Reducing Psychological Side Effects of Ketamine
Conditions
Brief summary
Patient will receive lamotrigine vs. placebo with small sips of water. Lamotrigine reaches peak level 1-4 hours after oral administration.
Detailed description
1:1 randomization without stratification use web-based software (Redcap) before surgery. Allocation will be concealed from the patient, the nurse, the operating room team. Both patient and the operating room team will be blinded to the treatment allocation (double blind). Standard preoperative care as per anesthesia care team. Patient will receive lamotrigine vs. placebo with small sips of water. Lamotrigine reaches peak level 1-4 hours after oral administration. Single dose lamotrigine is safe and is not associated with rash. Standard intraoperative care as per the anesthesia care team. All patients will receive Ketamine 1 mg/kg at induction. Ketamine 5mcg/kg/min will be started at induction and stopped at the end of surgery. Standard postoperative care as per PACU team. The psychologic side-effects will be measured using Brief Psychiatric Rating Scale (BPRS) using an online tool. Research fellow will receive standardized training in administering BPRS from Dr. Amit Anand using structured material. Dr. Anand has used this training for other current research projects.
Interventions
DRUGLamotrigine 300 MG
300 mg of oral Lamotrigine. One of the key studies in this area was reported at the Society of Neuroscience meeting in 1997 and later published in the Archives of General Psychiatry. This study reported that, in healthy subjects 300 mg oral lamotrigine significantly decreased ketamine-induced perceptual abnormalities as assessed by the Clinician-Administered Dissociative States Scale (P\<.001).31 Furthermore lamotrigine increased the immediate mood-elevating effects of ketamine (P\<.05).
DRUGPlacebo
300 mg of oral Placebo
DRUGKetamine
1mg/kg bolus at induction followed by 5 microgram/kg/min infusion till the end of the surgery
Sponsors
The Cleveland Clinic
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
The Pharmacy will know the treatment
Intervention model description
randomization without stratification
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* 18 -65 Years of age * Planned overnight hospital stay
Exclusion criteria
* Pregnant and planning to become pregnant * No known History of seizure * No known History of Schizophrenia * No known History of unstable angina * Patients taking Antiepileptic medications * Known history of Lamotrigine intake in past. * Any history of allergic reaction to lamotrigine in the past.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Psychologic Side-effects | in PACU (up to 90 minutes after ketamine infusion) | The primary outcome of psychologic side-effects was measured in PACU (up to 90 minutes after ketamine infusion). This included four key items of the Brief Psychiatric Rating Scale (BPRS) corresponding to positive symptoms of schizophrenia: conceptual disorganization, hallucinatory behavior, suspiciousness, and unusual thought content. Each symptom is rated 1-7 ( 1 = not present, 2 = very mild, 3 = mild, 4 = moderate, 5 = moderately severe, 6 = severe, 7 = extremely severe ), and, therefore, the total score as the primary outcome based on four key items of BPRS will be between 4 (best score) and 28 (worst score). |
| Number of Patients With Psychologic Disturbances- | Up to 90 minutes of PACU arrival | The psychologic side-effects were measured in PACU (up to 90 minutes after ketamine infusion). This included four key items of the Brief Psychiatric Rating Scale (BPRS) corresponding to positive symptoms of schizophrenia: conceptual disorganization, hallucinatory behavior, suspiciousness, and unusual thought content. Each symptom is rated 1-7 ( 1 = not present, 2 = very mild, 3 = mild, 4 = moderate, 5 = moderately severe, 6 = severe, 7 = extremely severe ), and, therefore, the total score as the primary outcome based on four key items of BPRS will be between 4 (best score) and 28 (worst score). Patients who had a total score of 4 (all symptoms not present) were determined as not having psychologic disturbance and patients who had a total score of \> 4 (having any symptoms present) were determined as having psychologic disturbance. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Total Opioid Consumption in PACU (mg) | from entry to PACU to leaving PACU, up to 4 hours | Total cumulative opioid use (total IV morphine equivalents) in postoperative anesthesia care unit (PACU) |
| Pain Score in PACU | from entry to PACU to leaving PACU | Pain score was scaled from 0-10 where 0 means no pain and 10 means most pain. The time-weighted average of pain scores was used if the pain score was measured multiple times. |
| Number of Patients Who Had PONV (Postoperative Nausea Vomiting) | after surgery up to discharge | PONV was measured through Postoperative Nursing Progress Record, where nausea vomiting severity was recorded as 0 (none), 1 (mild), 2 (moderate), 3 (severe). Patients whose score was 0 were determined as not having PONV and patients whose score was positive were determined as having PONV. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Opioid Related Side-effects (ORSDS)-POD2 | postoperative day 2 | ORSDS is a 4 point-scale that evaluates 3 symptom distress dimensions (frequency, severity, bothersomeness for 12 opioid-related side effects, with a score of each item ranging from 0 to 4 where higher scores mean more side effects). The final ORSDS score is the average of all 12 scores from those 12 items, ranging from 0 to 4 where a higher score means a worse outcome. This one measure ORSDS at postoperative day 2. |
| Opioid Related Side-effects (ORSDS)-POD1 | postoperative day 1 | ORSDS is a 4 point-scale that evaluates 3 symptom distress dimensions (frequency, severity, bothersomeness for 12 opioid-related side effects, with a score of each item ranging from 0 to 4 where higher scores mean more side effects). The final ORSDS score is the average of all 12 scores from those 12 items, ranging from 0 to 4 where a higher score means worse outcome. This one measure ORSDS at postoperative day 1 |
| PACU Length of Stay, Hours | in PACU | Hours spent in PACU (Postanesthesia Care Unit). |
| Daily Average Opioid Use During Hospital Stay | from admission up to discharge | The average daily opioid use (mg) during the hospital stay. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Lamotrigine Preoperatively, the patient will receive 300 mg of oral lamotrigine pill with small sips of water once. | 23 |
| Placebo Preoperatively, the patient will receive a 300 mg oral placebo pill with small sips of water once. | 23 |
| Total | 46 |
Baseline characteristics
| Characteristic | Placebo | Total | Lamotrigine |
|---|---|---|---|
| Age, Continuous | 42 years STANDARD_DEVIATION 12 | 43 years STANDARD_DEVIATION 12 | 44 years STANDARD_DEVIATION 13 |
| ASA status, No (%) I | 0 Participants | 1 Participants | 1 Participants |
| ASA status, No (%) II | 12 Participants | 21 Participants | 9 Participants |
| ASA status, No (%) III | 11 Participants | 24 Participants | 13 Participants |
| BPRS(Brief Psychiatric Rating Scale) baseline score | 25 scores | 25 scores | 25 scores |
| Chronic pulmonary disease | 0 Participants | 2 Participants | 2 Participants |
| Depression | 5 Participants | 9 Participants | 4 Participants |
| Diabetes | 0 Participants | 1 Participants | 1 Participants |
| History of alcoholism | 2 Participants | 5 Participants | 3 Participants |
| Hypertension | 5 Participants | 9 Participants | 4 Participants |
| Other neurological disorders | 0 Participants | 1 Participants | 1 Participants |
| Positive symptoms of schizophrenia based on four key items of BPRS (Brief Psychiatric Rati)-baseline | 2 Participants | 3 Participants | 1 Participants |
| Psychoses | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 4 Participants | 7 Participants | 3 Participants |
| Race/Ethnicity, Customized White | 19 Participants | 39 Participants | 20 Participants |
| Renal failure | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 14 Participants | 25 Participants | 11 Participants |
| Sex: Female, Male Male | 9 Participants | 21 Participants | 12 Participants |
| Surgery duration (hours) | 3 hours | 3.5 hours | 4 hours |
| Surgery type Abdominal | 17 Participants | 37 Participants | 20 Participants |
| Surgery type General | 4 Participants | 5 Participants | 1 Participants |
| Surgery type Orthopedic | 2 Participants | 4 Participants | 2 Participants |
| Total dose of Ketamine, mg | 142 mg STANDARD_DEVIATION 54 | 143 mg STANDARD_DEVIATION 51 | 143 mg STANDARD_DEVIATION 48 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 23 | 0 / 23 |
| other Total, other adverse events | 0 / 23 | 0 / 23 |
| serious Total, serious adverse events | 0 / 23 | 0 / 23 |
Outcome results
Primary
Number of Patients With Psychologic Disturbances-
The psychologic side-effects were measured in PACU (up to 90 minutes after ketamine infusion). This included four key items of the Brief Psychiatric Rating Scale (BPRS) corresponding to positive symptoms of schizophrenia: conceptual disorganization, hallucinatory behavior, suspiciousness, and unusual thought content. Each symptom is rated 1-7 ( 1 = not present, 2 = very mild, 3 = mild, 4 = moderate, 5 = moderately severe, 6 = severe, 7 = extremely severe ), and, therefore, the total score as the primary outcome based on four key items of BPRS will be between 4 (best score) and 28 (worst score). Patients who had a total score of 4 (all symptoms not present) were determined as not having psychologic disturbance and patients who had a total score of \> 4 (having any symptoms present) were determined as having psychologic disturbance.
Time frame: Up to 90 minutes of PACU arrival
Population: A total of 3 people were missing on this outcome
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Lamotrigine | Number of Patients With Psychologic Disturbances- | 0 Participants |
| Placebo | Number of Patients With Psychologic Disturbances- | 3 Participants |
p-value: 0.11Fisher Exact
Primary
Psychologic Side-effects
The primary outcome of psychologic side-effects was measured in PACU (up to 90 minutes after ketamine infusion). This included four key items of the Brief Psychiatric Rating Scale (BPRS) corresponding to positive symptoms of schizophrenia: conceptual disorganization, hallucinatory behavior, suspiciousness, and unusual thought content. Each symptom is rated 1-7 ( 1 = not present, 2 = very mild, 3 = mild, 4 = moderate, 5 = moderately severe, 6 = severe, 7 = extremely severe ), and, therefore, the total score as the primary outcome based on four key items of BPRS will be between 4 (best score) and 28 (worst score).
Time frame: in PACU (up to 90 minutes after ketamine infusion)
Population: 46 patients were analyzed but 3 people were missing on the primary outcome.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lamotrigine | Psychologic Side-effects | 4 score on a scale |
| Placebo | Psychologic Side-effects | 4 score on a scale |
p-value: 0.0895% CI: [0, 0]Wilcoxon (Mann-Whitney)
Secondary
Number of Patients Who Had PONV (Postoperative Nausea Vomiting)
PONV was measured through Postoperative Nursing Progress Record, where nausea vomiting severity was recorded as 0 (none), 1 (mild), 2 (moderate), 3 (severe). Patients whose score was 0 were determined as not having PONV and patients whose score was positive were determined as having PONV.
Time frame: after surgery up to discharge
Population: Two patients were missing on this outcome.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Lamotrigine | Number of Patients Who Had PONV (Postoperative Nausea Vomiting) | 5 Participants |
| Placebo | Number of Patients Who Had PONV (Postoperative Nausea Vomiting) | 5 Participants |
p-value: 198.3% CI: [0.3, 3.8]Chi-squared
Secondary
Pain Score in PACU
Pain score was scaled from 0-10 where 0 means no pain and 10 means most pain. The time-weighted average of pain scores was used if the pain score was measured multiple times.
Time frame: from entry to PACU to leaving PACU
Population: The final study population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lamotrigine | Pain Score in PACU | 4.9 score on a scale | Standard Deviation 3.1 |
| Placebo | Pain Score in PACU | 4.4 score on a scale | Standard Deviation 2.8 |
p-value: 0.5898.3% CI: [-1.7, 2.6]t-test, 2 sided
Secondary
Total Opioid Consumption in PACU (mg)
Total cumulative opioid use (total IV morphine equivalents) in postoperative anesthesia care unit (PACU)
Time frame: from entry to PACU to leaving PACU, up to 4 hours
Population: The final study population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lamotrigine | Total Opioid Consumption in PACU (mg) | 5 mg |
| Placebo | Total Opioid Consumption in PACU (mg) | 10 mg |
p-value: 0.6398.5% CI: [-9.5, 5]Wilcoxon (Mann-Whitney)
Other Pre-specified
Daily Average Opioid Use During Hospital Stay
The average daily opioid use (mg) during the hospital stay.
Time frame: from admission up to discharge
Population: The final study population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lamotrigine | Daily Average Opioid Use During Hospital Stay | 24 mg |
| Placebo | Daily Average Opioid Use During Hospital Stay | 24 mg |
Other Pre-specified
Opioid Related Side-effects (ORSDS)-POD1
ORSDS is a 4 point-scale that evaluates 3 symptom distress dimensions (frequency, severity, bothersomeness for 12 opioid-related side effects, with a score of each item ranging from 0 to 4 where higher scores mean more side effects). The final ORSDS score is the average of all 12 scores from those 12 items, ranging from 0 to 4 where a higher score means worse outcome. This one measure ORSDS at postoperative day 1
Time frame: postoperative day 1
Population: The final study population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lamotrigine | Opioid Related Side-effects (ORSDS)-POD1 | 0.38 score on a scale |
| Placebo | Opioid Related Side-effects (ORSDS)-POD1 | 0.57 score on a scale |
Other Pre-specified
Opioid Related Side-effects (ORSDS)-POD2
ORSDS is a 4 point-scale that evaluates 3 symptom distress dimensions (frequency, severity, bothersomeness for 12 opioid-related side effects, with a score of each item ranging from 0 to 4 where higher scores mean more side effects). The final ORSDS score is the average of all 12 scores from those 12 items, ranging from 0 to 4 where a higher score means a worse outcome. This one measure ORSDS at postoperative day 2.
Time frame: postoperative day 2
Population: the final study population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lamotrigine | Opioid Related Side-effects (ORSDS)-POD2 | 0.18 score on a scale |
| Placebo | Opioid Related Side-effects (ORSDS)-POD2 | 0.26 score on a scale |
Other Pre-specified
PACU Length of Stay, Hours
Hours spent in PACU (Postanesthesia Care Unit).
Time frame: in PACU
Population: the final study population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lamotrigine | PACU Length of Stay, Hours | 1 hours |
| Placebo | PACU Length of Stay, Hours | 2 hours |