Comparison of Treatment by IN Ketamine to IV Morphine in Acute Pain

Patients who present with acute traumatic injuries in the pre-hospital setting or to the emergency department (ED) are treated with opioids, the current gold standard for severe acute pain therapy. Treatment with opioids has many disadvantages: the need of skilled manpower to administer the medication IV, numerous side effects- mainly cardiorespiratory depression- which necessitates post medication administration continuous monitoring of patients. IV administration may be difficult or impossible to provide in a number of extreme circumstances. For these reasons, there is a constant search for alternate treatment options for pain in acute traumatic injuries. IN ketamine has only recently been studied favorably in our department in adults, in an open, prospective study (Shimonovich at al 2016), and warrants further investigation in the setting of acute traumatic pain. Ketamine is a safe and efficacious analgesic and is overall well received both by patients and physicians. Side effects include: hallucinations and dissociation. As opposed to opioids, ketamine does not alter patients' respiratory and hemodynamic stability giving ketamine great therapeutic potential for pain reduction in trauma patients, pre-hospital patients, and battlefield injuries. The study we are conducting is designed to test and analyze the safety and efficacy of IN Ketamine compared to IV morphine in a setting of acute traumatic pain in the ED, when both medications are administered by the protocol as is customary for treatment of pain in the Emergency Medicine department, and will be a prospective, randomized, double blind, controlled study.

Study Overview

• Status: Unknown
• Conditions: Acute Traumatic Pain
• Intervention / Treatment: Drug: Morphine; Drug: Ketamine

Detailed Description

The procedure:

1. Eligible patients will be identified by the ED personnel. They will make sure to inquire about and also visually inspect the patient's nares regarding nasal congestion, deviated septum, obstruction or injury.
2. Research physician will address the patient, explain about the trial and ask the patient to sign a consent form.
3. The patient will be randomized and assigned to a trial group: "A" or "B" and it will be noted in the Data sheet.
4. According to physician order (IV amount and IN amount) and patient group assignment, the nurse will prepare two blinded syringes that will be marked "A" or "B" (the assigned group) and "IN" or "IV" and note in the data sheet the time of syringe preparation.
5. The IV syringe will contain either Morphine or Normal Saline (up to 10 ml), and the IN syringe will contain either Ketamine or Normal saline (up to 2 ml).

6. The amount in the syringes will be calculated based on the patients' weight:

   IV-0.1 mg/kg: Morphine vial contains 10 mg/10 ml = 1mg/ml ----> 0.1 ml/kg IN-1 mg/kg: Ketamine vial contains 100 mg/2 ml = 50mg/ml ---> 0.02ml/kg

7. Administration of the medication is limited to one hour from preparation in the syringe.
8. The nurse will hand the syringes to the researcher (blinded and coded) and note in the data sheet the time of administration and the amount to administer IN and IV.
9. Prior to administering medication to the patient the researcher will measure vital signs (blood pressure, heart rate, respiratory rate, and O2 saturation) as well as pain level on a 100 mm VAS (visual analogue scale) questionnaire.

10. After administration of medications the researcher will measure vital signs (blood pressure, heart rate, respiratory rate, and O2 saturation) as well as pain level on a 100 mm VAS questionnaire every 5 minutes for the first 30 minutes and then every 15 minutes after that at 30, 45, 60, and 90 minutes.

    Saturation >95% on room air; if lower than 90%, the patient will be placed on 40% oxygen mask.

11. Measurement of vital signs will not interfere with any other treatment that the patients receives for their injury in the ED.
12. If the patient will be moved to another department from the ED, they will be withdrawn from the study.
13. Cardiorespiratory follow-up (as per bullet point number 8 above), will be concluded at 1.5 hours post-intervention, and clinical follow-up will continue as long as the patient remains in the ED.
14. 90 minutes after drug administration, if pain had not subsided sufficiently according to treating physician's clinical assessment, patient will receive further analgesic medications by physician order, as per ED protocol. The protocol takes into account concurrent medications (in this case either morphine or ketamine. Neither morphine nor ketamine will be used in these patients after test drug administration.

• Study Type: Interventional
• Enrollment (Anticipated): 120
• Phase: Phase 3

Contacts and Locations

Study Locations

• Israel
  • Tel Aviv, Israel, 6423906
    • Tel Aviv Sourasky Medical Center, department of Emergency Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• be 18-70 years old
• self-report pain greater than or equal to 7/10 on a numerical-verbal scale
• weigh 50-100 kg
• have an ASA (American Society of Anaesthesiologists' classification) score of 1-2
• have systolic blood pressure of 90-160 mmHg

Exclusion Criteria:

• have had opioid analgesia administered within 2 hours of the study
• are chronic analgesia users (of opioid or others)
• have known allergies to morphine or ketamine
• have had a large meal within an hour prior to trauma
• are pregnant
• have a psychiatric history
• have nasal congestion, nasal trauma, epistaxis, or a deviated nasal septum
• have suffered any head or face trauma: any trauma that is manifested by an external mark in the face or skull.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Morphine group; Morphine group will receive IV medication and IN saline.	Drug: Morphine; IV morphine -0.1 mg/kg: Morphine vial contains 10 mg/10 ml = 1mg/ml ----> 0.1 ml/kg; Other Names: no other Intervention name
Experimental: Ketamine group; Ketamine group will receive IV saline and IN medication.	Drug: Ketamine; IN ketamine: 1 mg/kg: Ketamine vial contains 100 mg/2 ml = 50mg/ml ---> 0.02ml/kg; Other Names: no other Intervention name

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Effectiveness of intranasal ketamine in decreasing pain intensity [patient assessed - VAS pain score] [ Time Frame: 2 hour post administration	Time to achieve a clinically meaningful pain reduction was defined as the first time-point at which the patient reported 15mm of pain reduction or more. Maximal pain reduction was defined as the lowest VAS score reported by the patient over the course of follow-up. Time to maximal pain reduction was defined as the time at which the patient has the lowest VAS score over the course of the 2 hours follow-up.	2 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
• adverse effects [Opiate Related Symptom Distress Scale] [ Time Frame: 2 hour post administration ]	Adverse effects were recorded at the end of two hours using the 'Opiate Related Symptom Distress Scale' and included measurements of the presence, frequency, intensity and disruptiveness of 12 common opiate side-effects. Among these were nausea, vomiting, urinary retention, constipation, difficulty concentrating, dizziness, confusion, and others.	2 hours
• patient satisfaction [Interview] [ Time Frame: 2 hours post administration ]	patients were asked to provide subjective comments	2 hours post administration

Collaborators and Investigators

• Sponsor: Tel-Aviv Sourasky Medical Center
• Collaborators: Medical Corps, Israel Defense Force

Study record dates

Study Major Dates

• Study Start (Anticipated): December 1, 2019
• Primary Completion (Anticipated): December 1, 2021
• Study Completion (Anticipated): December 1, 2021

Study Registration Dates

• First Submitted: March 5, 2018
• First Submitted That Met QC Criteria: April 18, 2018
• First Posted (Actual): April 30, 2018

Study Record Updates

• Last Update Posted (Actual): June 25, 2019
• Last Update Submitted That Met QC Criteria: June 23, 2019
• Last Verified: June 1, 2019

More Information

Terms related to this study

• Keywords: Intra nasal ketamine; IV morphine; acute traumatic pain
• Additional Relevant MeSH Terms: Pain; Neurologic Manifestations; Acute Pain; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anesthetics, Dissociative; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Analgesics, Opioid; Narcotics; Ketamine; Morphine
• Other Study ID Numbers: TASMC-18-PH-0459-17-CTIL

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: a table summering pain assessing questioners will be available from corresponding author on reasonable request.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No