKLR activity (Wang et al, 2022). Pyruvate kinase (gene PKLR, protein PKR) is a rate-limiting enzyme in glycolysis. Reduced PKR activity leads to an increase in intracellular 2,3-diphosphoglycerate (2,3-DPG), and a concomitant decrease of adenosine triphosphate (ATP), factors that promote sickle hemoglobin (HbS) polymerization and red blood cell (RBC) sickling. On this basis, we explored how the "high risk" PKLR intron 2 variants affect levels of PKR protein expression, 2,3-DPG, ATP, oxygen dissociation (p50) and sickling kinetics (t50). Methods: We studied a total of 416 subjects which included 125 HbSS, 89 HbAS, and 202 ethnic-matched healthy controls (HbAA) enrolled under protocol NCT03685721 approved by the NHLBI Institutional Review Board. DNA was genome scanned using Ilumina's Infinium "MEGA" chip (1.7m markers). The results were quality controlled followed by genotype imputation based on the 1000 Genomes Project phase 3 data using the Michigan Imputation Server. Whole blood levels of ATP and 2,3-DPG were measured using LC-MS/MS with LLOQ at 50.0 μg/mL and converted to intracellular concentrations by dividing by the hematocrit (as a fraction). PKR was detected by antibody-based capture and detection using an electrochemiluminescence immunoassay (Meso Scale Discovery, Rockville, MD, USA) and the signal normalized to a control sample. A Hemox Analyzer [TCS, Scientific Corp, New Hope, PA] was used to obtain p50 values (defined as the partial pressure of oxygen at which Hb is 50% saturated with oxygen). t50 is single parameter measure of sickling kinetics (Dunkelberger et al, 2018). Single variant analyses (under additive genetic model adjusted for age and sex) were conducted in each of the Hb sub-populations for associations between the 7 PKLR variants (intron 4 - rs2071053, and intron 2 -rs8177970, rs116244351, rs114455416, rs12741350, rs3020781, and rs8177964) and the 5 parameters (PKR, 2,3-DPG, ATP, p50 and t50). False-discovery rate (FDR) adjusted p-values were calculated to account for the multiple testing issue. Results: Table 1A shows levels of the 5 parameters (ATP/HCT, 2,3-DPG/HCT, PKR, p50 and t50) in the 3 Hb genotypic groups (HbAA, HbAS and HbSS). Because patients with SCD have variable anemia, ATP and 2,3-DPG were normalized against HCT. The observed trending higher ATP / HCT and significantly elevated 2,3-DPG /HCT in HbSS compared to HbAS and to HbAA are consistent with previous reports (Poillon et al, 1990). HbSS subjects also had higher PKR protein expression, as well as right-shifted p50 values, compared to HbAS and HbAA (Table 1A), which suggest HbSS RBCs have lower specific activity of PKR. A one-way ANOVA showed that the differences in these mean values were highly significant (Table 1A). All 7 PKLR variants were associated with ATP levels in the HbAS group, of which 4 (rs8177970, rs116244351, rs114455416 and rs8177964) in intron 2 remained statistically significant after multiple testing adjustment (Table 1B). We also identified association between 3 variants (intron 2 - rs12741350, rs3020781, intron 4 - rs071053) and 2,3-DPG levels in the HbSS, as well as t50 in the HbAS group. Conclusion: ATP is essential for maintaining RBC membrane integrity and shape; reduced ATP dehydrates RBCs and promotes sickling. In a previous report, a PKLR intron 2 'high-risk" haplotype was implicated in acute sickle pain by affecting PKLR expression (Wang et al, 2022). In this follow-up study, we show that the same intron 2 "high-risk" haplotype negatively affects ATP levels when accounting for PKR expression, thus providing a biological basis for PKLR as a genetic modifier of SCD pain presentation. 3 of the 7 variants are also associated with elevated 2,3-DPG levels in HbSS as well as t50 (a single parameter that depends primarily on sickling kinetics) in HbAS. The variant associations are observed more clearly in HbAS but not in HbSS, possibly because of the much more homogeneous cell population in HbAS. We conclude that PKLR intron variants may directly contribute to the severity and frequency of acute pain episodes in SCD, thus additional studies with larger sample sizes are warranted. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Case report: a rare case of concomitant haemophilia a and sickle cell disease

Co-existing haemophilia A and sickle cell disease is rarely reported in the medical literature.1 Haemophilia A, an X-linked recessive bleeding disorder due to reduced factor VIII levels, has a reported incidence of 1:10,000 males globally.1 Sickle cell disease (SCD), an autosomal recessive disorder with abnormal haemoglobin production (HbS), affects 20–25 million people globally.1 This case presentation describes a rare presentation of haemophilia A and SCD in a 4-year-old male recently immigrated from Uganda, who presented with a four day history of a painful right knee and background of easy bruising and bleeding. Clinical examination was consistent with haemarthrosis. Initial screening bloods demonstrated Hb 85 g/L, MCV 88 fL, WCC 19×109/L and Plt 518×109/L. Peripheral blood film examination demonstrated numerous sickle cells and target cells. Haemoglobin variant studies performed by HPLC demonstrated an elevated HbA2 (4.5%), elevated HbF (14.2%) and HbS (80%) consistent with SCD. Given clinical history and haemarthrosis, coagulation screening was performed which demonstrated an INR 1.2 and APTT 89 s. Factor VIII levels were greatly reduced at 1% (reference range 50–165%), consistent with haemophilia A. This case highlights the need for clinical correlation when interpreting laboratory findings as not all pain episodes in SCD are consistent with vaso-occlusive crisis.

Family Functioning, Medical Self-Management, and Health Outcomes Among School-Aged Children With Sickle Cell Disease: A Mediation Model.

Informed by the Pediatric Self-Management Model, the present study tested relationships between parent and family functioning, sickle cell disease (SCD) self-management, and health outcomes for children with SCD. 83 children with SCD and a parent completed baseline data as part of a larger investigation of a family-based, problem-solving intervention for children with SCD (M age = 8.47). Youth and parents completed a measure of child health-related quality of life (HRQOL), and parents completed measures of family efficacy, parenting stress, and SCD self-management. SCD pain episodes and urgent health utilization information over the past year were obtained via medical chart review. SCD self-management mediated the relationship between parent-reported family efficacy and parent proxy HRQOL, as well as the relationship between parenting stress and child and parent proxy HRQOL. Mediation models were nonsignificant for outcomes beyond HRQOL, including SCD pain episodes and urgent health utilization. Fostering family efficacy and reducing parenting stress may be meaningful intervention targets for improving SCD self-management and child HRQOL among school-aged children. Although findings were consistent with the Pediatric Self-Management Model in terms of HRQOL, the model was not supported for pain episodes or urgent health utilization, highlighting the need for multi-method, longitudinal research on the SCD self-management behaviors that are linked to preventable health outcomes.

How patients' self-disclosure about sickle cell pain episodes to significant others relates to living with sickle cell disease.

This cross-sectional study examines to whom and how fully sickle cell disease (SCD) patients talk to others about sickle cell pain, how helpful it is to talk with others about these pain episodes, and the association between talking to others about sickle cell pain episodes and patients' psychological adjustment and coping strategies in managing the disease. A convenience sample of 73 African American patients with SCD (30 men and 43 women), were recruited from two SCD clinics at the time of routine medical visits. Most participants had been diagnosed with hemoglobin SS, and they reported an average number of 8.61 pain episodes in the previous 12 months. Participants were asked to whom, how fully, and how helpful it was to talk to significant others about SCD pain episodes experienced in the last 12 months. Patients also completed measures of their psychological adjustment as well as how they would manage a future sickle cell pain episode. Self-report ratings were made on Likert-type scales. Based on paired samples t-tests, participants talked significantly more fully about their thoughts and feelings concerning pain episodes to God and to their primary medical providers than to either their parents, siblings, or an intimate partner/close friend. Bivariate correlations indicated that amount and helpfulness of talking about pain episodes to God and to parents were significantly associated with better psychological adjustment on selected measures. Also, bivariate correlations indicated that helpfulness in talking with siblings, intimate partner/close friend, and primary medical providers was positively related with willingness to go to a physician in the event of a future pain episode. The results document to whom and how helpful it is to talk with others about SCD pain episodes and how SCD disclosure is related to strategies for managing this disease.

Responsiveness of the PedsQL to Pain-Related Changes in Health-Related Quality of Life in Pediatric Sickle Cell Disease

To determine if caregiver report of the pediatric quality of life inventory (PedsQL) is responsive to changes in health-related quality of life (HRQL) associated with pain episodes in pediatric sickle cell disease (SCD). 81 caregivers of children ages 2-19 years with SCD completed the PedsQL as part of routine psychosocial screenings at 2 time points, ranging from 6 to 18 months apart. Frequency of SCD-related pain episodes between time points was assessed using medical chart review. The frequency of pain episodes between time points was a significant predictor of decreases in physical, psychosocial, and total HRQL, even after controlling for time interval, demographic, and medical variables. The caregiver report of the PedsQL appears to be a useful tool for capturing changes in HRQL over time associated with pain episodes in SCD.

Association of Placenta Growth Factor with Hemolysis and Inflammation in Sickle Cell Disease (SCD)

BACKGROUND: Placenta Growth Factor (PlGF) is a member of the vascular endothelial growth factor family of cytokines. Although expressed at high levels by the placenta during pregnancy, PlGF is also released by immature erythrocytes and is elevated in SCD. PlGF appears to play a role in inflammation and may be associated with the frequency of pain episodes in SCD. More recently, PlGF has been reported to increase the expression of endothelin-1 and endothelin-B receptor in human pulmonary microvascular endothelial cells and monocytes, and therefore may play a role in the development of SCD-associated pulmonary hypertension (PHT).OBJECTIVE: We have previously reported that SCD patients with PHT exhibit higher levels of inflammatory markers compared to patients without PHT. The purpose of this study was to evaluate the association of PlGF with PHT (and other SCD-related complications), and to explore the link between PlGF and laboratory markers of hemolysis and inflammation in SCD patients.METHODS: We performed a cross-sectional study of patients followed at the Sickle Cell Clinic at UNC-Chapel Hill. Doppler echocardiography was used to determine the pulmonary artery systolic pressure, and PHT was subsequently defined using an age-, sex-and BMI-adjusted reference range. Nitric oxide metabolites (NOx), PlGF and soluble VCAM (all quantified by ELISA), as well as laboratory markers of hemolysis were obtained at the time of patient evaluation. Student's t-tests (a = 0.05) were used to compare mean values of PlGF in patients with SCD-related complications. Furthermore, Spearman's correlation coefficient was used to assess for correlations between PlGF and laboratory variables.RESULTS: Plasma samples were available in 71 of the 74 subjects evaluated. Levels of PlGF were significantly higher in patients with PHT (12.3 ng/ml vs. 8.9 ng/ml, p = 0.005), and patients with a history of stroke (12.8 ng/ml vs 9.3 ng/ml p = 0.027) compared to those patients without these complications. There was however no association of PlGF with the frequency of acute pain episodes, acute chest syndrome, leg ulcers, priapism or retinopathy. We observed significant positive correlations between lactate dehydrogenase (r2 = 0.13, p = 0.002), reticulocyte counts (r2 = 0.08, p = 0.02), soluble VCAM (r2 = 0.09, p = 0.009), NT-proBNP (r2 = 0.13, p = 0.003), and absolute monocyte count (r2 = 0.08, p = 0.02) with PlGF. There were significant negative correlations between PlGF and hemoglobin (r2 = 0.19, p < 0.0001), and borderline significant negative correlations between PlGF and NOx (r2 = 0.05, p = 0.08).CONCLUSIONS: Our results indicate that PlGF is strongly associated with PHT and stroke, and correlates with soluble VCAM in SCD patients. This suggests that inflammation may play a role in the pathogenesis of SCD-associated vasculopathy. The correlation of PlGF with laboratory measures of hemolysis and NOx suggests that hemolysis, possibly with associated scavenging of nitric oxide, contributes to the inflammatory state in SCD.

Prise en charge de la douleur drépanocytaire selon les critères de l'Organisation mondiale de la santé

Twenty-four percent of the Gabonese population has sickle cell trait, and 1–3% has sickle cell disease. Patients’ management must follow well-defined protocols that take into account the debilitating effect of severe pain episodes. Objectives. – To evaluate the three-step analgesic ladder for control of pain for sickle cell disease pain crises. Methodology. – This is a prospective and descriptive study based on surveys filled between February 2000 and March 2001. Surveys were restricted to sickle cell disease patients having developed pain crises before and during their stay at the hospital. The assessment of the pain was based on the DEGR and EVA scales. The treatment followed the World Health Organisation’s analgesic ladder. The criteria used for estimate pain severity and sedation duration were measured before, 2 and 24 h after treatment administration began (H0, H2 and H24) to evaluate its effectiveness. Results. – Sixty children were included. All the social layers of the population were represented. The school level was variable. Fifty-six percent of the patients suffered their first pain crisis before they were 1 year old. Thirty-one percent had annual crises and 20% monthly crises. Pain was located in joints in 35% of the cases, and in joints and bones in 15% of the cases. Eighty-one percent of the pain crises were successfully treated in stage I. The passage to stage II occurred in the remaining cases (18.3% of the cases). Conclusion. – The WHO’s three-step analgesic ladder for control of pain is effective for the sickle cell disease pain episodes. Stage I drugs relieved the pain for 81.6% of the patients in a relatively short time (2–16 h). It was not possible to go to stage III.

Thrombogenesis in sickle cell disease

Thirty-three subjects with sickle cell disease (SCD), 11 during episodes of pain and 22 during periods without pain, were evaluated for in vivo thrombogenic activities as compared with 10 normal black control subjects. Measurements were performed for (1) platelet surface activation, assessing flow cytometric expression of activated integrin αIIbβ3 receptor (GPIIb/IIIa, CD41a) and P-selectin (CD62p); (2) platelet and erythrocyte surface procoagulant activities, measuring flow cytometric binding of activated factor (FVa) and annexin V; (3) plasma levels of platelet-specific secreted proteins platelet factor 4 (PF4) and β-thromboglobulin (βTG); (4) plasma markers of thrombin generation, prothrombin activation fragment (F1.2), and thrombin: antithrombin complex (TAT); and (5) plasma markers of fibrinolysis, D -dimer, and plasmin:antiplasmin complex (PAP). As compared with control subjects, asymptomatic subjects with SCD demonstrated significantly increased platelet activation (P < .01 for P-selectin and annexin V binding), elevated plasma levels of PF4 and βTG (P < .01 and P < .03, respectively), and increased plasma concentrations of F1.2, TAT, PAP, and D -dimer (P < .05 in all cases). During episodes of SCD pain, platelet activation was increased as compared with periods without pain (P < .01 for expression of activated integrin αIIbβ3 receptor and P-selectin and binding of FVa and annexin V), erythrocytes expressed procoagulant activities (P < .01 for FVa and annexin V binding), and platelet microparticles appeared in the circulation (3% to 30%; P < .001). SCD pain episodes were associated with elevated plasma levels of F1.2, TAT, PAP, and D -dimer (P < .05 as compared with asymptomatic intervals). The frequency of pain episodes correlated with enhanced platelet procoagulant activity (r = 0.61, P < .05) and elevated plasma fibrinolytic activity (r = 0.74, P < .01) measured during periods without pain. Plasma fibrinolytic activity was inversely correlated with time to the next pain episode (r = –0.50, P < .05). Thus, asymptomatic subjects with SCD exhibit ongoing platelet activation, thrombin generation, and fibrinolysis that increases during episodes of pain. These changes are predictive of frequency of pain and interval to next pain episode, thereby implicating thrombogenic activity in the development of SCD pain episodes. (J Lab Clin Med 2001;137:398-407)