Low Dose Ketamine and Acute Pain Crisis

Current treatment standard for acute pain crisis in sickle cell disease (SCD) is largely supportive care: opioid analgesics, hydration, oxygen, and blood transfusion. Sickle cell disease (SCD) is a chronic condition associated with serious and disabling acute consequences such as a vaso-occlusive (VOC) or pain crisis. Uncontrolled pain is the hallmark of a VOC, and often results in acute unscheduled care in the patient's clinic or hospital emergency department (ED). The pain associated with acute VOC in sickle cell disease is caused by the change in the structure of red blood cells. This change leads to microvascular obstruction, a decrease in laminar blood flow, diminished tissue oxygen exchange, and ultimately microenvironmental changes resulting in severe pain.1 During these pain crises, patients sometimes require high doses of opioids for analgesia. Poor pain control, in the setting of high dose opioid administration, is the most common reason for a patient to be hospitalized with acute VOC. Opioid analgesics are fraught with challenges including the development of tolerance, dependence, and opioid-induced hyperalgesia (whereby the use of opioids actually makes patients more sensitive to pain). Finding non-opioid alternatives for intravenous analgesia is problematic based on limited availability and poor side-effect profile. One alternative suggested for use in patients with VOC is ketamine, a potent N-methyl-D-aspartate (NMDA) antagonist.

The current evidence suggests that the counterintuitive effects of opioids are related to activation of NMDA receptors. These effects may be more pronounced in patients with sickle cell disease, as approximately half of these patients have chronic pain and are on long term opioids. The NMDA receptor is activated in response to injury of inflammation, precipitating heightening pain perception, and is therefore an important analgesic target for patients receiving opioids. Ketamine is a potent NMDA receptor antagonist that even at low doses has demonstrated efficacy as an adjunct to opioids for acute pain control. Multiple emergency department studies have shown that low doses of ketamine, <1mg/kg, provides analgesic effects, decreases pain scores, and decreases total opioid use.2-4 While these studies do not focus specifically on adult patients with SCD, ketamine has shown promise in similar pediatric populations. Unfortunately, there are no high-quality studies examining ketamine usage in adult patients with SCD, making highly addictive opioid medications the standard for pain relief during a crisis. The goal of this study is to determine the effectiveness of one non-opioid analgesic, ketamine, in the treatment of acute pain in a vulnerable patient population.

PRIMARY AIM: The investigators will determine the comparative efficacy of low doses of ketamine as an adjunct to opioids versus standard care (opioids alone) for the treatment of acute severe pain in patients with sickle cell related pain crisis. The investigators propose a double-blinded, randomized, placebo-controlled pilot study. The primary outcome will be assessed by patient-reported pain intensity and use of rescue opioid analgesia. Adverse events, length of the encounter, and hospitalization will be evaluated as secondary outcomes. Our central hypothesis is that the ketamine will decrease overall pain intensity, visit length of stay, and hospitalizations. The investigators will enroll patients at both a community hospital emergency department and a tertiary care, academic center. Both locations evaluate and treat patients with acute VOC and will provide an adequate volume for this pilot trial. At the end of this study the investigators expect to determine the effectiveness of ketamine in the treatment of acute pain in patients with SCD presenting after a VOC. Our team is composed of physician-scientists, competent and confident in conducting both clinical and methodological aspects of the trial.