Post-Traumatic Stress Disorder
Conditions
Keywords
pharmacotherapy, combat disorders
Brief summary
This was a six-week pilot study testing the efficacy of tramadol extended-release (ER) for posttraumatic stress disorder (PTSD). Men and women aged 21-55 years with combat-related PTSD or PTSD resulting from a civilian trauma were recruited. Blinded tramadol ER was begun with a 100 mg daily dose for the first week, with an option to increase to 200 mg/day for the 2nd week. Dose adjustments, using a range of 100-300 mg tramadol ER per day (or 1 to 3 placebo tabs), were permitted thereafter. The primary hypothesis was that tramadol ER 100 to 300 mg every morning for 6 weeks would reduce the symptoms of PTSD relative to placebo. The primary outcome measures were PTSD symptoms as rated by the Clinician-Administered PTSD Scale (CAPS) and Clinicians Global Impressions scale at baseline and weeks one, two, four, and six.
Detailed description
This was a single-site, double-blind, placebo-controlled, randomized, 6-week, parallel-group, flexible-dose outpatient trial of tramadol ER 100-300 mg once every morning for PTSD. Double-blinded clinical outcome measures were obtained during screening, and at weeks 0 (pre-randomization), 1, 2, 4, and 6; outcome was also assessed at week 7, the follow-up and study discharge visit, which occurred one week after the discontinuation of study medicine. Tramadol ER (or placebo) was started at 100 mg daily and increased weekly over the next two weeks, as tolerated, to a maximum of 300 mg daily. Dose change was also permitted at week 4. Matching drug and placebo were prepared by a research pharmacy using over-encapsulation in locking DB capsules supplied by Capsugel. Lactose was used as a filler to attain uniformity in weight. Randomization used a 1:1 allocation ratio and was via a block design, with stratification by military service. Other than the research pharmacists, all study personnel, all staff, and all subjects were blind.
Interventions
DRUGTramadol
Tramadol hydrochloride Extended Release(ER) will be supplied as tablets of Ultram® ER 100mg. Tramadol ER (100-300mg) or matching placebo will be self-administered by oral route every morning (with or without food) for 6 weeks. Patients will be instructed to take it the same way (either with food or without food) each time they take their dose. Each patient will be provided with 1 week supply of Tramadol ER or matching placebo on visits 2 (week 0) and 3 (week 1) and 2 weeks supply on visits 4 (week 2) and 5 (week 4).
DRUGPlacebo
Matching placebo will be self-administered by oral route every morning (with or without food) for 6 weeks. Patients will be instructed to take it the same way (either with food or without food) each time they take their dose. Each patient will be provided with 1 week supply of Tramadol ER or matching placebo on visits 2 (week 0) and 3 (week 1) and 2 weeks supply on visits 4 (week 2) and 5 (week 4).
Sponsors
U.S. Army Medical Research and Development Command
INTRuST, Post-Traumatic Stress Disorder - Traumatic Brain Injury Clinical Consortium
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
21 Years to 55 Years
Healthy volunteers
No
Inclusion criteria
1. Men and women, military veterans and non-veterans, aged 21-55 years 2. Active PTSD as determined by diagnostic evaluation and standardized interview (Structured Clinical Interview for the DSM (SCID)) 3. Literacy and ability to give informed consent 4. In women of child-conceiving potential, a negative pregnancy test and use of an approved birth control method 5. Glasgow Coma Scale (GCS) score of 15, Extension of GCS with 7-point Amnesia Scale score of 6 (amnesia for traumatic event of 30 min or fewer) or 7 (no amnesia for impact of head) (Nell et al 2000) 6. Clinically judged to be at low risk for adverse sequelae from taking tramadol 7. Concomitant medications must be approved by the PI
Exclusion criteria
1. Pregnant or nursing women 2. Homeless persons 3. Suicidal or homicidal ideation with plans or intent 4. History of opioid dependence or abuse 5. Psychosis or history thereof, substance dependence or abuse (other than tobacco dependence; lifetime opioid abuse is exclusionary) within the past 60 days, anorexia nervosa, antisocial personality disorder, or other psychiatric disorder judged by the investigator to be more clinically significant than PTSD 6. Serious or unstable illness, endocrinopathy, or metabolic instability, including renal insufficiency, liver disease, hydrocephalus, history of stroke, history of seizures, history of brain tumor 7. Use of non-study medications except those approved by the PI 8. Newly started in psychotherapy (\< 3months) 9. History of hypersensitivity, allergy, or other significant adverse effects from tramadol
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Clinician-Administered PTSD Scale (CAPS) | Weeks 0 (baseline),1, 2, 4, 6 | The Clinician-Administered PTSD Scale (CAPS) is an interview-based measure of severity of PTSD symptoms. A total score is calculated with a range of 0-136, with higher numbers indicating more severe symptoms. |
| Clinical Global Impression -- Improvement (CGI-I) -- Subject | Week 6, assessing clinician's judgment of change from week 0 to week 6 | The Clinicial Global Impression - Improvement (CGI-I) is a single item rated by a clinician. The range is 1 (very much improved)) to 7 (very much worse). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Visual Analog Scales (VAS) | Change from week 0 to 6 | Self-rated 100-mm visual analog scales \[0 to 100 scale; higher score indicates more of the rated state\] to rate poor sleep, happiness, irritability, nervousness and pain. Change is calculated by subtracting week 6 from week 0. |
| Quick Inventory of Depressive Symptoms (QIDS) | Weeks 0, 1, 2, 4 and 6 | Quick Inventory of Depressive Symptoms - Self Report (QIDS) is a self-report scale of severity of depression. A total score is calculated with a range of 0 to 27, with higher numbers indicating greater severity. |
Countries
United States
Participant flow
Recruitment details
41 subjects were consented to achieve sample of 40; one never returned for evaluation.
Pre-assignment details
40 evaluable subjects
Participants by arm
| Arm | Count |
|---|---|
| Tramadol ER Tramadol: Tramadol hydrochloride Extended Release(ER) will be supplied as tablets of Ultram® ER 100mg. Tramadol ER (100-300mg) or matching placebo will be self-administered by oral route every morning (with or without food) for 6 weeks. Patients will be instructed to take it the same way (either with food or without food) each time they take their dose. Each patient will be provided with 1 week supply of Tramadol ER or matching placebo on visits 2 (week 0) and 3 (week 1) and 2 weeks supply on visits 4 (week 2) and 5 (week 4). | 22 |
| Placebo Placebo: Matching placebo will be self-administered by oral route every morning (with or without food) for 6 weeks. Patients will be instructed to take it the same way (either with food or without food) each time they take their dose. Each patient will be provided with 1 week supply of Tramadol ER or matching placebo on visits 2 (week 0) and 3 (week 1) and 2 weeks supply on visits 4 (week 2) and 5 (week 4). | 18 |
| Total | 40 |
Baseline characteristics
| Characteristic | Placebo | Tramadol ER | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 18 Participants | 22 Participants | 40 Participants |
| Age, Continuous | 33.7 years STANDARD_DEVIATION 7 | 32.2 years STANDARD_DEVIATION 7.7 | 32.9 years STANDARD_DEVIATION 7.4 |
| Region of Enrollment United States | 18 participants | 22 participants | 40 participants |
| Sex: Female, Male Female | 5 Participants | 2 Participants | 7 Participants |
| Sex: Female, Male Male | 13 Participants | 20 Participants | 33 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 22 | 0 / 18 |
| other Total, other adverse events | 7 / 22 | 7 / 18 |
| serious Total, serious adverse events | 0 / 22 | 0 / 18 |
Outcome results
Primary
Clinical Global Impression -- Improvement (CGI-I) -- Subject
The Clinicial Global Impression - Improvement (CGI-I) is a single item rated by a clinician. The range is 1 (very much improved)) to 7 (very much worse).
Time frame: Week 6, assessing clinician's judgment of change from week 0 to week 6
Population: 33 men and 7 women with PTSD
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tramadol ER Men | Clinical Global Impression -- Improvement (CGI-I) -- Subject | 2.3 units on a scale | Standard Deviation 1.1 |
| Placebo Men | Clinical Global Impression -- Improvement (CGI-I) -- Subject | 2.6 units on a scale | Standard Deviation 1.1 |
| Tramadol ER Women | Clinical Global Impression -- Improvement (CGI-I) -- Subject | 2.0 units on a scale | Standard Deviation 1.4 |
| Placebo Women | Clinical Global Impression -- Improvement (CGI-I) -- Subject | 1.6 units on a scale | Standard Deviation 0.5 |
p-value: <0.1ANOVA
Primary
Clinician-Administered PTSD Scale (CAPS)
The Clinician-Administered PTSD Scale (CAPS) is an interview-based measure of severity of PTSD symptoms. A total score is calculated with a range of 0-136, with higher numbers indicating more severe symptoms.
Time frame: Weeks 0 (baseline),1, 2, 4, 6
Population: 33 men and 7 women with PTSD
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tramadol ER Men | Clinician-Administered PTSD Scale (CAPS) | Week 4 | 46.4 units on a scale | Standard Deviation 30.2 |
| Tramadol ER Men | Clinician-Administered PTSD Scale (CAPS) | Week 1 | 62.5 units on a scale | Standard Deviation 24.7 |
| Tramadol ER Men | Clinician-Administered PTSD Scale (CAPS) | Week 6 | 46.5 units on a scale | Standard Deviation 32.2 |
| Tramadol ER Men | Clinician-Administered PTSD Scale (CAPS) | Week 2 | 54.4 units on a scale | Standard Deviation 25.7 |
| Tramadol ER Men | Clinician-Administered PTSD Scale (CAPS) | Week 0 | 79.1 units on a scale | Standard Deviation 17.8 |
| Placebo Men | Clinician-Administered PTSD Scale (CAPS) | Week 2 | 68.5 units on a scale | Standard Deviation 26.2 |
| Placebo Men | Clinician-Administered PTSD Scale (CAPS) | Week 4 | 61.0 units on a scale | Standard Deviation 28.4 |
| Placebo Men | Clinician-Administered PTSD Scale (CAPS) | Week 6 | 51.0 units on a scale | Standard Deviation 28.6 |
| Placebo Men | Clinician-Administered PTSD Scale (CAPS) | Week 1 | 69.8 units on a scale | Standard Deviation 25 |
| Placebo Men | Clinician-Administered PTSD Scale (CAPS) | Week 0 | 81.9 units on a scale | Standard Deviation 24.8 |
| Tramadol ER Women | Clinician-Administered PTSD Scale (CAPS) | Week 2 | 67.0 units on a scale | Standard Deviation 31.1 |
| Tramadol ER Women | Clinician-Administered PTSD Scale (CAPS) | Week 0 | 90.0 units on a scale | Standard Deviation 5.7 |
| Tramadol ER Women | Clinician-Administered PTSD Scale (CAPS) | Week 1 | 68.5 units on a scale | Standard Deviation 10.6 |
| Tramadol ER Women | Clinician-Administered PTSD Scale (CAPS) | Week 4 | 39.5 units on a scale | Standard Deviation 55.9 |
| Tramadol ER Women | Clinician-Administered PTSD Scale (CAPS) | Week 6 | 36.0 units on a scale | Standard Deviation 50.9 |
| Placebo Women | Clinician-Administered PTSD Scale (CAPS) | Week 4 | 47.0 units on a scale | Standard Deviation 14.3 |
| Placebo Women | Clinician-Administered PTSD Scale (CAPS) | Week 1 | 71.0 units on a scale | Standard Deviation 24.3 |
| Placebo Women | Clinician-Administered PTSD Scale (CAPS) | Week 0 | 91.0 units on a scale | Standard Deviation 19 |
| Placebo Women | Clinician-Administered PTSD Scale (CAPS) | Week 2 | 62.2 units on a scale | Standard Deviation 15.4 |
| Placebo Women | Clinician-Administered PTSD Scale (CAPS) | Week 6 | 41.0 units on a scale | Standard Deviation 14.4 |
Comparison: Women were excluded from analysis because of the small sample size and unequal distribution across groups.p-value: 0.286ANOVA
Secondary
Quick Inventory of Depressive Symptoms (QIDS)
Quick Inventory of Depressive Symptoms - Self Report (QIDS) is a self-report scale of severity of depression. A total score is calculated with a range of 0 to 27, with higher numbers indicating greater severity.
Time frame: Weeks 0, 1, 2, 4 and 6
Population: 33 men and 7 women with PTSD
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tramadol ER Men | Quick Inventory of Depressive Symptoms (QIDS) | QIDS week 4 | 7.7 units on a scale | Standard Deviation 5.6 |
| Tramadol ER Men | Quick Inventory of Depressive Symptoms (QIDS) | QIDS week 1 | 8.7 units on a scale | Standard Deviation 4.8 |
| Tramadol ER Men | Quick Inventory of Depressive Symptoms (QIDS) | QIDS week 6 | 6.7 units on a scale | Standard Deviation 4.8 |
| Tramadol ER Men | Quick Inventory of Depressive Symptoms (QIDS) | QIDS week 2 | 7.7 units on a scale | Standard Deviation 4.7 |
| Tramadol ER Men | Quick Inventory of Depressive Symptoms (QIDS) | QIDS week 0 | 11.2 units on a scale | Standard Deviation 4.2 |
| Placebo Men | Quick Inventory of Depressive Symptoms (QIDS) | QIDS week 2 | 11.6 units on a scale | Standard Deviation 5.6 |
| Placebo Men | Quick Inventory of Depressive Symptoms (QIDS) | QIDS week 4 | 10.0 units on a scale | Standard Deviation 5.2 |
| Placebo Men | Quick Inventory of Depressive Symptoms (QIDS) | QIDS week 6 | 7.1 units on a scale | Standard Deviation 4.1 |
| Placebo Men | Quick Inventory of Depressive Symptoms (QIDS) | QIDS week 1 | 11.8 units on a scale | Standard Deviation 4.2 |
| Placebo Men | Quick Inventory of Depressive Symptoms (QIDS) | QIDS week 0 | 13.7 units on a scale | Standard Deviation 4.4 |
| Tramadol ER Women | Quick Inventory of Depressive Symptoms (QIDS) | QIDS week 2 | 12.0 units on a scale | Standard Deviation 9.9 |
| Tramadol ER Women | Quick Inventory of Depressive Symptoms (QIDS) | QIDS week 0 | 15.5 units on a scale | Standard Deviation 2.1 |
| Tramadol ER Women | Quick Inventory of Depressive Symptoms (QIDS) | QIDS week 1 | 11.0 units on a scale | Standard Deviation 5.7 |
| Tramadol ER Women | Quick Inventory of Depressive Symptoms (QIDS) | QIDS week 4 | 9.0 units on a scale | Standard Deviation 8.5 |
| Tramadol ER Women | Quick Inventory of Depressive Symptoms (QIDS) | QIDS week 6 | 6.5 units on a scale | Standard Deviation 4.9 |
| Placebo Women | Quick Inventory of Depressive Symptoms (QIDS) | QIDS week 4 | 7.1 units on a scale | Standard Deviation 4.6 |
| Placebo Women | Quick Inventory of Depressive Symptoms (QIDS) | QIDS week 1 | 8.4 units on a scale | Standard Deviation 4.2 |
| Placebo Women | Quick Inventory of Depressive Symptoms (QIDS) | QIDS week 0 | 12.6 units on a scale | Standard Deviation 4.8 |
| Placebo Women | Quick Inventory of Depressive Symptoms (QIDS) | QIDS week 2 | 7.0 units on a scale | Standard Deviation 2.2 |
| Placebo Women | Quick Inventory of Depressive Symptoms (QIDS) | QIDS week 6 | 4.5 units on a scale | Standard Deviation 1.7 |
Secondary
Visual Analog Scales (VAS)
Self-rated 100-mm visual analog scales \[0 to 100 scale; higher score indicates more of the rated state\] to rate poor sleep, happiness, irritability, nervousness and pain. Change is calculated by subtracting week 6 from week 0.
Time frame: Change from week 0 to 6
Population: 33 men and 7 women with PTSD
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tramadol ER Men | Visual Analog Scales (VAS) | Nervousness | 15.0 change in mm | Standard Deviation 31.9 |
| Tramadol ER Men | Visual Analog Scales (VAS) | Happiness | -18.5 change in mm | Standard Deviation 33.4 |
| Tramadol ER Men | Visual Analog Scales (VAS) | Pain | 7.5 change in mm | Standard Deviation 22.8 |
| Tramadol ER Men | Visual Analog Scales (VAS) | Irritability | 18.0 change in mm | Standard Deviation 30.5 |
| Tramadol ER Men | Visual Analog Scales (VAS) | Poor sleep | 26.8 change in mm | Standard Deviation 38.5 |
| Placebo Men | Visual Analog Scales (VAS) | Irritability | 14.2 change in mm | Standard Deviation 39.4 |
| Placebo Men | Visual Analog Scales (VAS) | Nervousness | 9.5 change in mm | Standard Deviation 24.3 |
| Placebo Men | Visual Analog Scales (VAS) | Pain | 10.4 change in mm | Standard Deviation 21.3 |
| Placebo Men | Visual Analog Scales (VAS) | Happiness | -11.0 change in mm | Standard Deviation 27.3 |
| Placebo Men | Visual Analog Scales (VAS) | Poor sleep | 6.7 change in mm | Standard Deviation 31.5 |
| Tramadol ER Women | Visual Analog Scales (VAS) | Irritability | 52.5 change in mm | Standard Deviation 16.3 |
| Tramadol ER Women | Visual Analog Scales (VAS) | Poor sleep | 51.0 change in mm | Standard Deviation 31.1 |
| Tramadol ER Women | Visual Analog Scales (VAS) | Happiness | -40.3 change in mm | Standard Deviation 2.5 |
| Tramadol ER Women | Visual Analog Scales (VAS) | Nervousness | 34.0 change in mm | Standard Deviation 5.7 |
| Tramadol ER Women | Visual Analog Scales (VAS) | Pain | 41.0 change in mm | Standard Deviation 1.4 |
| Placebo Women | Visual Analog Scales (VAS) | Nervousness | 36.4 change in mm | Standard Deviation 26.9 |
| Placebo Women | Visual Analog Scales (VAS) | Happiness | -29.6 change in mm | Standard Deviation 42.2 |
| Placebo Women | Visual Analog Scales (VAS) | Poor sleep | 32.8 change in mm | Standard Deviation 14.1 |
| Placebo Women | Visual Analog Scales (VAS) | Irritability | 39.0 change in mm | Standard Deviation 22.4 |
| Placebo Women | Visual Analog Scales (VAS) | Pain | 5.6 change in mm | Standard Deviation 31.8 |
Comparison: Analysis is for sleep only (men)p-value: =0.03ANOVA