Low Dose Ketamine and Acute Pain Crisis
Low Dose Ketamine and Acute Pain Crisis
BACKGROUND:

 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). During these pain crises, patients sometimes require high doses of opioids
 for analgesia. 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 the limited availability this class of drugs. Ketamine is a
 potent N-methyl-D-aspartate (NMDA) receptor antagonist that even at low doses has
 demonstrated efficacy as an adjunct to opioids for acute pain control.

 OBJECTIVE:

 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.

 METHODS:

 The investigators propose a double-blinded, randomized, placebo-controlled pilot study to
 determine the efficacy of ketamine 0.3mg/kg vs. placebo for the treatment of acute pain
 crisis. The investigators will include all eligible emergency department ≥18 years. The
 investigators will stratify 42 patients by location, 21 patients per site. Numeric Rating
 Scale (NRS) will be recorded as a part of the study log at 0, 1, 2 and 3hrs after the study
 drug administration.

 HYPOTHESIS:

 The investigators hypothesize that the ketamine will decrease overall pain intensity, visit
 length of stay, and hospitalizations.
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.
Inclusion Criteria:

 -  All English-speaking adult patients >=18yrs old patients presenting with acute pain
 crisis

 Exclusion Criteria:

 -  Inability to provide consent,

 -  Allergy to ketamine

 -  Pregnant or breastfeeding. W

 -  Signs and symptoms of intracranial hypertension

 -  Neurologic deficits

 -  Headache only

 -  Temperature >102F

 -  Sustained blood pressure >=180/110

 -  Sustained heart rate >130

 -  Current priapism

 -  Patients requiring a blood transfusion at the time of acute presentation