Pathophysiology and principles of management of the many faces of the acute vaso‐occlusive crisis in patients with sickle cell disease

Abstract

Effective management of sickle cell pain entails a thorough understanding of its pathophysiology and the pharmacogenomics of the opioids used to manage it. In recent years, there has been significant progress along these two lines. At the pathophysiologic level, there is evidence that the severity and frequency of painful stimuli modulate their transmission at the level of the dorsal horn of the spinal cord. This modulation is achieved via two channels: the a-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and NMDA receptors. Initially, the AMPA channel controls the transmission of stimuli of mild-moderate severity. Once the AMPA channel reaches its limit of membrane depolarization, the NMDA channel is activated and facilitates the transmission of painful stimuli in a progressive fashion leading to central sensitization and glial activation. At the level of pharmacogenomics, the metabolism of each opioid is patient-specific. Glucuronidation is unique for the metabolism of morphine, hydromorphone, and oxymorphone. The metabolism of all other opioids requires specific Cytochrome P450 (CYP) isoenzymes. The activity of each isoenzyme and the activity of the metabolites of each opioid vary among patients depending on their genetic makeup and coexistent environmental factors such as the use of other medications that may enhance or inhibit the CYP isoenzyme activity. The clinical picture of sickle cell disease (SCD) in general and sickle cell anemia (SS) in particular has evolved significantly over the years. In the 1950s, 1960s, and 1970s, many patients died during childhood or young adulthood (1-3) and the knowledge of healthcare providers about sickle cell pain and its management were suboptimal. Since then, things have improved significantly but not totally. With the advent of newborn screening, penicillin/antibiotic prophylaxis, better vaccines, better antibiotics, safer blood transfusion, iron chelation therapy and hydroxyurea survival and the quality of life of patients with SCD improved (4, 5), and it is not unusual nowadays to have occasional patients with SCD who are 50-70 yr old. With increased longevity, however, a host of new phenomena appeared and the incidence of new complications of SCD became apparent and previously milder complications became more severe and more common. The acute vaso-occlusive crisis (VOC), for example, is no more characterized by the intermittent sudden onset and sudden offset only with pain-free periods in between recurrent VOCs; chronic pain syndromes have become more common and more severe requiring special treatments and interventions, neuropathic pain has been well documented in transgenic sickle cell mice, and most importantly numerous comorbidities emerged that complicate the already complex disease. There are at least 23 comorbid conditions reported in SCD (6). Despite these advances, management of acute sickle cell pain did not change much; it is still fixed at the level of type, amount, frequency, and

Chronic Opioid Therapy and Central Sensitization in Sickle Cell Disease

“…VOCs are characterized by severe pain, in variable locations, lacking any clear objective signs of etiology. 5 The pathophysiology of VOC is complex and still remarkably poorly understood, but involves interactions among activated endothelium, malformed “sickled” red blood cells, both chronic and acute inflammatory processes, and the nervous system. 6–17 Patients experiencing VOC are at increased risk for subsequent acute chest syndrome or stroke, both potentially life-threatening complications.…”

Low-dose methotrexate in sickle-cell disease: a pilot study with rationale borrowed from rheumatoid arthritis

“…Vaso-occlusive crises (VOC) are important features of sickle cell disease (SCD), which is characterized by ischemic injury of potentially all major organs in the body [1–3]. Tissue damage initially results from hypoxia and then from oxygen re-exposure, that causes massive production of reactive oxygen species (ROS), local activation of endothelial cells, platelets, neutrophils, monocytes, resident tissue macrophages and perivascular mast cells [4].…”

“…For decades, nonsteroidal anti-inflammatory drugs (NSAID) have been recommended for treatment of light and moderate pain in SCD patients [1, 14]. Similar to NSAID, low-dose methotrexate (MTX) exhibits anti-inflammatory activity that has been successfully used for therapy of several chronic inflammatory diseases, such as rheumatoid arthritis [15], psoriasis [16], uveitis [17], juvenile dermatomyositis [18], localized scleroderma [18], Crohn’s disease [18], Wegener granulomatosis [19], and sarcoidosis [20].…”

Use of genome-editing tools to treat sickle cell disease

“…Sickle cells also have a tendency to hemolyze, shortening their lifespan and leading to chronic anemia. Detailed reviews on the genetics (Steinberg and Sebastiani 2012) and physiopathology (Paradowski 2015; Ballas 2015) of SCD are available for further reading.…”