Mu Opioid Receptor (OPRM-1) Polymorphisms among Patients with Sickle Cell Disease.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3804-3804
Author(s):  
Sharmila Mehta ◽  
Nicholas Campbell ◽  
Lakiea Bailey ◽  
Ferdane Kutlar ◽  
Dedrey Elam ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Allele Frequency ◽  
Sickle Cell ◽  
Opioid Analgesics ◽  
Mu Opioid Receptor ◽  
Wild Type ◽  
Cell Disease ◽  
Opioid Use ◽  
Mu Opioid ◽  
Pain Frequency

Abstract Opioid analgesics form an important component of the management of acute and chronic pain in patients with sickle cell disease (SCD). Chronic opioid use, sometimes associated with dependence and addiction in a subset of patients, may pose difficult management problems. This adds to the sometime antagonistic relationship that can develop between providers and patients with SCD. Pain management can become a sociological and psychological issue in the management of SCD. The Mu opioid receptor (OPRM-1) is the primary site of action of endogenous opioid peptides (enkephalins and endorphins) and of opioid analgesics, such as morphine, methadone, fentanyl, heroin, and related compounds. Rapid activation of the mu receptor results in a euphoric effect, conferring the reinforcing or rewarding effects of opioids and thus contributing to the development of addiction. It has been known that there is variation between individuals in sensitivity to opioids suggesting potential variation in the receptor protein and the gene. Some recent data have shown that polymorphisms in the OPRM-1 gene affect pain threshold and tolerance as well as opioid requirements for optimal pain control. In an effort to unravel the complex issues surrounding pain frequency, pain tolerance, opioid usage, and opioid addiction in this patient population, we conducted a study of our adult sickle cell patients for the frequency of the two common cSNPs and another SNP in the IVSII (G691C) of the OPRM-1 gene. DNA samples from randomly selected patients were used in this study. The OPRM-1 gene was PCR amplified and subjected to cycle sequencing on an ABI Prism automated sequencer. The results showed that of the 97 adult SCD patients screened for the C17T polymorphism (GenBank accession #AY292291 and 292290), 67 (69.7%) had the wild type (CC), 28 (29.1%) were heterozygous (CT), and 11 (11.4%) were homozygous (TT) for the SNP. This represents an allele frequency for the T of 0.26. Of the 39 sequenced samples for the A1189G, all (100%) showed the wild type (AA). These results closely resemble those reported by Bond et al (PNAS, 95;9608,1998) for the frequency of the two cSNPs in the African-American population (allele frequency of 0.21 for the C17T and 0.016 for the A118G). Of the 16 samples screened for IVS II G691C polymorphism (GenBank accession #AY299483), 6 (37.5%) had the wild type (GG), 9 (56.3%) were heterozygous (GC), and 1 (6.2%) was homozygous (CC). Our results among SCD patients show a high frequency of C17T polymorphism in the OPRM-1 gene. Detailed studies in higher numbers of SCD patients and clinical correlations with pain frequency and threshold, opioid usage, opioid abuse and drug seeking behavior will be undertaken. It is expected that these studies will clarify the role of OPRM-1 polymorphisms as a genetic modifier associated with pain frequency, with tolerance as well as opioid use and abuse.

Daily home opioid use in adults with sickle cell disease: The PiSCES project

2015 ◽  
Vol 11 (3) ◽  
pp. 243 ◽  
Author(s):  
Wally R. Smith, MD ◽  
Donna K. McClish, PhD ◽  
Bassam A. Dahman, PhD ◽  
James L. Levenson, MD ◽  
Imoigele P. Aisiku, MD, MSCR ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Symptom Burden ◽  
Opioid Analgesics ◽  
Cell Disease ◽  
Opioid Use ◽  
Short Acting ◽  
Negative Coping ◽  
Long Acting ◽  
Opioid Users

Background: Although opioid prescribing in sickle cell disease (SCD) can be controversial, little is published about patterns of opioid use.Objective: To report on home opioid use among adults with SCD.Design: Cohort study.Participants: Adults with SCD (n = 219) who completed daily pain diaries for up to 6 months and had at least one home pain day.Main measures: Use of long-acting or short-acting opioids, other analgesics, or adjuvants; the proportion of home days, home pain days, and home crisis days with opioid use; these two outcomes according to patient characteristics.Key results: Patients used opioids on 12,311 (78 percent) of 15,778 home pain days. Eighty-five patients (38.8 percent) used long-acting opioids with or without short-acting opioids and 103 (47.0 percent) used only short-acting opioids. Twenty-one (9.6 percent) patients used only non-opioid analgesics and 10 (4.6 percent) used no analgesics. Both pain intensity and pain frequency were higher among opioid users (analysis of variance [ANOVA], p < 0.0001). Opioid users used hydroxyurea more often than nonusers, even when controlling for mean pain on pain days. Among all patients, significant relationships were found between any opioid use and somatic symptom burden, SCD stress, negative coping, and physical and mental quality of life (QOL); the relationship with SCD stress and physical QOL remained when controlled for mean pain. Among opioid users, similar associations were found between frequency of opioid use and some disease-related and psychosocial variables.Conclusions: In this adult SCD sample, opioids were used by the majority of patients. Pain was the overwhelming characteristic associated with use, but disease-related and psychosocial variables were also associated.

scholarly journals Daily Associations between Child and Parent Psychological Factors and Home Opioid Use in Youth with Sickle Cell Disease

2019 ◽  
Vol 54 (1) ◽  
pp. 61-66 ◽  
Author(s):  
Amanda L Stone ◽  
Zaria Williams ◽  
Melissa McNaull ◽  
Anna C Wilson ◽  
Cynthia W Karlson
Keyword(s):  
Side Effects ◽  
Sickle Cell Disease ◽  
Negative Affect ◽  
Sickle Cell ◽  
Psychological Factors ◽  
Opioid Analgesics ◽  
Cell Disease ◽  
Opioid Use ◽  
Home Setting ◽  
At Home

Abstract Background Opioid analgesics are frequently used in the home setting to manage episodic pain in youth with sickle cell disease (SCD). Given the risk of adverse side effects, including constipation and sedation, understanding factors associated with at-home opioid use is important for maximizing pain relief while minimizing negative side effects. Purpose The present study aimed to evaluate the relationship between individual psychological factors (pain catastrophizing and negative affect), caregiver psychological factors (catastrophizing about child’s pain and caregiver negative affect), and home opioid use in youth with SCD. Methods Youth with SCD (n = 32) and a caregiver (n = 28) recruited during a routine outpatient hematology visit completed electronic 14 day diaries assessing pain, opioid use, and psychological factors. Results Approximately 28% of youth (n = 9) reported pain ≥50% of diary days and a third of youth (n = 11, 34%) used opioid analgesics at least one of the diary days. The number of days opioid analgesics were used ranged from 0 to 7 (50% of diary days). Results from generalized linear mixed models indicated greater child negative affect accounted for increased odds of opioid use on a given day when accounting for pain intensity. Greater caregiver catastrophizing about children’s pain was also associated with increased odds of children’s opioid use. Conclusions Child and parent psychological factors relate to child opioid use at home for SCD-related pain. Future research is warranted in larger samples to identify targets for interventions to enhance pain management while reducing opioid-related risk and side effects.

scholarly journals Hospitalization Events among Children and Adolescents with Sickle Cell Disease in Basra, Iraq

Anemia ◽  
2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Zeina A. Salman ◽  
Meaad K. Hassan
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Readmission Rate ◽  
Length Of Hospital Stay ◽  
Acute Chest Syndrome ◽  
Cell Disease ◽  
Opioid Use ◽  
Asthma Symptoms ◽  
The Mean ◽  
High Readmission Rate

Objectives. Despite improvements in the management of sickle cell disease (SCD), many patients still experience disease-related complications requiring hospitalizations. The objectives of this study were to identify causes of hospitalization among these patients and factors associated with the length of hospital stay (LOS) and readmission.Methods. Data from 160 patients (<14 years old) with SCD who were admitted to the Basra Maternity and Children’s Hospital from the first of January 2012 through July 2012 were analyzed.Results. The main causes of hospitalization were acute painful crises (73.84%), infections (9.28%), acute chest syndrome (8.02%), and acute splenic sequestration crisis (6.32%). The mean LOS was4.34±2.85days. The LOS for patients on hydroxyurea (3.41±2.64days) was shorter than that for patients who were not (4.59±2.86days),P<0.05. The readmission rate (23.1%) was significantly higher among patients with frequent hospitalizations in the previous year (OR 9.352, 95% CI 2.011–43.49), asthma symptoms (OR 4.225, 95% CI 1.125–15.862), and opioid use (OR 6.588, 95% CI 1.104–30.336). Patients on hydroxyurea were less likely to be readmitted (OR 0.082, 95% CI 0.10–0.663).Conclusions. There is a relatively high readmission rate among patients with SCD in Basra. The use of hydroxyurea significantly decreases the LOS and readmission rate.

Abstract P726: Cytochrome B5 Reductase 3 Modifies The Brain-Blood Axis Response To Ischemic Stroke In Mice With Sickle Cell Disease

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Katherine C Wood ◽  
Heidi M Schmidt ◽  
Scott Hahn ◽  
Mehdi Nouraie ◽  
Mara Carreno ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Ischemic Stroke ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
African Ancestry ◽  
Cytochrome B5 ◽  
Heme Iron ◽  
Wild Type ◽  
Cell Disease ◽  
Cytochrome B5 Reductase

Introduction: Stroke and silent infarcts are serious complications of sickle cell disease (SCD), occurring frequently in children. Decreased nitric oxide bioavailability and responsiveness contribute to neurovascular disease. Cytochrome b5 reductase 3 (Cyb5R3) is a heme iron reductase that reduces oxidized soluble guanylate cyclase heme iron (Fe 3+ --> Fe 2+ ) to preserve nitric oxide signaling. A loss-of-function Cyb5R3 missense variant (T117S) occurs with high frequency (0.23 minor allele) in persons of African ancestry. Hypothesis: We hypothesized that impaired reductase function of T117S Cyb5R3 exacerbates brain damage after ischemic stroke in SCD. Methods: Bone marrow transplant was used to create male SCD mice with wild type (SS/WT) or T117S (SS/T117S) Cyb5R3. Blood was sampled before and after middle cerebral artery occlusion (55 minutes occlusion, 48 hours reperfusion). Infarct volume (IV) was determined by 2,3,5-triphenyltetrazolium chloride. Intravascular hemolysis and correlation (Pearson’s R) of hematology changes with IV were determined. Baseline Walk-PHaSST (NCT00492531) data were analyzed for stroke occurrence. Results: Brain IV (63 vs 27 cm 3 , P=0.003) and mortality (3/6 vs 0/8) were greater in SS/T117S vs SS/WT. Red blood cells, hemoglobin and hematocrit declined as IV increased. Plasma oxyhemoglobin increased in parallel with IV (r = 0.74, P=0.09). There were different signatures to hematologic changes that occurred with IV in SCD. Relative to wild type, T117S contracted the erythroid compartment (red blood cell: -13% vs 13%, P=0.003; hematocrit: -20% vs 1%, P=0.008; hemoglobin: -18% vs 2%, P=0.007). Mean platelet volume correlated with IV in SS/T117S (r = 0.87, P=0.06), while the inverse occurred in SS/WT (r = -0.63, P=0.09) Monocytes increased in parallel with IV in SS/T117S (r = 0.73, P=0.16), but followed the opposite trajectory in SS/WT (r = -0.77, P=0.04). WalkPHaSST participants with T117S Cyb5R3 self-reported more ischemic stroke (7.4% vs 5.1%) relative to wild type. Conclusion: Cyb5R3 is an important modifier of the evolution and outcome of ischemic brain injury in SCD and its hematologic consequences. Our findings indicate a bidirectional relationship between stroke and anemia in SCD that may axially turn on Cyb5R3 activity.

Age-related prescription medication utilization for the management of sickle cell disease among Texas Medicaid patients

2021 ◽  
Vol 17 (4) ◽  
pp. 301-310
Author(s):  
Nidhi Shukla, MS, MBA ◽  
Jamie C. Barner, PhD, FAACP, FAPhA ◽  
Kenneth A. Lawson, PhD, FAPhA ◽  
Karen L. Rascati, PhD
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Age Groups ◽  
Dual Therapy ◽  
Cell Disease ◽  
Opioid Use ◽  
Medication Utilization ◽  
Age Related ◽  
Nonopioid Analgesics ◽  
Chi Square Analysis

Introduction: Sickle cell disease (SCD) is associated with recurrent complications and healthcare burden. Although SCD management guidelines differ based on age groups, little is known regarding actual utilization of preventative (hydroxyurea) and palliative therapies (opioid and nonopioid analgesics) to manage complications. This study assessed whether there were age-related differences in SCD index therapy type and SCD-related medication utilization.Design and patients: Texas Medicaid prescription claims from September 1, 2011 to August 31, 2016 were retrospectively analyzed for SCD patients aged 2-63 years who received one or more SCD-related medications (hydroxyurea, opioid, or nonopioid analgesics).Outcome measures: The primary outcomes were SCD index drug type and medication utilization: hydroxyurea adherence, and days’ supply of opioid, and nonopioid analgesics. Chi-square, analysis of variance, and Kruskal–Wallis tests were used.Results: Index therapy percentages for included patients (N = 2,339) were the following: opioids (45.7 percent), nonopioids (36.6 percent), dual therapy-opioids and nonopioids (11.2 percent), and hydroxyurea (6.5 percent), and they differed by age-groups (χ2 = 243.0, p 0.0001). Hydroxyurea as index therapy was higher among children (2-12:9.1 percent) compared to adults (26-40:3.7 percent; 41-63:2.9 percent). Opioids as index therapy were higher among adults (18-25:48.0 percent; 26-40:54.9 percent; 41-63:65.2 percent) compared to children (2-12:36.6 percent). Mean hydroxyurea adherence was higher (p 0.0001) for younger ages, and opioid days’ supply was higher for older ages.Conclusions: Texas Medicaid SCD patients had low hydroxyurea utilization and adherence across all age groups. Interventions to increase the use of hydroxyurea and newer preventative therapies could result in better management of SCDrelated complications and reduce the frequency of pain crises, which may reduce the need for opioid use.

scholarly journals Psychological Predictors of Pain in Children and Adolescents With Sickle Cell Disease: A Scoping Review

2018 ◽  
Vol 36 (2) ◽  
pp. 150-159
Author(s):  
Clare Donohoe ◽  
Ellen Lavoie Smith
Keyword(s):  
Sickle Cell Disease ◽  
Children And Adolescents ◽  
Sickle Cell ◽  
Middle Eastern ◽  
The United States ◽  
Health Science ◽  
Psychological Characteristics ◽  
Cell Disease ◽  
Pain Frequency ◽  
Psychological Risk

Objective: Sickle cell disease (SCD) is a common red blood cell disorder that disrupts the lives of many African Americans and those of Middle Eastern heritage within the United States due to frequent pain. There is limited research quantifying biopsychosocial factors, specifically psychological characteristics, that influence pain in children and adolescents with SCD. The aim of this literature review was to identify psychological characteristics that are predictive or associated with pain in children and adolescents with SCD. Method: This review was conducted using PRISMA guidelines. Four databases, PubMed, CINAHL, PsycINFO, and Scopus, were searched using specific terms to address the aim of the review (SCD, pain, pediatrics and adolescents, and psychological characteristics). Results: The review identified a lack of consensus regarding the definitions and measurement of pain frequency and intensity. A variety of psychological characteristics were associated with pain including coping strategies, anxiety, depressive symptoms, catastrophizing, and stress. Overall, the study designs restricted the ability to fully identify psychological characteristics that predict pain. Conclusions: Health science researchers must strive for a deeper understanding about the presentation of SCD pain and psychological risk factors associated with increased pain to provide targeted screening and treatment.

scholarly journals Medical marijuana certification for patients with sickle cell disease: a report of a single center experience

2020 ◽  
Vol 4 (16) ◽  
pp. 3814-3821 ◽  
Author(s):  
Susanna A. Curtis ◽  
Dana Lew ◽  
Jonathan Spodick ◽  
Jeanne E. Hendrickson ◽  
Caterina P. Minniti ◽  
...  
Keyword(s):  
Health Care ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Medical Marijuana ◽  
Care Utilization ◽  
Cell Disease ◽  
Opioid Use ◽  
Admission Rates ◽  
Single Center Experience ◽  
Few Data

Abstract More than one-third of adults with sickle cell disease (SCD) report using cannabis-based products. Many states list SCD or pain as qualifying conditions for medical marijuana, but there are few data to guide practitioners whether or whom should be certified. We postulated that certifying SCD patients may lead to a reduction in opioid use and/or health care utilization. Furthermore, we sought to identify clinical characteristics of patients who would request this intervention. Retrospective data obtained over the study period included rates of health care and opioid utilization for 6 months before certification and after certification. Patients who were certified but failed to obtain medical marijuana were compared with those who obtained it. Patients who were certified were invited to participate in a survey regarding their reasons for and thoughts on certification. Patients who were certified for medical marijuana were compared with 25 random patients who did not request certification. Fifty adults with SCD were certified for medical marijuana and 29 obtained it. Patients who obtained medical marijuana experienced a decrease in admission rates compared with those who did not and increased use of edible cannabis products. Neither group had changes in opioid use. Patients who were certified for medical marijuana had higher rates of baseline opioid use and illicit cannabis use compared with those who did not request certification. Most patients with SCD who requested medical marijuana were already using cannabis illicitly. Obtaining medical marijuana decreased inpatient hospitalizations.

scholarly journals A comment on pattern of opioid use in sickle cell disease

2017 ◽  
Vol 92 (4) ◽  
pp. E42-E43 ◽  
Author(s):  
Xiulu Ruan ◽  
Hong Wu ◽  
Dian Wang
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Cell Disease ◽  
Opioid Use

Nitrated Lipids in a Murine Model of Sickle Cell Disease at Baseline.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3758-3758
Author(s):  
Jeffrey Schwartz ◽  
Paul R.S. Baker ◽  
Francisco J. Schopfer ◽  
Bruce A. Freeman
Keyword(s):  
Linoleic Acid ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Ion Trap ◽  
Internal Standard ◽  
Wild Type ◽  
Cell Disease ◽  
Inflammatory Signaling ◽  
No Bioavailability ◽  
Anti Inflammatory

Abstract Introduction Sickle cell disease (SCD) is increasingly recognized as a disorder of inflammatory homeostasis. One major focus in recent years has been understanding the role of Nitric Oxide (NO) in the pathophysiology of SCD. NO is a critical mediator of inflammatory pathways and current evidence supports the precept that NO bioavailability is decreased in SCD, resulting in normal concentrations of NO at baseline but an inability to increase NO during stress. Nitrated fatty acids, such as Nitrolinoleate (LNO2), have recently been reported as potent and abundant anti-inflammatory signaling mediators with the ability to cause vasorelaxation and inhibition of platelet and neutrophil activation. Evidence supports their anti-inflammatory signaling is mediated through the release of NO and NO-related products. LNO2 has not previously been described in patients with SCD and our objective was to quantify LNO2 in a murine model of SCD at baseline. Methods Whole blood was obtained from transgenic sickle cell and wild type mice (n = 5 and 6, respectively). Blood was centrifuged and separated into plasma and packed red blood cells (RBCs). These biological samples were prepared for lipid analysis by the method of Bligh and Dyer; care was taken so that the pH of the extraction milieu was consistently maintained at 7 so as to avoid artifactual nitration. Samples were analyzed for free LNO2 content by electrospray ionization tandem mass spectrometry. Using a hybrid triple quadrupole ion trap mass spectrometer, MRM transitions were monitored that specifically identified nitrated linoleic acid species; these species were concomitantly confirmed by the qualitative analytical abilities of the ion trap. The presence of nitrated linoleic acid was confirmed by HPLC chromatographic retention times, MS/MS “fingerprints” and was quantitated by the inclusion of a known quantity of 13C-labeled LNO2. Results LNO2 concentration was calculated as a function of the ratio of analyte to internal standard peak areas by using an internal standard curve linear over five orders of magnitude. Free LNO2 in the RBCs and plasma of 5 transgenic sickle cell mice were 3.97 ± 2.56 nM and 12.37 ± 9.83 nM, respectively. Free LNO2 in the RBCs and plasma of 6 wild type mice were 9.49 ± 8.32 nM and 14.91 ± 10.08 nM, respectively. There were no significant differences in LNO2 concentration between any of the groups. Conclusions LNO2 is present in both transgenic sickle cell mice and wild type mice in comparable concentrations at baseline. As a mediator of NO anti-inflammatory signaling, this is consistent with human studies showing comparable concentrations of NO metabolites at baseline between sickle cell patients and healthy controls. Further study of LNO2 in sickle cell disease is warranted to better understand its role in the inflammatory process associated with acute stress, such as vaso-occlusive pain crisis and acute chest syndrome, when NO bioavailability is decreased.

Toll-Like Receptor 4 Mediates Heme Induced Acute Lung Injury: Preclinical Study of Resatorvid in Sickle Cell Disease

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2113-2113 ◽  
Author(s):  
Samit Ghosh ◽  
Olufolake Adisa ◽  
Yu Yang ◽  
Fang Tan ◽  
Solomon F Ofori-Acquah
Keyword(s):  
Acute Lung Injury ◽  
Sickle Cell Disease ◽  
Lung Injury ◽  
Sickle Cell ◽  
Acute Chest Syndrome ◽  
Toll Like Receptor ◽  
Wild Type ◽  
Cell Disease ◽  
Toll Like Receptor 4 ◽  
Breath Rate

Abstract Abstract 2113 Sickle cell disease (SCD) is characterized by multiple exacerbating events that cause intravascular hemolysis. Heme released into the circulation is scavenged by multiple plasma proteins and delivered to the liver for degradation. Our recent data indicate that this process is impaired in SCD resulting in excess protein-free plasma heme (PFPH) that triggers a lethal form of acute lung injury (ALI) in mice. In this study, we tested the hypothesis that toll-like receptor 4 (TLR4) mediates heme-induced ALI. Wild-type and two TLR4 mutant strains (B6.B10ScN-Tlr4lps-del/JthJ and C3H/HeJ) were intravenously injected with a dose range of ferric heme (0–210 micromoles/kg) and respiratory function monitored using a pulse oximeter. Excess PFPH was associated with reductions in oxygen saturation (SpO2) and breath rate in the wild-type mice but not in the TLR4 variants. Lungs of heme-treated wild-type mice were congested, edematous, hemorrhagic, and had thickened alveolar walls, while no histological abnormalities were found in the TLR4 variants. All heme-treated wild-type mice succumbed within 2 hours, while all TLR4 variants survived. Transgenic mice expressing exclusively human sickle hemoglobin (SS) were intravenously injected with a small molecule TLR4 inhibitor (resatorvid/TAK-242), or a lipid vehicle prior to induction of lung injury with heme (35 micromoles/kg). TAK-242 preserved lung function in the majority of SS mice that failed to scavenge excess PFPH, while both SpO2 and breath rate deteriorated in vehicle treated mice. The unique response to heme by TAK-242 and vehicle-treated SS mice was supported by histological analysis and survival (TAK-242; 76.9% vehicle; 23.5%, n=13–17; log-rank survival test, p<0.01). We provide the first evidence that the interaction between heme and TLR4 can be pathological, specifically causing a lethal form of ALI. Our data on TAK-242, a phase II drug, offers an attractive option to explore TLR4 inhibition as a novel therapeutic strategy to limit progression of acute chest syndrome. Disclosures: Ofori-Acquah: Emory University: Patents & Royalties.

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