Pediatric Pain Management in Sickle Cell Disease
By Wendy Webb, CPNP-AC and Genevieve D’Souza, MD
Department of Anesthesiology, Perioperative and Pain Medicine
Stanford University School of Medicine
Stanford, California
Sickle cell disease is an inherited hemoglobinopathy with defect in Hb synthesis, causing red blood cells to elongate and sickle at the time of injury with cellular hypoxia thus becoming wedged within the blood vessels and hindering blood flow. When the body detects this ischemia to an organ, it compensates by releasing mass amounts of reticulocytes from the bone marrow into the system.
Unlike the normal lifespan of RBCs being 120 days, the sickled RBCs live 10-20 days (Ware, de Montalembert, Tshilo, & Abboud, 2017). The irregular blood cells were first discovered on a peripheral blood smear in 1904 by James B. Herrick and his intern (Apanah & Rizzolo, 2013); yet, in the 114 years that have followed the discovery, little progress has been made in preventing a sickle cell crisis in an individual.
Sickle cell disease has various subtypes. HbAS (heterozygous for hemoglobins A and S) is asymptomatic and may sickle under prolonged, severe hypoxic stress. HbSD (heterozygous for hemoglobins S and D) is intermediate between HbAS and HbSC, which results in moderate degree of anemia. In HbSC (heterozygous for hemoglobins S and C), the sickling tendency is less pronounced under normal conditions due to a relatively normal hematocrit, yet may be prone to severe vaso-occlusive events under hypoxic stress. HbSS (homozygous for hemoglobin S) is the most severe of its form and causes periodic vaso-occlusive crisis (VOC), as well as progressive end-organ damage.
Pain in sickle cell disease arises from numerous causes. Major pain syndromes in sickle cell are considered an acute pain syndrome. The table below lists some of the common causes for acute pain syndrome.
| Hemolysis | Megaloblastic erythropoiesis |
| Vaso-occlusion | Splenic sequestration |
| Skeletal | Painful bone pain crisis |
| Cardiopulmonary | Cardiomegaly |
| Neurological | Cerebrovascular accident (CVA) |
| Genitourinary | Urinary tract infection |
Over time with frequent sickle cell crisis, Chronic Pain Syndrome is seen with arthritis, arthropathy, aseptic (avascular) necrosis, leg ulcers, and vertebral body collapse.
The undertreatment of pain associated with a vaso-occlusive crisis for a person with SCD has led to a significant global burden with ER costs estimated to be greater than $356 million (Ware et al., 2017). According to the CDC, By the age of six, most children with SCD have spent at least one day in the hospital, with blood transfusions being the most common treatment. Transfusions have significantly decreased the mortality rate in patients and remain the standard treatment for SCD; however, it comes with a higher risk for blood-borne infections, erythrocyte alloimmunization, and hemosiderosis (Ware et al., 2017). Iron overload from chronic transfusions results in end-organ failure, leading to early mortality (Hsieh, Fitzhugh & Tisdale, 2011).
By the time an infant is six to 12 months of age, most of the circulating fetal hemoglobin (HbF) is replaced by adult hemoglobin (HbA). This has no clinical relevance in the way of normal physiology; however, since it is believed low levels of HbF is associated with higher risk for developing VOC in an individual with hemoglobinopathy, the FDA approved hydroxyurea for SCD treatment (Apanah & Rizzolo, 2013). The chemotherapeutic agent is disease-altering by increasing HbF levels and decreasing the rate of painful episodes by 50% (Agrawal, Patel, Shah, Nainiwal & Trivedi, 2014). The most common side effect for hydroxyurea is reversible bone marrow suppression by temporarily reducing neutrophils, reticulocytes, and platelets.
Few treatment options are available for SCD pain management. In an acute clinical presentation, the cornerstone of therapy is hydration, oxygen, and analgesia. A basal rate with rescue doses of hydromorphone or morphine from a Patient Controlled Analgesia (PCA) is reserved for severe pain that requires hospital admission. NSAIDs are often used for baseline pain, yet may lead to nephropathy and renal failure in VOC (Armstead & D’Souza, 2011). For moderate pain, oxycodone is an effective oral pain medication for symptom management. The use of adjunct medications, such as tricyclic antidepressants, stimulants, and benzodiazepines enhance the effects of pain medications (Apanah & Rizzolo, 2013).
Over the lifetime of a child living with SCD, a tailored multidisciplinary approach to pain management is recommended for those times of crisis (Armstead & D’Souza, 2011). Physical therapy and occupational therapy help reduce painful episodes while maintaining function. A transcutaneous electrical nerve stimulation (TENS) unit reduces pain and assists in relaxation by utilizing electrical impulses to stimulate the targeted muscle groups. Heat, massage, hypnosis, and acupuncture are all integrative multimodal approaches for the pediatric sickle cell population. Acupuncture accesses intrinsic physiological responses to decrease pain without introducing outside chemicals to the body (Tsai, Reynoso, Shin & Tsung, 2018). Like most children living with a chronic disease, children with sickle cell often experience a shift in their mood; therefore, cognitive-behavior therapy and psychological interventions provide healthy coping tools (Armstead & D’Souza, 2011).
In summary, pain that arises from sickle cell disease and the consequences of a VOC play an integral role in a child’s mortality and morbidity. Current common treatment options are disease-altering, but not curative in any way. Allogenic hematopoietic stem cell transplant (allo-HCT) is the first treatment to be considered a cure for sickle cell, yet does not come without serious risks (Hsieh, Fitzhugh, & Tisdale, 2011). Future directions for the treatment of SCD may be gene therapy providing an alternative cure for those living with sickle cell disease.
References
- Agrawal RK, Patel RK, Shah V, Nainiwal L, Trivedi B. (2014). Hydroxyurea in sickle cell disease: drug review. Indian J Hematol Blood Transfus. June; 30(2):91-96.
- Apanah S, Rizzolo D. (2013). Sickle cell disease: taking a multidisciplinary approach. JAAPA 26: 28-33
- Armstead, V. E., D’Souza, G. (2011). Sickle Cell Pain. In B. C. McClain and S. Suresh. (Eds.) Handbook of pediatric chronic pain: current science and integrative practice (177-191).
- Hsieh, M.M, Fitzhugh, C. D., Tisdale, J.F. (2011). Allogeneic hematopoietic stem cell transplantation for sickle cell disease: the time is now. Blood, 118(4), 1197-1207.
- Tsai, S-L., Reynoso, E., Shin, D.W., Tsung, J.W. (2018). Acupuncture as a Nonpharmacologic Treatment for Pain in a Pediatric Emergency Department. Pediatric Emergency Care, 00(00), 1-7.
- Ware, R.E., de Montalembert, M., Tshilo, L., Abboud, M.R. (2017). Sickle Cell Disease. www.thelancet.com 390, 311-323. https://www.cdc.gov/ncbddd/sicklecell/documents/scd_in_ca.pdf Nov 2013
