ATLANTA (Sept. 21, 2020) – Children’s Healthcare of Atlanta and Emory University School of Medicine have received $8.7 million from the National Heart, Lung and Blood Institute (NHLBI) through the National Institutes of Health (NIH) to determine if giving additional arginine can reduce pain during a sickle cell disease pain crisis. Claudia R. Morris, MD, Pediatric Emergency Medicine Physician at Children’s, will lead a multi-center study of intravenous arginine therapy in collaboration with Carlton Dampier, MD, and Nitya Bakshi, MD, both pediatric hematologists at the Aflac Cancer and Blood Disorders Center of Children’s.
In children with sickle cell disease, severe pain can occur when normal blood flow is disrupted by sickled cells collecting in small blood vessels, often resulting in a visit to the emergency department. Arginine, a type of amino acid and building block of protein, is naturally produced in the body or obtained through food and helps regulate normal blood flow. Too little arginine may cause blood vessels to constrict, reducing blood flow and contributing to sickle cell disease-related pain.
“I think pain crises occur, in part, due to a nutritional deficiency of arginine,” said Dr. Morris, Principal Investigator and Professor of Pediatrics and Emergency Medicine at Emory University. “Human red blood cells contain arginase, an arginine-consuming enzyme that induces an arginine deficiency when red blood cells break apart during hemolysis, a key feature of sickle cell disease-causing severe anemia. Sickle cell disease patients are metabolically different during a pain crisis, and the severity of their arginine deficiency is reflected in the severity of their pain.”
The randomized controlled trial led by Dr. Morris will utilize the national Pediatric Emergency Care Applied Research Network (PECARN). Children’s and Emory University joined PECARN in 2019 to compare intravenous arginine to a placebo among 400 patients over a six-year study. Patients will receive treatment three times a day during an average four- to five-day hospital stay, and the team will examine time to crisis resolution, in addition to pain levels. Children’s and Emory University will serve as the lead site and clinical coordinating center among 10 sites for the study. The University of Utah will serve as the trial’s data coordinating center.
“If successful, arginine would be an important addition to the drugs available to decrease sickle cell disease pain, as it may reduce or eliminate pain that has already started,” said Dr. Dampier, Co-investigator and Professor of Pediatrics at the Emory University.
Dr. Morris first began studying arginine therapy as an integrative nutritional approach to treating severe sickle cell disease-related pain 20 years ago. In a 2013 arginine study she led, results showed a more than 50% reduction in opioid use and lower pain scores in those treated with arginine compared to a placebo. In May, she published findings in the journal Blood, indicating arginine improves mitochondrial function and decreases oxidative stress. These data informed the current trial by demonstrating patients who present with pain are significantly deficient in arginine and supplying a higher dose, or loading dose, of arginine during the beginning of treatment was beneficial.
“Arginine appears to treat pain, as well as underlying arginine deficiency that develops during a sickle cell disease pain crisis,” said Dr. Morris.
During an oral arginine trial conducted in Nigeria, where the most sickle cell disease patients of any country reside, Dr. Morris served as mentor and advisor to Richard Onalo, MD, MBBS, Head of the Department of Pediatrics at University of Abuja in Nigeria, whose project was included in the “Best of ASH” summary during the 2019 American Society of Hematology meeting. The team saw a nearly two-day decrease in length of hospital stay, decreased time to crisis resolution, decreased analgesia use and decreased pain. Oral arginine is less expensive and more accessible than its intravenous counterpart, demonstrating its versatility on a global scale.
“I’m very interested in non-opioid, integrative approaches to pain,” added Dr. Morris.
Sickle cell disease is a lifelong, inherited blood disorder affecting 100,000 people in the U.S. One in 13 African American babies is born with the sickle cell disease trait due to its origins in sub-Saharan Africa. Sickle cell disease causes the hemoglobin protein in red blood cells to become sickled, deoxygenated and rigid during a process known as polymerization. This results in anemia that reduces healthy red blood cells used to deliver oxygen to the body.
Symptoms of sickle cell disease may include fatigue, swelling of the hands and feet, jaundice and severe episodes of pain. Pain crises are the most common complication and the primary reason a child with the disease goes to the emergency department. Other complications from sickle cell disease include stroke, permanent organ damage, infections and delayed growth. Blood and marrow transplant (BMT) is the only known treatment for the disease, but not all patients are medically eligible for it.
The Aflac Cancer and Blood Disorders Center is the largest pediatric hematology program in the country, including the largest pediatric sickle cell disease program that treats more than 2,000 unique sickle cell disease patients each year. To learn more about the arginine trial utilizing PECARN, visit clinicaltrials.gov/ct2/show/NCT02536170.