Low Dose Ketamine Versus Morphine for Moderate to Severe Pain in the Emergency Department
Condition: Pain
MeSH terms: Emergencies
Study type: Interventional
Phase: Phase 4

Summary: 
      The primary objectives of the study are to evaluate the efficacy of subdissociative dose
      intravenous ketamine compared with intravenous morphine in relieving acute pain in the ED.
      Secondary objectives will include the rate of adverse effects and need for rescue analgesia.
      The hypothesis is that intravenous administration of subdissociative dose ketamine at 0.3
      mg/kg is superior to intravenous morphine at 0.1mg/kg in treating moderate and severe acute
      pain in patients presenting to the ED.
    

Detailed description: 
      Rationale: Opioids are traditionally accepted as a cornerstone of acute pain management in
      the Emergency Department (ED). Morphine is one of the most commonly used parenteral opioid
      analgesics whose initial dose of 0.1 mg/kg has been extensively researched and recommended
      for control of severe acute pain in the ED. However, intravenous administration of opioids is
      associated with thefollowing side effects: hypotension, respiratory depression, dizziness,
      pruritis and nausea. In addition, in patients with pre-existing renal and/or hepatic
      insufficiency, these effects may be pronounced and require interventions. Thus, the
      administration of an equipotent analgesic that does not cause hypotension and respiratory
      depression would enhance patient safety in the ED.

      Ketamine is a noncompetitive N-methyl D-aspartate (NMDA) receptor antagonist that blocks the
      release of excitatory neurotransmitter glutamate and provides anesthesia, amnesia and
      analgesia by virtue of decreasing central sensitization and "wind-up" phenomenon. Due to its
      high lipid solubility, ketamine rapidly crosses the blood-brain barrier, provides rapid onset
      of action (peak concentration at is reached 1 minute after IVP) and rapid recovery to
      baseline (duration of action 5-15 minutes after IVP) (1). When given at subdissociative doses
      of 0.1-0.5 mg/kg, either as an adjunct to opioid analgesic or as a solo agent, ketamine
      provides good analgesia while preserving airway patency, ventilation, and cardiovascular
      stability (2). In addition, a small dose of ketamine may increase the analgesic potency of
      opioids thus decreasing their dosing requirements (3). Based on the aforementioned facts,
      ketamine offers an attractive option for providing safe and convenient pain control for
      patients in the ED.

      A double-blind trial of 40 adult patients with acute musculoskeletal trauma compared low-dose
      ketamine administered by subcutaneous infusion (0.1 mg/kg/h) with intermittent intravenous
      morphine (0.1 mg/kg IV every 4 hours ) and demonstrated better pain relief, less sedation and
      less nausea and vomiting with ketamine infusion than with intermittent morphine. In addition,
      none of the patients in the ketamine group required supplementary analgesia (4). A
      prospective, randomized trial compared two analgesic regimens, morphine with ketamine (K
      group) or morphine with placebo (P group) for severe acute pain in 73 trauma patients with a
      visual analog scale (VAS) score of at least 60/100. Morphine was administered at 0.1mg/kg;
      patients in the K group received 0.2 mg/kg of intravenous ketamine over 10 minutes while
      patients in the P group received isotonic sodium chloride solution. The results showed
      comparable change in VAS score at 30 minutes (34 mm (K) vs. 39 mm (P)) but reduced morphine
      consumption in the ketamine group (0.14 mg/kg (K) vs 0.2 mg/kg (P)) (5).

      A chart review analysis of 35 ED patients receiving low dose ketamine at doses 0.1mg-0.6mg/kg
      in addition to intravenous morphine demonstrated a decrease in pain intensity for 54% of the
      patients by a documented 3 point pain decrease on a 10-point scale. The ketamine doses ranged
      from 5 mg to 35 mg with median dose of 10 mg and mean dose of 15.7mg. In addition, only one
      patient had a brief dysphoric reaction that did not require intervention (6).

      Hypothesis: Intravenous administration of subdissociative dose ketamine at 0.3 mg/kg is
      superior to intravenous morphine at 0.1 mg/kg in treating moderate and severe acute pain in
      patients presenting to the ED.

      Methods: Prospective, randomized, double-blind trial evaluating and comparing analgesic
      effect of intravenous Ketamine administered in sub-dissociative doses: 0.3 mg/kg given over
      10 minutes with intravenous Morphine given at 0.1mg/kg as a single IVP.

      Description: Once patient is triaged, an initial pain score will be assessed and patient's
      stated weight will be recorded in the chart. Patients will then have an initial evaluation by
      an attending ED physician and once found to be eligible for the study (deemed by treating
      physician to warrant administration of intravenous analgesia) patient will be randomized to
      receive either morphine at 0.1 mg /kg given as IVP or ketamine at 0.3 mg/given as IVP.
      Patients' vital signs will be recorded at triage, at the beginning of the study and at 15,
      30, 60, 90, 120 minutes post-administration. Patients will be placed on a monitor and
      continuous pulse oximetry (oxygen saturation), blood pressure, heart rate and respiratory
      rate will be recorded. We will compare efficacy as a difference between 2 groups in pain
      relief from the baseline (at triage) to 30 minutes post-analgesic administration. The primary
      outcome is the difference between 2 groups in pain relief at 30 minutes. The secondary
      outcome is side effects. We will compare the safety profile of each analgesic with respect to
      incidence of hypotension, respiratory depression, nausea and vomiting, pruritis, need for an
      opioid reversal agent (naloxone), tachycardia, laryngospasm, hypersalivation, dizziness,
      agitation and need for benzodiazepines (midazolam) administration for symptomatic evidence of
      emergence reaction. All the data will be entered and analyzed via SPSS. Data analyses will
      include frequency distributions, and ANOVA to assess a difference in pain scores between the
      groups at various time points. All patients will be analyzed with an intent to treat
      analysis. However, a subgroup analysis will be done for any emergence reaction or event which
      occurs often.
    

Intervention name(s): Morphine; Ketamine
Intervention type(s): Drug; Drug
Intervention description(s): Morphine: 0.1 mg /kg given as IVP; Ketamine:0.3 mg/given as IVP
Intervention MeSH terms: Ketamine; Morphine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: pain; Ketamine; Emergency Medicine; morphine