Tramadol Extended-Release (ER) for Posttraumatic Stress Disorder (PTSD)

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Double-Blind, Placebo-Controlled, Flexible-Dose Pilot Clinical Trial of Once-Daily Extended-Release Tramadol for the Treatment of PTSD

Conditions
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Post-Traumatic Stress Disorder

Intervention / Treatment
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* Drug: Tramadol
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women, military veterans and non-veterans, aged 21-55 years Active PTSD as determined by diagnostic evaluation and standardized interview (Structured Clinical Interview for the DSM (SCID)) Literacy and ability to give informed consent In women of child-conceiving potential, a negative pregnancy test and use of an approved birth control method 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) Clinically judged to be at low risk for adverse sequelae from taking tramadol Concomitant medications must be approved by the PI Exclusion Criteria: Pregnant or nursing women Homeless persons Suicidal or homicidal ideation with plans or intent History of opioid dependence or abuse 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 Serious or unstable illness, endocrinopathy, or metabolic instability, including renal insufficiency, liver disease, hydrocephalus, history of stroke, history of seizures, history of brain tumor Use of non-study medications except those approved by the PI Newly started in psychotherapy (< 3months) History of hypersensitivity, allergy, or other significant adverse effects from tramadol

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tramadol ER<br>Tramadol in an extended release formulation with an initial dosage of 100 mg daily, increased weekly over the next two weeks, as tolerated, to a maximum of 300 mg daily | Drug: Tramadol<br>* 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).<br>* Other names: Ultram® ER;|
| Placebo Comparator: Placebo capsule<br>Lactose encapsulated to match appearance of experimental drug | Drug: Placebo<br>* 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).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Weeks 0 (baseline),1, 2, 4, 6 | 
| 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). | Week 6, assessing clinician's judgment of change from week 0 to week 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Change from week 0 to 6 | 
| 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. | Weeks 0, 1, 2, 4 and 6 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pharmacotherapy, combat disorders