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

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ClinicalTrials.gov Identifier: NCT03511833
Recruitment Status : Not yet recruiting
First Posted : April 30, 2018
Last Update Posted : June 25, 2019
Sponsor:
Collaborator:
Medical Corps, Israel Defense Force
Information provided by (Responsible Party):
michal roll, Tel-Aviv Sourasky Medical Center

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Acute Traumatic Pain Drug: Morphine Drug: Ketamine Phase 3

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 120 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Eligible patients will be randomized according to a blocked randomization scheme using www.sealedenvelope.com (site accessed Sep 10, 2017), which permits assignment of the participant to either group "A" or "group B" (the IN ketamine or IV morphine group). Only the pharmacy will have knowledge of which group is Ketamine and which group is Morphine. Eligible patients will be divided in equal proportions (58 in group A and 58 in group B). Both medications will be prepared by the pharmacy as coded kits, and will be stored in the ER safe with clear signage: "For ketamine/morphine clinical trial only". Shelf life of the kits is 6 months. Each vial in a kit will be marked by the group name either "A" or "B" and by either "IN" or "IV". The "IV" vials will either contain: morphine (10 mg of morphine in 10 ml saline) or 10 ml saline for IV administration, and the "IN" vials will either contain ketamine (100 mg in 2ml saline) or 2 ml saline for nasal administration.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Other
Official Title: Comparison of Treatment by IN Ketamine to IV Morphine in Acute Pain
Estimated Study Start Date : December 2019
Estimated Primary Completion Date : December 2021
Estimated Study Completion Date : December 2021

Resource links provided by the National Library of Medicine


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 Name: 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 Name: no other Intervention name




Primary Outcome Measures :
  1. Effectiveness of intranasal ketamine in decreasing pain intensity [patient assessed - VAS pain score] [ Time Frame: 2 hour post administration [ Time Frame: 2 hours ]
    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.


Secondary Outcome Measures :
  1. • adverse effects [Opiate Related Symptom Distress Scale] [ Time Frame: 2 hour post administration ] [ Time Frame: 2 hours ]
    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. • patient satisfaction [Interview] [ Time Frame: 2 hours post administration ] [ Time Frame: 2 hours post administration ]
    patients were asked to provide subjective comments



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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03511833


Contacts
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Contact: Pinchas Halpern, MD +97236973829 DR_HALPERIN@tlvmc.gov.il
Contact: Daniel Trotzky, MD +972507308675 danieltro@tlvmc.gov.il

Locations
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Israel
Tel Aviv Sourasky Medical Center, department of Emergency Medicine Not yet recruiting
Tel Aviv, Israel, 6423906
Contact: Pinchas Halpern, MD    972-3-6973829    dr_halperin@tasmc.health.gov.il   
Contact: Daniel Trotzky, MD    +972507308675    danieltro@tlvmc.gov.il   
Principal Investigator: Pinchas Halpern, MD         
Sponsors and Collaborators
Tel-Aviv Sourasky Medical Center
Medical Corps, Israel Defense Force

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Responsible Party: michal roll, Director, R&D Department, Tel-Aviv Sourasky Medical Center
ClinicalTrials.gov Identifier: NCT03511833     History of Changes
Other Study ID Numbers: TASMC-18-PH-0459-17-CTIL
First Posted: April 30, 2018    Key Record Dates
Last Update Posted: June 25, 2019
Last Verified: June 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: a table summering pain assessing questioners will be available from corresponding author on reasonable request.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)

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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

Keywords provided by michal roll, Tel-Aviv Sourasky Medical Center:
Intra nasal ketamine
IV morphine
acute traumatic pain

Additional relevant MeSH terms:
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Acute Pain
Pain
Neurologic Manifestations
Signs and Symptoms
Morphine
Ketamine
Analgesics, Opioid
Narcotics
Central Nervous System Depressants
Physiological Effects of Drugs
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Anesthetics, Dissociative
Anesthetics, Intravenous
Anesthetics, General
Anesthetics
Excitatory Amino Acid Antagonists
Excitatory Amino Acid Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action