Ketamine for Acute Painful Crisis in Sickle Cell Disease Patients: Prospective Randomized Control Trial

Sickle cell disease is an inherited hematological disorder where the shape of red blood cells (RBC) is altered into a sickle-like cells resulting in red blood cell destruction and therefore anemia and other complications. It's a widely spread condition in African American population as well as the Southern and Eastern Provinces of Arabian Peninsula.

Acute painful episodes are a very common complication of the disease process, mainly thought to be a result of tissue ischemia due to occlusion of the microcirculation with clusters of sickled RBC(1). This usually involves long bones or spine but can involve other areas. Acute painful crises can also be precipitated by cold exposure, dehydration, infection, hypoxia, acidosis, hypercarbia, or in some cases it is not related to a specific trigger. This condition puts the patient in severe pain requiring multiple Emergency Department (ED) visits and sometimes admission to the hospital. Currently the mainstay of therapy for acute painful crises is hydration and IV analgesia (2). This makes pain control challenging for the emergency physician as management of acute painful crises requires multiple doses of intravenous (IV) opioids. A retrospective study of 19 patients and 57 visits showed that accumulative dose of IV morphine ranged between 4 milligram (mg) and 26.7 (0.05-0.5 mg/kg) during 70% of the visits. 50% of the patients were admitted after less than 3 hours of ED treatment, 28% of the discharged patients returned to the ED within 3 days (3). Also, as other chronic pain patients, sickle cell disease patients develop opioid induced hyperalgesia (OIH) leading to activation of N- methyl D Aspartate receptors (NMDA) (1).

The use of ketamine, a non-competitive NMDA receptor antagonist, may have the potential to modulate the OIH through impaired sensitization of spinal neurons to nociceptive stimuli and may, therefore, impede development of and blunt neuropathic pain. Extensive search of literature databases showed few published reports and retrospective studies including few patients which have addressed the use of low-dose ketamine in the management of acute painful crises in sickle cell disease (SCD) (4-6). A retrospective study (5) included 5 children and adolescents received a low-dose ketamine infusion for the treatment of sickle cell-related pain demonstrated reduced pain scores in 40% of patients and significant reduction in opioid utilization in only 20% of patients. However, that report was retrospective in nature, non-powered, and included few patients. A recent Canadian retrospective study including 9 adult and adolescent patients demonstrated statistically significant reduced cumulative morphine consumption (146±16.5 mg/day vs. 112.±12.2 mg/day) and pain scores after adding intravenous ketamine in patients with painful sickle cell crises (7). Similarly, another American investigators reported decreased opioid consumption with infusing low-dose ketamine as an adjuvant analgesic in 30 patients presented with sickle cell disease with vaso-occlusive crisis (VOC), that study was retrospective (2). Moreover, in year 2017, a prospective, randomized, double dummy trial was done comparing the adverse effects and analgesic efficacy of low-dose ketamine for acute pain in the ED either by single intravenous push or short infusion. This study shows that low-dose ketamine administered as short infusion is related with a significantly lower rates of feeling of unreality and sedation with no difference in analgesic efficacy in comparison to intravenous push (8)

To the best of investigator's knowledge, there is no large, prospective, comparative, controlled clinical trial investigated in the addition of low-dose ketamine in shortening the ER stays and improving the quality of analgesia in patients with VOC.

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