Chronic Pain, PTSD
Conditions
Keywords
PTSD, chronic pain, ketamine infusion
Brief summary
The purpose of the study is to investigate the effectiveness of low dose IV ketamine infusion in the treatment of patients with PTSD and comorbid chronic pain. Hypothesis: A single ketamine infusion should be associated with significantly greater reduction in core PTSD symptom levels after the treatment and such an effect is not only due to its analgesic properties but also through unknown mechanism of action that maybe related to NMDA/AMPA receptor modulation.
Detailed description
To date, treatment options (i.e. psychotherapy, antidepressant medications) for patients with PTSD, are relatively few, and considering their limited efficacy, novel therapies have gained interest among researchers and treatment providers alike. Among patients with chronic pain about one third suffer from comorbid PTSD, which further complicates their already challenging pharmacological regimens. Low dose ketamine infusion has shown promise in PTSD, and in treatment of chronic pain, however they have not been studied in comorbid population and under rigorous control conditions. The investigators compared the effects of a single dose of either ketamine (0.5 mg/kg) or ketorolac (15 mg) over a 40-minute of IV infusion in chronic pain patients with and without PTSD, in double blind, randomized study. Measures were collected before, during, 1 day and 7 days after the infusion.
Interventions
DRUGA single low dose ketamine infusion as compared to the IV infusion of active placebo - ketorolac on chronic pain and PTSD symptoms.
Subjects were randomized into 4 treatment groups: chronic pain subjects treated with ketorolac, chronic pain subjects treated with ketamine, chronic pain+PTSD subjects treated with ketorolac, and chronic pain+PTSD subjects treated with ketamine.
Sponsors
University of Michigan
VA Ann Arbor Healthcare System
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Outcomes Assessor)
Masking description
All study personnel, including rater, patients, and data analysts, were blinded to randomization order. Only the anesthesiologist performing the infusion was not blinded in order to prepare for possible side effects of each medication.
Intervention model description
Patient with and without PTSD were randomized to receive either ketamine or ketorolac. Single IV infusion of ketamine hydrochloride (0.5 mg/kg) was administered over 40 minutes. Ketorolac 15 mg was reconstituted in 500 cc of normal saline administered over 40 minutes.
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
Veterans with chronic pain as defined by having any chronic pain beyond 6 months in duration with and without PTSD diagnoses (participants must meet DSM-V criteria for current post-traumatic stress disorder (PTSD) and have received a diagnosis of PTSD greater than or equal to 3 months prior to assessment); they also will be either free of concomitant use of psychotropic and/or pain medications for at least 6 weeks or on stable doses of those medications within the last 6 weeks prior to randomization and for the duration of the study; if applicable, current frequency and duration of psychotherapy sessions must remain stable for at least 6 weeks prior to beginning of the study.
Exclusion criteria
Inability to speak English, inability or unwillingness to provide written informed consent; moderate-to-severe cognitive impairment (Mini-Mental State Examination scores\<20 administered by a trained clinician); current or lifetime history of psychotic or bipolar disorder; current bulimia or anorexia nervosa, alcohol abuse or dependence in the previous 3 months; serious unstable medical illness or sleep apnea; HTN, prolonged QT interval, peptic ulcer disease or recent history of GI-bleed, renal insufficiency, active substance use disorder, active suicidal or homicidal ideation on presentation; pregnancy (confirmed by baseline lab test), the initiation of female hormonal treatments within 3 months of screening, or inability or unwillingness to use a medically accepted contraceptive method for the duration of the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Visual Analogue Scale (VAS) | 24 hrs post-infusion | Severity of chronic pain symptoms; using a ruler, the score is determined by measuring the distance (mm) on the 10-cm line between the no pain anchor and the patient's mark, providing a range of scores from 0-100; a higher score indicates greater pain intensity. |
| Impact of Event Scale-Revised (IES-R) | 24 hrs post-infusion | Severity of PTSD symptoms; items are rated on a 5-point scale ranging from 0 (not at all) to 4 (extremely). The IES-R yields a total score (ranging from 0 to 88); higher scores mean worse symptoms |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Visual Analogue Scale (VAS) | 1 week post-infusion | Severity of chronic pain symptoms; using a ruler, the score is determined by measuring the distance (mm) on the 10-cm line between the no pain anchor and the patient's mark, providing a range of scores from 0-100; a higher score indicates greater pain intensity. |
| Brief Pain Inventory (Short Form) | 1 week post-infusion | Severity of pain, impact of pain on daily function, location of pain, pain medications and amount of pain relief in the past 24 hours or the past week; No scoring algorithm, but worst pain or the arithmetic mean of the four severity items can be used as measures of pain severity (a range of 0-10, with 10 being worse scores); the arithmetic mean of the seven interference items can be used as a measure of pain interference (a range of 0-10, with 10 being worse scores). The total score is reported for severity items and interference items, which range from 0-40 and 0-70, respectively. Higher values represent worse outcome. |
| Impact of Event Scale-Revised (IES-R) | 1 week post-infusion | Severity of PTSD symptoms; items are rated on a 5-point scale ranging from 0 (not at all) to 4 (extremely). The IES-R yields a total score (ranging from 0 to 88); higher scores mean worse symptoms |
Other
| Measure | Time frame | Description |
|---|---|---|
| Clinician-Administered Dissociative States Scale (CADSS) | baseline-1 week post-infusion | Dissociative, psychotomimetic, and manic symptoms; 27-item scale with 19 subject-rated items and 8 items scored by an observer; higher scores mean worse present-state dissociative symptomatology |
| Patient-Rated Inventory of Side Effects (PRISE20) | baseline-1 week post-infusion | Patient self report used to qualify side effects by identifying and evaluating the tolerability of each symptoms; 20 items; higher scores mean worse side effects |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Chronic Pain With PTSD+IV Ketamine Infusion A single low dose ketamine infusion as compared to the IV infusion of active placebo - ketorolac on chronic pain and PTSD symptoms.: Subjects were randomized into 4 treatment groups: chronic pain subjects treated with ketorolac, chronic pain subjects treated with ketamine, chronic pain+PTSD subjects treated with ketorolac, and chronic pain+PTSD subjects treated with ketamine. | 10 |
| Chronic Pain With PTSD+IV Ketorolac Infusion A single low dose ketamine infusion as compared to the IV infusion of active placebo - ketorolac on chronic pain and PTSD symptoms.: Subjects were randomized into 4 treatment groups: chronic pain subjects treated with ketorolac, chronic pain subjects treated with ketamine, chronic pain+PTSD subjects treated with ketorolac, and chronic pain+PTSD subjects treated with ketamine. | 9 |
| Chronic Pain Without PTSD+IV Ketamine Infusion A single low dose ketamine infusion as compared to the IV infusion of active placebo - ketorolac on chronic pain and PTSD symptoms.: Subjects were randomized into 4 treatment groups: chronic pain subjects treated with ketorolac, chronic pain subjects treated with ketamine, chronic pain+PTSD subjects treated with ketorolac, and chronic pain+PTSD subjects treated with ketamine. | 10 |
| Chronic Pain Without PTSD+IV Ketorolac Infusion A single low dose ketamine infusion as compared to the IV infusion of active placebo - ketorolac on chronic pain and PTSD symptoms.: Subjects were randomized into 4 treatment groups: chronic pain subjects treated with ketorolac, chronic pain subjects treated with ketamine, chronic pain+PTSD subjects treated with ketorolac, and chronic pain+PTSD subjects treated with ketamine. | 10 |
| Total | 39 |
Baseline characteristics
| Characteristic | Chronic Pain With PTSD+IV Ketamine Infusion | Chronic Pain With PTSD+IV Ketorolac Infusion | Chronic Pain Without PTSD+IV Ketamine Infusion | Chronic Pain Without PTSD+IV Ketorolac Infusion | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants | 9 Participants | 10 Participants | 10 Participants | 39 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants | 8 Participants | 9 Participants | 10 Participants | 37 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Region of Enrollment United States | 10 Participants | 9 Participants | 10 Participants | 10 Participants | 39 Participants |
| Sex: Female, Male Female | 4 Participants | 3 Participants | 1 Participants | 1 Participants | 9 Participants |
| Sex: Female, Male Male | 6 Participants | 6 Participants | 9 Participants | 9 Participants | 30 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 9 | 0 / 10 | 0 / 10 |
| other Total, other adverse events | 0 / 10 | 0 / 9 | 0 / 10 | 0 / 10 |
| serious Total, serious adverse events | 0 / 10 | 0 / 9 | 0 / 10 | 0 / 10 |
Outcome results
Primary
Impact of Event Scale-Revised (IES-R)
Severity of PTSD symptoms; items are rated on a 5-point scale ranging from 0 (not at all) to 4 (extremely). The IES-R yields a total score (ranging from 0 to 88); higher scores mean worse symptoms
Time frame: 24 hrs post-infusion
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Chronic Pain With PTSD+IV Ketamine Infusion | Impact of Event Scale-Revised (IES-R) | 36.33333333 units on a scale | Standard Deviation 17.27715254 |
| Chronic Pain With PTSD+IV Ketorolac Infusion | Impact of Event Scale-Revised (IES-R) | 37 units on a scale | Standard Deviation 15.77973384 |
| Chronic Pain Without PTSD+IV Ketamine Infusion | Impact of Event Scale-Revised (IES-R) | 10.44444444 units on a scale | Standard Deviation 14.34495653 |
| Chronic Pain Without PTSD+IV Ketorolac Infusion | Impact of Event Scale-Revised (IES-R) | 15.64705882 units on a scale | Standard Deviation 17.05484233 |
Primary
Visual Analogue Scale (VAS)
Severity of chronic pain symptoms; using a ruler, the score is determined by measuring the distance (mm) on the 10-cm line between the no pain anchor and the patient's mark, providing a range of scores from 0-100; a higher score indicates greater pain intensity.
Time frame: 24 hrs post-infusion
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Chronic Pain With PTSD+IV Ketamine Infusion | Visual Analogue Scale (VAS) | 37.22222222 units on a scale | Standard Deviation 24.69705336 |
| Chronic Pain With PTSD+IV Ketorolac Infusion | Visual Analogue Scale (VAS) | 49.66666667 units on a scale | Standard Deviation 23.44141634 |
| Chronic Pain Without PTSD+IV Ketamine Infusion | Visual Analogue Scale (VAS) | 29.88888889 units on a scale | Standard Deviation 24.15286962 |
| Chronic Pain Without PTSD+IV Ketorolac Infusion | Visual Analogue Scale (VAS) | 38.70588235 units on a scale | Standard Deviation 28.12197696 |
Secondary
Brief Pain Inventory (Short Form)
Severity of pain, impact of pain on daily function, location of pain, pain medications and amount of pain relief in the past 24 hours or the past week; No scoring algorithm, but worst pain or the arithmetic mean of the four severity items can be used as measures of pain severity (a range of 0-10, with 10 being worse scores); the arithmetic mean of the seven interference items can be used as a measure of pain interference (a range of 0-10, with 10 being worse scores). The total score is reported for severity items and interference items, which range from 0-40 and 0-70, respectively. Higher values represent worse outcome.
Time frame: 1 week post-infusion
Population: BPI- pain scale and pain interference
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Chronic Pain With PTSD+IV Ketamine Infusion | Brief Pain Inventory (Short Form) | Pain interference Scale | 38.62 units on a scale | Standard Deviation 24.03 |
| Chronic Pain With PTSD+IV Ketamine Infusion | Brief Pain Inventory (Short Form) | Pain severity Scale | 20.75 units on a scale | Standard Deviation 10.55 |
| Chronic Pain With PTSD+IV Ketorolac Infusion | Brief Pain Inventory (Short Form) | Pain severity Scale | 14.66 units on a scale | Standard Deviation 9.53 |
| Chronic Pain With PTSD+IV Ketorolac Infusion | Brief Pain Inventory (Short Form) | Pain interference Scale | 25.66 units on a scale | Standard Deviation 20.32 |
| Chronic Pain Without PTSD+IV Ketamine Infusion | Brief Pain Inventory (Short Form) | Pain severity Scale | 12.75 units on a scale | Standard Deviation 5.44 |
| Chronic Pain Without PTSD+IV Ketamine Infusion | Brief Pain Inventory (Short Form) | Pain interference Scale | 9.62 units on a scale | Standard Deviation 7.44 |
| Chronic Pain Without PTSD+IV Ketorolac Infusion | Brief Pain Inventory (Short Form) | Pain severity Scale | 22.66 units on a scale | Standard Deviation 9.13 |
| Chronic Pain Without PTSD+IV Ketorolac Infusion | Brief Pain Inventory (Short Form) | Pain interference Scale | 28.33 units on a scale | Standard Deviation 21.96 |
Secondary
Impact of Event Scale-Revised (IES-R)
Severity of PTSD symptoms; items are rated on a 5-point scale ranging from 0 (not at all) to 4 (extremely). The IES-R yields a total score (ranging from 0 to 88); higher scores mean worse symptoms
Time frame: 1 week post-infusion
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Chronic Pain With PTSD+IV Ketamine Infusion | Impact of Event Scale-Revised (IES-R) | 28.22 units on a scale | Standard Deviation 22.6 |
| Chronic Pain With PTSD+IV Ketorolac Infusion | Impact of Event Scale-Revised (IES-R) | 33.66666667 units on a scale | Standard Deviation 20.43281674 |
| Chronic Pain Without PTSD+IV Ketamine Infusion | Impact of Event Scale-Revised (IES-R) | 11.44 units on a scale | Standard Deviation 17.47 |
| Chronic Pain Without PTSD+IV Ketorolac Infusion | Impact of Event Scale-Revised (IES-R) | 13.41 units on a scale | Standard Deviation 16.84 |
Secondary
Visual Analogue Scale (VAS)
Severity of chronic pain symptoms; using a ruler, the score is determined by measuring the distance (mm) on the 10-cm line between the no pain anchor and the patient's mark, providing a range of scores from 0-100; a higher score indicates greater pain intensity.
Time frame: 1 week post-infusion
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Chronic Pain With PTSD+IV Ketamine Infusion | Visual Analogue Scale (VAS) | 48.22 units on a scale | Standard Deviation 31.59 |
| Chronic Pain With PTSD+IV Ketorolac Infusion | Visual Analogue Scale (VAS) | 52.88 units on a scale | Standard Deviation 21.55 |
| Chronic Pain Without PTSD+IV Ketamine Infusion | Visual Analogue Scale (VAS) | 43.33 units on a scale | Standard Deviation 19.28 |
| Chronic Pain Without PTSD+IV Ketorolac Infusion | Visual Analogue Scale (VAS) | 48.23 units on a scale | Standard Deviation 21.72 |
Other Pre-specified
Clinician-Administered Dissociative States Scale (CADSS)
Dissociative, psychotomimetic, and manic symptoms; 27-item scale with 19 subject-rated items and 8 items scored by an observer; higher scores mean worse present-state dissociative symptomatology
Time frame: baseline-1 week post-infusion
Other Pre-specified
Patient-Rated Inventory of Side Effects (PRISE20)
Patient self report used to qualify side effects by identifying and evaluating the tolerability of each symptoms; 20 items; higher scores mean worse side effects
Time frame: baseline-1 week post-infusion