Subdissociative Dose Ketamine for Treatment of Acute Pain in Subjects With Chronic Pain

• Sponsor: Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT02920528
• Collaborator: Air Force Research Laboratory (Other)
• Enrollment: 106
• Location: 1
• Arms: 3
• Actual Duration (Months): 28
• Patients Per Site Per Month: 3.8

Study Details

Study Description

Brief Summary

This is a prospective, randomized controlled trial which will be conducted to determine whether sub-dissociative dose ketamine (SDDK) can improve pain control in subjects with chronic pain syndrome presenting to the emergency department with exacerbation of their chronic pain. The investigators also aim to determine whether use of SDDK can reduce the amount of subsequent opioid pain medications required for adequate pain relief in this population.

Condition or Disease	Intervention/Treatment	Phase
Chronic Pain	Drug: Ketamine; Drug: Placebo	Phase 3

Detailed Description

1. The informed consent process will be initiated by investigators in the emergency department.

2. All potential subjects will be informed that participation in the study could lead to a positive urine drug test that could remain positive for up to a month after the conclusion of the study.

3. Female subjects of child bearing age, will have a pregnancy test performed prior to enrollment; any subjects who are pregnant will be excluded from this project.

4. Each subject will be asked to grade his/her pain severity on a 100mm non-hatched visual analog scale (VAS) ranging from 0 (no pain) to 100 (worst, maximum pain).

5. Each subject will be asked to fill out a baseline pain questionnaire

6. Each subject will be placed on monitors for continuous pulse oximetry, Heart Rate, Respiratory Rate, and blood pressure every 5 minutes for the duration of the study of one hour and longer for any patient who needs continued care. The patients temperature will be taken prior to the start of the protocol.

7. Each subject will have an intravenous catheter placed.

8. Each subject will be sequentially assigned to one of three treatment groups, based on a computer-generated randomization schedule, to receive an intravenous infusion of sub-dissociative Ketamine (0.25mg/kg), sub-dissociative dose Ketamine (0.5mg/kg), or an equal amount of normal saline.

9. All medications will be prepared by an emergency department pharmacist and all study medication intravenous bags will be identical in appearance and will be administered by the emergency department nurse caring for the patient who will be blinded to the study drug.

10. Each subject will receive lightly tinted sunglasses to wear during the duration of the study to minimize bias as ketamine can evoke a tell-tale short- lived nystagmus

11. Each subject will receive the study medication over a 20 minute period via an automated pump. At this point, the subjects will be asked to rate their pain on a VAS and asked if they need additional pain medication that will consist of intravenous hydromorphone with the dose and frequency determined by the discretion of the treating physician and documented on the data collection sheet.

Study Design

• Study Type: Interventional
• Actual Enrollment: 106 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: Subdissociative Dose Ketamine for Treatment of Acute Pain in Subjects With Chronic Pain: A Randomized Controlled Trial
• Actual Study Start Date: May 1, 2017
• Actual Primary Completion Date: Jun 22, 2018
• Actual Study Completion Date: Sep 1, 2019

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo placebo controlled arm	Drug: Placebo; Normal Saline; Other Names: Normal Saline
Experimental: very low dose ketamine 0.25 mg/kg of sub-dissociative ketamine as an experimental arm	Drug: Ketamine; sub-dissociative ketamine; Other Names: ketalar
Experimental: low dose ketamine 0.50 mg/kg of sub-dissociative ketamine as an experimental arm	Drug: Ketamine; sub-dissociative ketamine; Other Names: ketalar

Outcome Measures

Primary Outcome Measures

1. To Compare the Percentage of Subjects Who Achieved Significant Pain Relief Between the 3 Treatment Groups as Measured by a Visual Analog Pain Scale at 60 Minutes A Decrease of at Least 20 mm on the VAS Will be Considered "Significant" Pain Relief [60 minutes]

   The primary endpoint was clinically significant pain relief defined a priori as a decrease in the pain VAS of at least 20 mm from baseline, which was arbitrarily chosen as the minimal amount that may be important to this group of patients and was extrapolated from studies of acute pain management in the ED. Using an effect size of 20-mm change in VAS as the marker for a successful outcome and the proportion of successes by group as the analysis point, we performed a power analysis using three groups: 0.5 mg/kg ketamine, 0.25 mg/kg ketamine, and placebo and found that a sample size of 96 subjects would be required to detect a statistically significant difference among groups with a power of 90% (a = 0.05). Expecting a loss of 10% of subjects due to patient withdrawal or incomplete data, 106 subjects were recruited. Only subjects who completed the 60-minute study and had data recorded for each of the time points were included in the analysis.

Secondary Outcome Measures

1. Assess the Risk for Adverse Events Associated With Sub-dissociative Dose Ketamine [1 hour]

   Subjects will be continuously assessed for complications secondary to the sub-dissociative ketamine

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• All adult subjects over the age of 18 with chronic pain* presenting to the emergency department with exacerbation of their chronic pain as their primary complaint

• Subjects who are willing and able to provide informed consent. *Chronic pain defined as greater > 3 months of symptoms and an initial VAS pain score > 70

Exclusion Criteria:

• History of overt psychosis, severe hypertension as defined by Systolic Blood Pressure

180 mm Hg or Diastolic Blood Pressure >110 mm Hg, unstable angina, Coronary Artery Disease, Congestive Heart Failure, porphyrias, thyroid disease, seizure disorder, inability to provide informed consent: dementia, non-English/Spanish speakers, subjects in custody, suicidal, or clinically intoxicated.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Emergency Department, Harbor-UCLA Medical Center	Torrance	California	United States	90501

Sponsors and Collaborators

• Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
• Air Force Research Laboratory

Investigators

• Principal Investigator: David Tanen, MD, Los Angeles Biomedical Institute

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - May 16, 2018

More Information

Publications

None provided.

• Responsible Party: David Tanen, Professor of Emergency Medicine, Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
• ClinicalTrials.gov Identifier: NCT02920528
• Other Study ID Numbers: 30612-01
• First Posted: Sep 30, 2016
• Last Update Posted: Apr 15, 2021
• Last Verified: Mar 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Additional relevant MeSH terms: Chronic Pain; Acute Pain; Ketamine

Study Results

Participant Flow

Arm/Group Title	Placebo	Very Low Dose Ketamine	Low Dose Ketamine
Arm/Group Description	placebo controlled arm Placebo: Normal Saline	0.25 mg/kg of sub-dissociative ketamine as an experimental arm Ketamine: sub-dissociative ketamine	0.50 mg/kg of sub-dissociative ketamine as an experimental arm Ketamine: sub-dissociative ketamine
Period Title: Overall Study
STARTED	35	36	35
COMPLETED	32	35	30
NOT COMPLETED	3	1	5

Baseline Characteristics

Arm/Group Title	Placebo	Very Low Dose Ketamine	Low Dose Ketamine	Total
Arm/Group Description	placebo controlled arm Placebo: Normal Saline	0.25 mg/kg of sub-dissociative ketamine as an experimental arm Ketamine: sub-dissociative ketamine	0.50 mg/kg of sub-dissociative ketamine as an experimental arm Ketamine: sub-dissociative ketamine	Total of all reporting groups
Overall Participants	32	35	30	97
Age, Customized (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	47.6 (15)	44.3 (11.2)	47.8 (11.5)	46.5 (12.6)
Sex: Female, Male (Count of Participants)
Female	18 56.3%	21 60%	18 60%	57 58.8%
Male	14 43.8%	14 40%	12 40%	40 41.2%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%
Region of Enrollment (participants) [Number]
United States	32 100%	35 100%	30 100%	97 100%
Baseline Pain as measured by validated Visualized Analog Scale (0 to 100 mm) (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	91.2 (9.4)	93.2 (8.9)	91.4 (8.5)	91.9 (8.9)

Outcome Measures

1. Primary Outcome

Title	To Compare the Percentage of Subjects Who Achieved Significant Pain Relief Between the 3 Treatment Groups as Measured by a Visual Analog Pain Scale at 60 Minutes A Decrease of at Least 20 mm on the VAS Will be Considered "Significant" Pain Relief
Description	The primary endpoint was clinically significant pain relief defined a priori as a decrease in the pain VAS of at least 20 mm from baseline, which was arbitrarily chosen as the minimal amount that may be important to this group of patients and was extrapolated from studies of acute pain management in the ED. Using an effect size of 20-mm change in VAS as the marker for a successful outcome and the proportion of successes by group as the analysis point, we performed a power analysis using three groups: 0.5 mg/kg ketamine, 0.25 mg/kg ketamine, and placebo and found that a sample size of 96 subjects would be required to detect a statistically significant difference among groups with a power of 90% (a = 0.05). Expecting a loss of 10% of subjects due to patient withdrawal or incomplete data, 106 subjects were recruited. Only subjects who completed the 60-minute study and had data recorded for each of the time points were included in the analysis.
Time Frame	60 minutes

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Very Low Dose Ketamine	Low Dose Ketamine
Arm/Group Description	placebo controlled arm Placebo: Normal Saline	0.25 mg/kg of sub-dissociative ketamine as an experimental arm Ketamine: sub-dissociative ketamine	0.50 mg/kg of sub-dissociative ketamine as an experimental arm Ketamine: sub-dissociative ketamine
Measure Participants	32	35	30
Count of Participants [Participants]	13 40.6%	28 80%	25 83.3%

2. Secondary Outcome

Title	Assess the Risk for Adverse Events Associated With Sub-dissociative Dose Ketamine
Description	Subjects will be continuously assessed for complications secondary to the sub-dissociative ketamine
Time Frame	1 hour

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Very Low Dose Ketamine	Low Dose Ketamine
Arm/Group Description	placebo controlled arm Placebo: Normal Saline	0.25 mg/kg of sub-dissociative ketamine as an experimental arm Ketamine: sub-dissociative ketamine	0.50 mg/kg of sub-dissociative ketamine as an experimental arm Ketamine: sub-dissociative ketamine
Measure Participants	32	35	30
Number [recorded adverse events]	1	14	12

3. Post-Hoc Outcome

Title	Follow-up Pain Scores Obtained by Telephone at 24 - 48 Hours
Description	Subjects were contacted by phone 24 - 48 hours after the completion of the study infusion. Subjects were asked to score their pain on 10-point numeric rating scale where 0 represented no pain and 10 represented the worst pain they could be having. Pain score was recorded in increments of 1 from 0 - 10. Results were compared between groups using the Mann-Whitney U-test.
Time Frame	24 - 48 hours after study drug infusion

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Very Low Dose Ketamine	Low Dose Ketamine
Arm/Group Description	placebo controlled arm Placebo: Normal Saline	0.25 mg/kg of sub-dissociative ketamine as an experimental arm Ketamine: sub-dissociative ketamine	0.50 mg/kg of sub-dissociative ketamine as an experimental arm Ketamine: sub-dissociative ketamine
Measure Participants	30	31	28
Median (Inter-Quartile Range) [units on a scale]	5	5	6

Adverse Events

Time Frame	Up to 48 hours after study enrollment
Arm/Group Title	Placebo		Very Low Dose Ketamine		Low Dose Ketamine
Arm/Group Description	placebo controlled arm Placebo: Normal Saline		0.25 mg/kg of sub-dissociative ketamine as an experimental arm Ketamine: sub-dissociative ketamine		0.50 mg/kg of sub-dissociative ketamine as an experimental arm Ketamine: sub-dissociative ketamine
All Cause Mortality
	Placebo		Very Low Dose Ketamine		Low Dose Ketamine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/32 (0%)		0/35 (0%)		0/30 (0%)
Serious Adverse Events
	Placebo		Very Low Dose Ketamine		Low Dose Ketamine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/32 (3.1%)		14/35 (40%)		12/30 (40%)
Gastrointestinal disorders
Nausea	0/32 (0%)	0	3/35 (8.6%)	3	3/30 (10%)	3
Nervous system disorders
Dizziness	1/32 (3.1%)	1	8/35 (22.9%)	8	3/30 (10%)	3
Hallucinations	0/32 (0%)	0	0/35 (0%)	0	2/30 (6.7%)	2
Anxiety	0/32 (0%)	0	0/35 (0%)	0	1/30 (3.3%)	1
Anxiety and Dizziness	0/32 (0%)	0	1/35 (2.9%)	1	2/30 (6.7%)	2
Anxiety and Palpitations	0/32 (0%)	0	1/35 (2.9%)	1	0/30 (0%)	0
Dysphoria	0/32 (0%)	0	1/35 (2.9%)	1	1/30 (3.3%)	1
Other (Not Including Serious) Adverse Events
	Placebo		Very Low Dose Ketamine		Low Dose Ketamine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/32 (0%)		0/35 (0%)		0/30 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.