Low Dose Ketamine Versus Morphine for Moderate to Severe Pain in the Emergency Department

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.

Inclusion Criteria:

1. ED patients18-55 years old presenting with moderate to severe (Numeric Pain Rating
Score >5) acute (less than 7 days)

2. abdominal, flank, back or musculoskeletal pain warranting (in the treating
physician's judgment) administration of intravenous opioid pain medication.

3. Patients must be awake, alert and oriented to time, place and person,

4. patient must be able to demonstrate understanding of the informed consent.

5. Patient must be able to verbalize how much pain they are having on the 10 point
Numeric Rating Pain Scale,

6. Patient mus be able to verbalize the nature of the side effects he may be
experiencing from the intravenous analgesia.

Exclusion Criteria:

1. Pregnancy or breast feeding

2. SBP<90

3. Weight greater than 115kg or less than 45kg,

4. altered mental status,

5. allergy to ketamine or morphine,

6. history of acute head or ocular trauma

7. presence of intracranial mass or vascular lesion, presence of psychiatric history

8. diagnosis or treatment (as assessed by electronic chart review).

9. history of seizure or intracranial hypertension

10. history of chronic pain, pain syndrome or fibromyalgia

11. presence of cardiovascular disease except controlled hypertension

12. history of acute head or ocular trauma, drug or alcohol abuse in the preceding 6
months

13. drugs or alcohol abuse in the preceding 6 months

14. SBP>180

15. HR<50

16. HR>150

17. RR<10

18. RR>30

19. administration of opiate pain medication in the past 4 hours prior to assessment
(i.e. home, EMS, triage, office, etc.)

20. presence of renal or hepatic insufficiency (as assessed by electronic chart review),