Pain Management In Sickle Cell Disease Research Articles

Δ 9 -Tetrahydrocannabinol alleviates hyperalgesia in a humanized mouse model of sickle cell disease.

People with sickle cell disease (SCD) often experience chronic pain as well as unpredictable episodes of acute pain, which significantly affect their quality of life and life expectancy. Current treatment strategies for SCD-associated pain primarily rely on opioid analgesics, which have limited efficacy and cause serious adverse effects. Cannabis has emerged as a potential alternative, yet its efficacy remains uncertain. In this study, we investigated the antinociceptive effects of Δ9-tetrahydrocannabinol (THC), cannabis' intoxicating constituent, in male HbSS mice, which express >99% human sickle hemoglobin, and male HbAA mice, which express normal human hemoglobin A, as a control. Acute THC administration (0.1-3 mg-kg-1, intraperitoneal, i.p.) dose-dependently reduced mechanical and cold hypersensitivity in HbSS, but not HbAA mice. In the tail-flick assay, THC (1 and 3 mg-kg-1, i.p.) produced substantial antinociceptive effects in HbSS mice. By contrast, THC (1 mg-kg-1, i.p.) did not alter anxiety-like behavior (elevated plus maze) or long-term memory (24-h novel object recognition). Subchronic THC treatment (1 and 3 mg-kg-1, i.p.) provided sustained relief of mechanical hypersensitivity but led to tolerance in cold hypersensitivity in HbSS mice. Together, the findings identify THC as a possible therapeutic option for the management of chronic pain in SCD. Further research is warranted to elucidate its mechanism of action and possible interaction with other cannabis constituents. Significance Statement The study explores THC's efficacy in alleviating pain in sickle cell disease (SCD) using a humanized mouse model. Findings indicate that acute THC administration reduces mechanical and cold hypersensitivity in SCD mice without impacting emotional and cognitive dysfunction. Subchronic THC treatment offers sustained relief of mechanical hypersensitivity but leads to cold hypersensitivity tolerance. These results offer insights into THC's potential as an alternative pain management option in SCD, highlighting both its benefits and limitations.

Differential clinical characteristics across traditional Chinese medicine (TCM) Syndromes in patients with sickle cell disease.

Pain is a common, debilitating, and poorly understood complication of sickle cell disease (SCD). The need for clinical pain management of SCD is largely unmet and relies on opioids as the main therapeutic option, which leads to a decreased quality of life (QoL). According to the literature, acupuncture has shown certain therapeutic effects for pain management in SCD. However, these clinical studies lack the guidance of Traditional Chinese Medicine (TCM) Syndrome Differentiation principles for treatment. To characterize differences in clinical presentation amongst TCM diagnosed Syndromes in SCD patients. Fifty-two patients with SCD and 28 age- and sex-matched healthy controls (HCs) were enrolled in an ongoing trial of acupuncture. Each participant completed a series of questionnaires on pain, physical function, fatigue, sleep, anxiety, depression and QoL and underwent cold- and pressure-based quantitative sensory testing at baseline. Data on prescription opioid use over the 12 months prior to study enrollment was used to calculate mean daily morphine milligram equivalents (MME). Differences among the three TCM Syndromes were analyzed by one-way ANOVA followed by Tukey post hoc testing. Two-sample t-tests were used to compare SCD and HC groups. TCM diagnosis criteria classified SCD patients into one of three TCM Syndromes: (a) Equal; (b) Deficiency; and (c) Stagnation. The Stagnation group exhibited higher pain interference, physical dysfunction, nociplastic pain, fatigue, anxiety, depression, MME consumption and lower sleep quality and QoL compared to the Equal group. Few differences were observed between HCs and the Equal SCD group across outcomes. Deficiency and Stagnation groups were differentiated with observed- and patient-reported clinical manifestations. These findings suggest that TCM diagnosed Syndromes in SCD can be differentially characterized using validated objective and patient-reported outcomes. Because characteristics of pain and co-morbidities in each SCD patient are unique, targeting specific TCM "Syndromes" may facilitate treatment effectiveness with a Syndrome-based personalized treatment plan that conforms to TCM principles. These findings lay the foundation for the development of tailored acupuncture interventions based on TCM Syndromes for managing pain in SCD. Larger samples are required to further refine and validate TCM diagnostic criteria for SCD.

Telemedicine Triage Model for Infusion Center-Based Management of Uncomplicated Acute Sickle Cell Pain Episodes

Introduction: Patients with sickle cell disease (SCD) develop acute episodes of pain for which they seek care in the hospital emergency department (ED). Infusion center (IC)-based care is an effective alternate treatment strategy for management of uncomplicated pain episodes. However, at our center, we could not obtain institutional buy in for dedicated IC resources. Hence, we developed a telemedicine-guided “add on” IC model, embedded within our institution's cancer infusion services. Here, we evaluate the feasibility of our telemedicine-guided IC model and its effectiveness in managing acute pain episodes and impact on SCD patient care. Methods: A multi-disciplinary team consisting of the SCD clinical team including Nurse Case Manager, Advanced Practice Provider (APP), MD and the IC team including IC leadership, IC charge RN, IC scheduler was assembled. An agreement was made between the SCD team and IC leadership that at least one “add on slot” would be made available for an acute SCD pain visit every day. A workflow was created integrating telemedicine for communication with patients and team members alike, and all team members were educated regarding the workflow (Figure 1). IC leadership was re-engaged when changes needed to be made to the workflow to accommodate more IC visits. Visit numbers for IC visits, emergency department (ED) same day discharges and inpatient (IP) hospitalizations were collected from the electronic medical record and compared for pre-IC development (Jan 1, 2017- Dec 31, 2018) and post IC (January 1, 2021 - Dec 31, 2022). Statistical analysis was performed using Graphpad/Prism assuming nonparametric distribution where applicable. Results: We were able to successfully implement our telemedicine-based IC workflow for management of acute SCD pain. Given the rapid increase in IC requests and need for accommodating more than one patient a day, we engaged nursing leadership and re-designed the workflow to identify additional “add on” slots at various IC locations in our health system, added extended hours and weekend capacity. IC visits for uncomplicated pain episodes increased nearly 9 fold, from 132 visits in the pre-IC period to 1151 visits in the post IC period. Seventeen patients used the IC in the pre-telemedicine period and 53 patients used the IC in the post-telemedicine period. The number of ED same day discharges decreased by 35.2%, from 372 visits in pre-IC phase to 241 visits in post IC period. The number of IP hospitalizations went from 281 to 278. ED visits per IC user per year decreased from 10.9 to 2.4 and IP hospitalizations per IC user per year decreased from 8.3 to 2.6. There was a positive correlation between number of IC visits and ED discharges (Spearman r 0.27, p= 0.06) and between number of IC visits and inpatient hospitalizations (Spearman r 0.4, p=0.006), indicating that the patients who were high users of IC based services also had high rates of ED use and hospitalizations. Twenty four patients who used the IC in 2022 did not have same day ED discharges, 15 patients did not have IP stays and 10 patients did not have IP or ED visits in 2022. Among these 10 patients, 8 had their first IC contact under the telemedicine triage IC model (2021-2022). Conclusions: Telemedicine based IC triage can be a successful model for delivery of IC based care for management of acute SCD pain and of great value in settings where dedicated resources are not available. The total number of ED discharges decreased after incorporation of our model, as did both ED discharges and IP hospitalizations per IC user per year. Patients with high numbers of IC visits were also high utilizers of hospital-based services. A cohort of patients were able to use the IC alone for pain management and did not use the ED or get hospitalized.

Patient, Caregiver, and Healthcare Provider Perspectives on Pharmacologic and Non-Pharmacologic Therapies for Pain in Sickle Cell Disease

Background: Pain is the main cause of poor quality of life among patients with sickle cell disease (SCD). While opioid therapy is the mainstay of treatment for acute SCD pain, it can be complicated by side effects and toxicities. A multimodal, multidisciplinary approach to pain management that promotes non-pharmacologic therapies can improve the quality of care for patients with SCD by addressing biopsychosocial components of the pain experience. Guided by the Consolidated Framework for Implementation Research (CFIR), this study utilized qualitative interviews with patients, caregivers, and healthcare providers at our institution to assess barriers to the use of non-pharmacologic and pharmacologic therapies for pain in SCD. Methods: Semi-structured qualitative interviews were conducted with adolescents and young adults (AYAs; ages 13-21) with SCD, caregivers of AYAs with SCD, and healthcare providers at our institution. AYAs had either a documented history of chronic pain and/or ≥1 admission/year for vaso-occlusive crises (VOCs) for at least one year from 2016-2022. After informed assent and/or consent were obtained, individual semi-structured interviews were conducted. Open-ended interview questions explored existing knowledge, perceptions, and barriers to pharmacologic and non-pharmacologic therapies for pain in SCD. Interviews proceeded until no new themes emerged in each group (i.e., thematic saturation). Interviews were analyzed using descriptive content analysis facilitated by Dedoose software. The CFIR and prior research informed a preliminary codebook, which was revised as new themes emerged. The coders independently coded transcripts and then met to discuss and resolve any discrepancies in coding. Results: Demographics: Eighteen AYAs, 17 caregivers, and 22 healthcare providers were interviewed. Of the AYAs, 61% were female, mean age was 17 years, and the most common SCD genotype was HgbSS (56%). Of the caregivers, 88% were mothers, with a mean age of 43 years. There were 15 AYA/caregiver dyads who participated. The following healthcare providers who care for patients with SCD were interviewed: physicians (31%), nurse practitioners (14%), nurses (14%), child life specialists (14%), psychologists (9%), art therapists (4.5%), healing touch providers (4.5%), physical therapists (4.5%), and social work (4.5%). Themes: Barriers to the use of non-pharmacologic therapies for pain management in SCD can broadly be grouped into two major themes: lack of knowledge about options and lack of access to non-pharmacologic options. Regarding lack of knowledge, most AYAs and caregivers endorsed a lack of knowledge about specific non-pharmacologic therapies (e.g., yoga therapy, healing touch, acupuncture), including their benefits, risks, and their abilities to reduce pain. Like AYAs and caregivers, many healthcare providers had limited knowledge about specific non-pharmacologic therapies and the evidence in support of their usage. Regarding lack of access to specific options, the majority of participants questioned the ability of patients to access non-pharmacologic options for pain management including availability of options and cost of access. Additional themes included a desire for more education about pain and pain management options. AYAs and caregivers were particularly interested in more information about yoga. Additionally, AYAs and caregivers were interested in education early in life before pain episodes occurred. Conclusions: Emerging themes among all groups include an interest in non-pharmacologic therapies for pain in SCD, but with limited knowledge on benefits, risks, options, and access to these therapies. As the American Society of Hematology (ASH) guidelines recommend non-pharmacologic therapies for sickle cell pain, it is crucial to implement these therapies into the management of pain in SCD. Education about different options paired with implementation options for ways to incorporate non-pharmacologic therapies is necessary to optimize pain control and improve quality of life. A particular focus on yoga therapy, with availability of a yoga therapist in medical settings, and organized yoga education events specific for SCD may be beneficial to engage individuals in yoga therapy with a trained yoga-therapist. As a next step, evaluation of these potential implementation strategies will occur within our health system.

Emergency Admissions and the Prescribing of Buprenorphine, Methadone, and Psychotropic Medications in People with Sickle Cell Disease: An Analysis of National Insurance Claims

Background Although there have been efforts to address overdose risks and treatment gaps in general populations receiving opioids, there is has been little research examining potential drug-related poisoning risks in some of the highest-need and complex populations, including those with sickle cell disease (SCD). Chronic opioid medications are necessary and well-tolerated for the treatment of chronic pain, diffuse inflammation, chronic organ damage, and vaso-occlusive pain crises for people with SCD. Previous studies have found that patients with SCD are not more likely to develop addiction to opioids than the general population. However, amid the ongoing endemic of drug-related poisonings in the U.S., epidemiological data is scarce regarding the clinical characteristics of people who have SCD and physiologic opioid tolerance and dependence. There has been particularly limited work on the intersection of sociodemographic characteristics, substance use, and other mental health conditions in the SCD population. Concern has also been raised about the ongoing opioid epidemic contributing to increased stigma, and greater barriers to the management of acute and chronic pain in SCD. Studies have shown that preoccupation with opioid prescription monitoring hindered the ability of physicians to provide comprehensive SCD care. People with SCD often face more restrictive utilization management policies for opioids than peers with other forms of chronic pain (i.e., cancer-related pain). In order for us to develop better interventions for people with SCD, real-world data is urgently needed to describe the current treatment landscape and identify gaps in care for people with SCD and physiologic opioid dependence or tolerance. Using administrative claims data in the US, we aim to: 1) quantify the burden of hospitalization and emergency room admission for medication-related poisoning events, 2) describe the prevalence of opioid prescriptions, such as buprenorphine and methadone, in people with SCD and physiologic opioid dependence or misuse. Methods In this retrospective cohort study of people with physiologic opioid dependence or opioid use disorder (OUD), we analyzed ten years (1/2006-12/2016) of data from the Merative™ MarketScan® Commercial and Multi-State Medicaid Databases. The predictor variable was SCD (versus a comparator group of people with chronic pain) with diagnoses identified using ICD-9/10 codes. The outcome variables were 1) emergency admissions or hospitalization for non-fatal drug/medication-related poisoning events during enrollment, and 2) prescriptions for buprenorphine, methadone, and other opioids, identified via procedure codes and linked pharmacy records respectively. We used multivariable cox regression to estimate the relationship between SCD diagnosis and time until poisoning events. Multivariable poisson regression models were used to assess the relationship between SCD and buprenorphine, methadone, and other opioid prescriptions. Results Our overall cohort consisted of 25,448 people with ICD9-10 opioid dependence or misuse, including 313 with SCD and 25,135 with non-SCD chronic pain. In the SCD cohort, the median age was 30.8 years, and 82% were enrolled in Medicaid. Compared to the non-SCD chronic pain cohort, the SCD cohort had more hospitalizations or emergency admission for iatrogenic events (37.4% vs 9.8%, aHR=2.21[2.12-2.31]). With regards to medication receipt compared to peers with non-SCD chronic pain, the SCD cohort had a lower prevalence of buprenorphine prescriptions (8% vs 30.1%, aRR=0.20[0.18-0.21]) and a higher prevalence of methadone prescriptions for chronic pain (63.6% vs 6.8%, aRR=5.36[5.21-5.51]) and non-methadone/non-buprenorphine opioid prescriptions (80.5% vs 33.7%, aRR=2.20[2.15-2.25]). Conclusions We observed an elevated rate of emergency admission and/or hospitalization for drug/medication-related poisoning, as well as a significant burden of psychiatric comorbidity in a cohort of people with SCD and physiologic opioid dependence or OUD. The prescribing of potentially safer opioids, such as buprenorphine, was uncommon in the cohort. Further research is urgently needed to optimize opioid treatment strategies, combat stigma, and improve the comprehensive management of pain and co-occurring disorders in the SCD population.

A Randomized Clinical Trial Testing the Effect of Digital Behavioral Interventions on Pain and Mental Health Among Adults with Sickle Cell Disease

Background: Patients with sickle cell disease (SCD) suffer a significant disease burden that affects their psychosocial well-being. Digital cognitive-behavioral therapy (CBT) has been utilized in other patient populations and shown to have clinical benefits. Although evidence-based, non-pharmacological interventions for pain management are widely used in other populations, this is not well studied in SCD. There are currently no large-scale, adequately powered clinical trials that evaluate the effectiveness and dissemination potential of digital behavioral pain management interventions for adults with SCD. Objective: The primary goal was to compare the effectiveness of two mobile-phone-delivered programs: 1) digital CBT program tailored for adults with SCD (CBT); or 2) pain and SCD education (Education) for reducing pain symptoms. The secondary goal was to assess whether baseline depression symptoms moderated the effect of these interventions on pain outcomes. Methods: Cognitive Behavioral Therapy and Real-Time Pain Management Intervention for Sickle Cell via Mobile Application (CaRISMA) is a multisite, randomized, pragmatic, comparative effectiveness trial conducted at seven comprehensive sickle cell centers and several community-based organizations in the U.S. The study enrolled adults with SCD who reported chronic pain or using short or long-acting opioids daily. Participants were randomized in a 1:1 ratio to receive either the CBT or Education programs. Both programs utilized identical Facebook Messenger chatbot apps, only the content differed. All intervention participants received health coach support involving weekly phone calls or text messages for a duration of 12 weeks. Participants completed follow up assessments at 3 and 6 months, and daily e-diary entries of 0-10 pain numerical rating scale, mood, and opioid use. The primary outcome was the 6-month change in the PROMIS pain interference. Secondary outcomes included average daily pain intensity for a 2-week period at each time point, change in mean % body area affected by pain (measured by a ‘paintable’ body image within the mobile app), PHQ-9 depression, GAD-7 anxiety, Adult Sickle Cell Quality of Life Measurement Information System (ASCQ-Me) quality of life (social functioning and emotional impact), and Sickle Cell Self-Efficacy Scale (SCSES). Generalized linear mixed models were used to compare changes in 6-month outcomes between study arms after accounting for design variables (study site and baseline depression). Results: Of the 574 participants screened for eligibility, 359 (63%) were consented and randomized (178 to CBT and 181 to Education). Seventy-five percent of participants connected with the chatbot but only 47% completed at least one CBT/education lesson. However, 80% of participants had at least one text message, phone or video session with a health coach. At 6-months, there was a significant decline in pain interference within each arm (CBT [-2.13, 95%CI (-3.42, -0.84)] and Education [-2.66, 95%CI (-3.97, -1.36)]); however, this decline did not differ between arms (p=0.57). There was not a significant 6-month change in daily pain intensity for either arm, however, for % body area covered in pain, both CBT and education conferred a similar relative decrease, 19.2% and 17.1%, respectively. There were significant 6-month improvements within-arms for PHQ-9, GAD-7, and both ASCQ-Me measures, but no between-arm differences emerged. (Table 1). Of these, only the 6-month change in ASCQ-Me emotional impact approached a significant difference between arms with digital CBT conferring slightly greater improvement in scores, 3.51 (95%CI: 2.29, 4.73) compared to education,1.79 (95%CI: .55, 3.04; p=.05). Baseline PHQ depression score (>= 10 vs < 10) did not moderate the effect of treatments on pain interference (p=0.52). Conclusions: Preliminary trial findings suggest that both digital CBT and Education, with health coach support, are effective approaches for management of SCD pain and mental health symptoms. Most participants connected with a health coach and may have derived benefit from this support, however, poor engagement with the digital CBT and education component of the study may have limited the study's ability to detect between arm differences. Secondary analyses will examine the effect of intervention engagement on treatment outcomes.

Ketamine for Pain in Sickle Cell Disease Reduces Opioid Usage

ContextPain attributable to sickle cell disease (SCD) is often unpredictable, recurrent, and requires complex treatments. Subanesthetic ketamine infusion has been studied in other diseases and disorders, but there is still limited data on its efficacy in pain management for SCD. ObjectivesThe primary objective is to determine if subanesthetic ketamine infusion reduces pain scores and opioid requirements in hospitalized pediatric patients with SCD. ResultsForty-six admissions among 22 patients between February 2018 and December 2019 were analyzed. We observed decrease in pain scores within 24 hours of ketamine initiation in 34 of 46 admissions (mean pain score per patient before ketamine initiation: 2.2–9.7, mean pain score per patient after ketamine initiation: 0–9.7; P < .05). We observed a decrease in pain scores in the remaining 12 admissions after greater than 24 hours of ketamine initiation. Opioid usage declined after ketamine infusion, with a difference of means in oral morphine equivalents before and after ketamine of 122.8 mg/day. The side effects observed with ketamine infusion included hallucinations in 11 (23.9%) admissions. Only four (8.7%) admissions required cessation of the infusion due to side effects. The readmission rate at two weeks and four weeks after first ketamine infusion was the same (12.5%) at both time points. For all patients in the cohort, the introduction of ketamine into pain regimens did not reduce the number of admissions in the year following ketamine initiation relative to the year prior. ConclusionIn pediatric patients with SCD, subanesthetic ketamine was safe as a continuous infusion and effectively reduced both pain scores and opioid requirements.

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.

Evaluating the feasibility of delivering a pain management programme for adults living with sickle cell disease.

Pain is the prominent feature of sickle cell disease (SCD) and negatively affects quality of life. Delivery of pain management programmes (PMPs) has been suggested in clinical guidelines for pain management in SCD; however, further evidence of the feasibility and effectiveness of PMPs in this population is needed. This study explored the feasibility of delivering a sickle cell pain management programme (SCPMP) for adults within a haemoglobinopathies service. A single arm, repeated-measures observational design was used to determine feasibility of delivering the SCPMP at one study site. Primary feasibility outcomes were recruitment, completion of treatment and outcome measures, satisfaction, credibility and acceptability to participants. Secondary feasibility outcomes were treatment outcomes and processes, frequency of vaso-occlusive crisis (VOC) and healthcare utilisation. Four of five feasibility criteria were met. Annual recruitment of eight participants to a SCPMP was not achieved. Twenty-nine people began a SCPMP during the study period. Twenty-five (86.2%) participants attended ≥5/8 sessions and 21(84%) programme completers provided all end of programme questionnaires. Mean scores of >7 on ten-point scales were seen across satisfaction and credibility questions. At least moderate (Hedges g >0.5) effect sizes were seen in pre-post SCPMP measures of pain interference, anxiety, depression, self-efficacy, pain-related worry and acceptance. A small (Hedges g 0.4) effect size was seen in HRQoL. Following SCPMP attendance, mean frequency of self-reported VOC and hospital admissions reduced. This study suggests that, given an adequate source of referrals, a SCPMP is feasible to deliver and appears acceptable and credible to participants. Exploration of influences on recruitment, such as barriers to group interventions, would be illuminating, prior to investigating feasibility of an adequately powered randomised-controlled trial.

Hematologists' Attitudes Toward Sickle Cell Disease Pain Management

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

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

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

An Outpatient Pain Plan and Emergency Department Pain Pathway for Adults With Sickle Cell Disease

Sickle cell disease (SCD), one of the most common inherited diseases, is associated with lifetime morbidity and reduced life expectancy. In the United States, SCD primarily affects Black patients and, to a lesser degree, those of Hispanic descent These populations are known to have health care disparities related to lower socioeconomic status, limited access to health care, and racial bias. The quality-adjusted life expectancy of patients with SCD is less than 35 years, because of progressive complications of the disease. The most common complication is severe episodic pain related to vaso-occlusive ischemic events. Despite guidelines, pain management often is delayed as patients struggle with resistance from clinicians based on concerns over opioid use or abuse, overdose, or drug-seeking behavior. Effective pain management can be accomplished with collaboration between clinicians and patients, a documented outpatient pain management plan, and when necessary, an emergency department clinical pain pathway for acute SCD pain management

Flurbiprofen inhibits heme induced NLRP3 inflammasome in Berkeley sickle cell disease mice.

Sickle cell disease (SCD) is accompanied by several complications, which emanate from the sickling of erythrocytes due to a point mutation in the β-globin chain of hemoglobin. Sickled erythrocytes are unable to move smoothly through small blood capillaries and therefore, cause vaso occlusion and severe pain. Apart from pain, continuous lysis of fragile sickled erythrocytes leads to the release of heme, which is a strong activator of the NLRP3 inflammasome, thus producing chronic inflammation in sickle cell disease. In this study, we identified flurbiprofen among other COX-2 inhibitors to be a potent inhibitor of heme-induced NLRP3 inflammasome. We found that apart from being a nociceptive agent, flurbiprofen exerts a strong anti-inflammatory effect by suppressing NF-κB signaling, which was evidenced by reduced levels of TNF-α and IL-6 in wild-type and sickle cell disease Berkeley mice models. Our data further demonstrated the protective effect of flurbiprofen on liver, lungs, and spleen in Berkeley mice. The current sickle cell disease pain management regime relies mainly on opiate drugs, which is accompanied by several side effects without modifying the sickle cell disease-related pathology. Considering the potent role of flurbiprofen in inhibiting NLRP3 inflammasome and other inflammatory cytokines in sickle cell disease, our data suggests that it can be explored further for better sickle cell disease pain management along with the possibility of disease modification.

Patient and Family Opioid Decision-Making for Pain Management in Sickle Cell Disease: A Qualitative Study

Pain is a significant symptom experienced frequently by individuals with sickle cell disease (SCD). Pain management includes strategies such as oral rehydration, non-pharmacological therapies (eg, massage, relaxation), and oral analgesics and opioids. Shared decision-making around pain management is emphasized repeatedly in recent guidelines; however, research is sparse regarding factors to be considered in shared decision-making approaches including the perceived risks and benefits of opioids. This qualitative descriptive study was conducted to explore perspectives of decision-making for opioid medications in SCD. We conducted 20 in-depth interviews with caregivers of children with SCD and individuals with SCD to elucidate the decision-making processes around home use of opioid therapy for pain management at a single center. Themes were identified in the domains of the Decision Problem (Alternatives and Choices; Outcomes and Consequences; Complexity), the Context (Multilevel Stressors and Supports; Information; Patient-Provider Interactions), and the Patient (Decision-Making Approaches; Developmental Status; Personal and Life Values; Psychological State). Key findings indicated opioid management for pain in SCD is important yet complex and requires collaboration among patients, families, and providers. Elements of patient and caregiver decision-making identified in this study may be applied to shared decision-making strategies in the clinical setting and future study. PerspectiveThis study illustrates the factors involved in decision-making around home opioid use for pain management in children and young adults with SCD. These findings can be applied to determining shared decision-making approaches around pain management between providers and patients, in accordance with recent SCD pain management guidelines.

An outpatient pain plan and ED pain pathway for adults with sickle cell disease.

Sickle cell disease (SCD), one of the most common inherited diseases, is associated with lifetime morbidity and reduced life expectancy. In the United States, SCD primarily affects Black patients and, to a lesser degree, those of Hispanic descent. These populations are known to have healthcare disparities related to lower socioeconomic status, limited access to healthcare, and racial bias. The quality-adjusted life expectancy of patients with SCD is less than 35 years, because of progressive complications of the disease. The most common complication is severe episodic pain related to vaso-occlusive ischemic events. Despite guidelines, pain management often is delayed as patients struggle with resistance from clinicians based on concerns over opioid use or abuse, overdose, or drug-seeking behavior. Effective pain management can be accomplished with collaboration between clinicians and patients, a documented outpatient pain management plan, and when necessary, an ED clinical pain pathway for acute SCD pain management.

Early Initiation of Sub-Anesthetic Ketamine Infusion in Adults with Vaso-Occlusive Crises Is Associated with Greater Reduction in Sickle Cell Pain Intensity: A Single Center's Experience.

Recurrent, severely painful episodes, known as vaso-occlusive crises (VOCs) are the hallmark of sickle cell disease (SCD) and the primary reason for hospitalization. Opioids have been the gold standard for VOC treatment without significant improvement pain outcomes. To aid analgesia and combat opioid related adverse effects (ORAEs), some SCD clinicians have trialed infusions of sub-anesthetic ketamine along with opioids to treat VOCs. In this retrospective analysis, we compared adult SCD patients who received early vs late adjunctive sub-anesthetic ketamine infusions for VOCs. We identified adult SCD patients (age 18-50 years) who presented to Duke University with a VOC and received sub-anesthetic ketamine infusions from July 2015 to June 2019. We assessed both daily opioid consumption (measured as oral morphine milligram equivalents (MME)) and self-reported 0-10 numeric pain ratings (NPR) at 1, 2, and 3 days after infusion initiation, as well as 1 day after discontinuation. A total of 56 patients were identified with a median age of 30 years. Compared to late administration, early infusion of sub-anesthetic ketamine was associated with a 24.5% (P = .0003) and 25.9% (P = .0006) reduction, respectively, in median NPR at 1 day and 2 days after infusion initiation but did not persist at 3 days following initiation of the infusion. A statistically significant reduction in MME was not observed. In a nonrandomized study of sickle cell patients with VOCs, early sub-anesthetic ketamine infusion led to greater reduction in subjective pain intensity than late initiation of the infusion. Randomized studies should further explore whether early vs late ketamine infusion improves management of acute SCD pain.

A rapid evidence assessment of sickle cell disease educational interventions.

To assess the impact of educational interventions on the knowledge and attitude of healthcare professionals (HCPs) regarding sickle cell disease (SCD) pain management in the UK. Variations and inadequate pain management due toHCPs' lack of knowledge and negative attitude is still an ongoing global concern for SCD patients despite availability of effective treatment and evidence-based guidelines. Several international studies have implemented interventions aimed at improving knowledge, attitude, and pain management. No review on the effectiveness of these interventions was found. Also, no previous intervention done in the UK was found from the thorough search of research databases. However, there are estimated 240,000 genetic carriers with about 12,500-15,000 estimated people living with SCD in the UK. Rapid Evidence Assessment of existing evidence. A rapid evidence assessment was conducted between March 2021-January 2022 following the PRISMA 2020 guidelines. Included papers must have an educational intervention about SCD or related symptom management where the learners were HCPs. Excluded papers were those not published in English or before 2010. The following databases were searched: CINAHL, MEDLINE, PubMed America and Europe, Scopus, PsycINFO and Web of Science. Data quality was assessed using the Mixed Methods Assessment Tool (MMAT) and analysed using a narrative approach. Ten studies were included in the final review. Overall, they reported improved outcomes in six main themes: knowledge, attitude, perception, adoption, satisfaction and efficiency. Five studies reported statistically significant improvement in at least one outcome, four studies reported positive improvement, and two studies reported no significant improvement in knowledge and attitude. These heterogeneous studies were implemented once, and all designs were prone to bias; this makes it difficult to state how effective interventions are for SCD. Current evidence of positive improvement in HCPs' knowledge and attitude is insufficient for generalisation and recommendation for adoption. However, we believe that implementing validated educational interventions remains essential for effective acute SCD pain management and patient-centred care. Further research is needed to find a suitable educational intervention that can be replicated. Quality SCD education, timely crisis management and reduced patient stigma are crucial in reducing the risk of rapid clinical decompensation to avoid developing life-threatening complications. Understanding SCD can also support the building of therapeutic relationships between the patient and practitioner. This review was not registered.

Sickle Cell Disease Associated Changes in the Gut Microbiome Contribute to Persistent Pain

Many patients with sickle cell disease (SCD) suffer from chronic pain, the underlying causes of which are unclear. Recent 16s ribosomal RNA sequencing studies revealed differences in the number and types of bacteria in the gastrointestinal tract of patients and mouse models of SCD relative to controls, but it is unclear if or how these changes contribute to symptomology. In these experiments, we used transgenic SCD mice to determine the extent to which disease related gut dysbiosis contributes to persistent pain. Reflexive pain behaviors were first measured in SCD mice following longitudinal probiotic or antibiotic treatment. Vehicle-treated SCD mice displayed significant mechanical allodynia relative to vehicle-treated wildtype mice, and antibiotic treatment further exacerbated mechanical allodynia in both genotypes. In contrast, probiotic treatment completely reversed persistent touch hypersensitivity in SCD mice. Persistent touch pain was also transiently reversed in SCD mice following fecal material transplant from healthy mice. In complementary experiments, wildtype recipient mice developed cold and touch hypersensitivity that persisted for several weeks after fecal material transplant from SCD donors. Using whole-cell patch clamp recordings, we further determined that these behavioral observations were accompanied by altered intrinsic plasticity in a select class of nodose ganglia sensory neurons, the peripheral terminals of which are well positioned to detect sensory information in the gut. Nodose ganglia neurons isolated from animals that received sickle cell fecal material transplants were hyperexcitable relative to those isolated from animals that received control fecal material transplants. These data are the first to suggest that disease-related gut dysbiosis induces pain through changes in vagal nerve activity. Ongoing studies are examining specific bacterial populations and/or metabolites responsible for these functional changes in order to develop novel therapeutics for chronic SCD pain management. Grant support from National Institutes of Health grants K99HL155791 and R01NS070711.

Moving Toward a Multimodal Analgesic Regimen for Acute Sickle Cell Pain with Non-Opioid Analgesic Adjuncts: A Narrative Review.

Purpose of ReviewSickle cell disease (SCD) is an inherited hemoglobinopathy with potential life-threatening complications that affect millions of people worldwide. Severe and disabling acute pain, referred to as a vaso-occlusive crisis (VOC), is a fundamental symptom of the disease and the primary driver for acute care visits and hospitalizations. Despite the publication of guidelines for VOC management over the past decade, management of VOCs remains unsatisfactory for patients and providers.Recent FindingsAcute SCD pain includes pain secondary to VOCs and other forms of acute pain. Distinguishing VOC from non-VOC pain may be challenging for both patients and clinicians. Further, although opioids have been the gold-standard for VOC pain management for decades, the current highest standard of care for all acute pain is a multimodal approach that is less dependent on opioids, and, instead incorporates analgesics and adjuvants from different mechanistic pathways. In this narrative review, we focus on a multimodal pharmacologic approach for acute SCD pain management and explore the evidence for existing non-opioid pharmacological adjuncts. Moreover, we present an explanatory model of pain, which is not only novel in its application to SCD pain but also captures the multidimensional nature of the SCD pain experience and supports the need for such a multimodal approach. This model also highlights opportunities for new investigative and therapeutic targets – both pharmacological and non-pharmacological.SummaryMultimodal pain regimens that are less dependent on opioids are urgently needed to improve acute pain outcomes for individuals with SCD. The proposed explanatory model for SCD pain offers novel opportunities to improve acute pain management for SCD patients.

Impact of a Standardized Emergency Department Pain Protocol for Children with Sickle Cell Disease

Background/Objective: Sickle cell disease (SCD) is a common heritable red blood cell disorder that transcends the lifespan. Abnormal sickle-shaped erythrocytes interfere with blood flow in small vessels resulting in vaso-occlusion. This vaso-occlusion leads to tissue ischemia and inflammation which causes severe pain and is commonly referred to as a vaso-occlusive crisis (VOC). VOC is the most common complication seen in SCD and accounts for the majority of Emergency Department (ED) visits and hospitalizations. The primary objective of this study was to evaluate if pain management of SCD in pediatric patients at our institution was in accordance with national and institutional pain management guidelines before and after implementation of a standardized pain management algorithm.&#x0D; Methods: We retrospectively analyzed electronic medical record (EMR) data at Riley Hospital for Children between June 2015-May 2018, as well as from January 2019-December 2019 from for all pediatric patients (0-21 years old) who presented to the Riley ED with a confirmed diagnosis of SCD and uncomplicated VOC. These timeframes represented pre and post implementation of a standardized pain management algorithm, which has been described separately. The data collected included time to first dose of analgesia, type and dose of analgesia, change in pain score, length of stay in the ED, and disposition (discharge or admission). Univariate analyses were used to compare data between encounters.&#x0D; Results: Prior to implementation, 186 patients were seen for a total of 504 encounters, the majority of whom were male (59%, p&lt;0.001) and had Hb SS disease (67%, p&lt;0.001). The mean length of an ER visit was approximately 5 hours (+/-113 minutes). The median pain score at presentation was 9 (0-10 scale), with an average of 23 minutes from check in to first documented pain score. However, 19% of patients had no initial pain score documented, which occurred more often if the patient’s initial analgesic was given orally (p&lt;0.001). The mean time from ED check in to first dose of analgesia (PO, IV, IN) was 76 minutes. The mean time between pain scores and medication administration increased between subsequent doses. 70% of these encounters resulted in hospitalization, with an average LOS of 4.1 days. Analysis of data following implementation of a standardized pain management algorithm is ongoing.&#x0D; Conclusion: Acute pain episodes are the leading cause of ED visits and hospitalizations for those with SCD. Thus, to properly meet the needs of patients with SCD and improve their outcomes, there needs to be collaborative, standardized and SCD- specific clinical guidelines for ED providers to utilize. Pre-implementation of a standardized acute pain management algorithm, our institution was not meeting national guidelines for administration of analgesia and assessment of pain. Post-implementation results are currently under analysis.&#x0D; Impact and Implications: Patients with SCD experience longer wait times in the ED and significant bias and mistrust regarding pain concerns. Standardized clinical guidelines have the potential to improve care and decrease variation in care delivery. The results from our study can inform institutional and national policy makers on gaps that exist in pediatric SCD, so that research funding can be appropriately allocated.