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Targeting pain at its source in sickle cell disease.

ABSTRACT: Sickle cell disease (SCD) is a genetic disorder associated with hemolytic anemia, end-organ damage, reduced survival, and pain. One of the unique features of SCD is recurrent and unpredictable episodes of acute pain due to vasoocclusive crisis requiring hospitalization. Additionally, patients with SCD often develop chronic persistent pain. Currently, sickle cell pain is treated with opioids, an approach limited by adverse effects. Because pain can start at infancy and continue throughout life, preventing the genesis of pain may be relatively better than treating the pain once it has been evoked. Therefore, we provide insights into the cellular and molecular mechanisms of sickle cell pain that contribute to the activation of the somatosensory system in the peripheral and central nervous systems. These mechanisms include mast cell activation and neurogenic inflammation, peripheral nociceptor sensitization, maladaptation of spinal signals, central sensitization, and modulation of neural circuits in the brain. In this review, we describe potential preventive/therapeutic targets and their targeting with novel pharmacologic and/or integrative approaches to ameliorate sickle cell pain.

SUBMITTER: Gupta K

PROVIDER: S-EPMC6087885 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Targeting pain at its source in sickle cell disease.

Gupta Kanika K Jahagirdar Om O Gupta Kalpna K

American journal of physiology. Regulatory, integrative and comparative physiology 20180328 1

Sickle cell disease (SCD) is a genetic disorder associated with hemolytic anemia, end-organ damage, reduced survival, and pain. One of the unique features of SCD is recurrent and unpredictable episodes of acute pain due to vasoocclusive crisis requiring hospitalization. Additionally, patients with SCD often develop chronic persistent pain. Currently, sickle cell pain is treated with opioids, an approach limited by adverse effects. Because pain can start at infancy and continue throughout life, p ...[more]

PMID: 29590553

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Project description:Sleep disturbance and depression are commonly encountered in primary care. In sickle cell disease, depression is associated with pain, poor treatment compliance, and lower quality of life. The prevalence of sleep disturbance and its effect upon quality of life in adults with sickle cell disease is unknown. The goal of this study was to determine the prevalence of sleep disturbance and if it is associated with pain and depression in sickle cell disease.Three hundred twenty eight adults with sickle cell disease enrolled on the Bethesda Sickle Cell Cohort Study were assessed using the Pittsburgh Sleep Quality Index and Beck Depression Inventory II screening measures as a cross-sectional survey. Scores greater than 5 (Pittsburgh Sleep Quality Index) and 16 (Beck Depression Inventory II) defined sleep disturbance and depression, respectively. Clinical and laboratory parameters were also assessed.The mean Pittsburgh Sleep Quality Index score was 8.4 (SD ± 4.2) indicating a 71.2% prevalence of sleep disturbance. The mean Beck Depression Inventory II score was 8.0 (SD ± 8.9). Sixty five (20.6%) participants had a score indicating depression, and half of these (10.0%) had thoughts of suicide. Both Pittsburgh Sleep Quality Index and Beck Depression Inventory II scores were significantly correlated (p <?.001). The number of days with mild/moderate pain (p =?.001) and a history of headaches (p =?.005) were independently associated with depression by multivariate regression analysis. Patients with sleep disturbance were older (p =?.002), had higher body mass index (p =?.011), had more days of pain (p =?.003) and more frequent severe acute painful events (emergency room visits and hospitalizations) during the previous 12 months (p <?.001).More than 70 percent of adults with sickle cell disease had sleep disturbance, while 21 percent showed evidence of clinical depression. Sleep disturbance and depression were correlated, and were most common among those with more frequent pain. Providers caring for adults with sickle cell disease and frequent pain should consider screening for these common co-morbidities. Additional study is needed to confirm these findings and to determine if treatments for pain, depression or sleep disturbances will improve quality of life measures in this patient population.ClinicalTrials.gov identifier: NCT00011648.

Project description:BackgroundThe up-regulation of P-selectin in endothelial cells and platelets contributes to the cell-cell interactions that are involved in the pathogenesis of vaso-occlusion and sickle cell-related pain crises. The safety and efficacy of crizanlizumab, an antibody against the adhesion molecule P-selectin, were evaluated in patients with sickle cell disease.MethodsIn this double-blind, randomized, placebo-controlled, phase 2 trial, we assigned patients to receive low-dose crizanlizumab (2.5 mg per kilogram of body weight), high-dose crizanlizumab (5.0 mg per kilogram), or placebo, administered intravenously 14 times over a period of 52 weeks. Patients who were receiving concomitant hydroxyurea as well as those not receiving hydroxyurea were included in the study. The primary end point was the annual rate of sickle cell-related pain crises with high-dose crizanlizumab versus placebo. The annual rate of days hospitalized, the times to first and second crises, annual rates of uncomplicated crises (defined as crises other than the acute chest syndrome, hepatic sequestration, splenic sequestration, or priapism) and the acute chest syndrome, and patient-reported outcomes were also assessed.ResultsA total of 198 patients underwent randomization at 60 sites. The median rate of crises per year was 1.63 with high-dose crizanlizumab versus 2.98 with placebo (indicating a 45.3% lower rate with high-dose crizanlizumab, P=0.01). The median time to the first crisis was significantly longer with high-dose crizanlizumab than with placebo (4.07 vs. 1.38 months, P=0.001), as was the median time to the second crisis (10.32 vs. 5.09 months, P=0.02). The median rate of uncomplicated crises per year was 1.08 with high-dose crizanlizumab, as compared with 2.91 with placebo (indicating a 62.9% lower rate with high-dose crizanlizumab, P=0.02). Adverse events that occurred in 10% or more of the patients in either active-treatment group and at a frequency that was at least twice as high as that in the placebo group were arthralgia, diarrhea, pruritus, vomiting, and chest pain.ConclusionsIn patients with sickle cell disease, crizanlizumab therapy resulted in a significantly lower rate of sickle cell-related pain crises than placebo and was associated with a low incidence of adverse events. (Funded by Selexys Pharmaceuticals and others; SUSTAIN ClinicalTrials.gov number, NCT01895361 .).

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Targeting pain at its source in sickle cell disease.

Publications

Targeting pain at its source in sickle cell disease.

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