Chronic Pain
Conditions
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.
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.
Interventions
DRUGKetamine
sub-dissociative ketamine
DRUGPlacebo
Normal Saline
Sponsors
United States Air Force Research Laboratory
Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo placebo controlled arm
Placebo: Normal Saline | 32 |
| Very Low Dose Ketamine 0.25 mg/kg of sub-dissociative ketamine as an experimental arm
Ketamine: sub-dissociative ketamine | 35 |
| Low Dose Ketamine 0.50 mg/kg of sub-dissociative ketamine as an experimental arm
Ketamine: sub-dissociative ketamine | 30 |
| Total | 97 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 3 |
| Overall Study | Did not meet inclusion criteria | 2 | 0 | 1 |
| Overall Study | Incomplete Data | 1 | 1 | 1 |
Baseline characteristics
| Characteristic | Placebo | Very Low Dose Ketamine | Low Dose Ketamine | Total |
|---|---|---|---|---|
| Age, Customized | 47.6 years STANDARD_DEVIATION 15 | 44.3 years STANDARD_DEVIATION 11.2 | 47.8 years STANDARD_DEVIATION 11.5 | 46.5 years STANDARD_DEVIATION 12.6 |
| Baseline Pain as measured by validated Visualized Analog Scale (0 to 100 mm) | 91.2 units on a scale STANDARD_DEVIATION 9.4 | 93.2 units on a scale STANDARD_DEVIATION 8.9 | 91.4 units on a scale STANDARD_DEVIATION 8.5 | 91.9 units on a scale STANDARD_DEVIATION 8.9 |
| Race and Ethnicity Not Collected | — | — | — | 0 Participants |
| Region of Enrollment United States | 32 participants | 35 participants | 30 participants | 97 participants |
| Sex: Female, Male Female | 18 Participants | 21 Participants | 18 Participants | 57 Participants |
| Sex: Female, Male Male | 14 Participants | 14 Participants | 12 Participants | 40 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 32 | 0 / 35 | 0 / 30 |
| other Total, other adverse events | 0 / 32 | 0 / 35 | 0 / 30 |
| serious Total, serious adverse events | 1 / 32 | 14 / 35 | 12 / 30 |
Outcome results
Primary
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
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | 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 | 13 Participants |
| Very Low Dose Ketamine | 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 | 28 Participants |
| Low Dose Ketamine | 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 | 25 Participants |
Secondary
Assess the Risk for Adverse Events Associated With Sub-dissociative Dose Ketamine
Subjects will be continuously assessed for complications secondary to the sub-dissociative ketamine
Time frame: 1 hour
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Assess the Risk for Adverse Events Associated With Sub-dissociative Dose Ketamine | 1 recorded adverse events |
| Very Low Dose Ketamine | Assess the Risk for Adverse Events Associated With Sub-dissociative Dose Ketamine | 14 recorded adverse events |
| Low Dose Ketamine | Assess the Risk for Adverse Events Associated With Sub-dissociative Dose Ketamine | 12 recorded adverse events |
Post Hoc
Follow-up Pain Scores Obtained by Telephone at 24 - 48 Hours
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
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Follow-up Pain Scores Obtained by Telephone at 24 - 48 Hours | 5 units on a scale |
| Very Low Dose Ketamine | Follow-up Pain Scores Obtained by Telephone at 24 - 48 Hours | 5 units on a scale |
| Low Dose Ketamine | Follow-up Pain Scores Obtained by Telephone at 24 - 48 Hours | 6 units on a scale |