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

Phase 4

Completed

Lead Sponsor: INTRuST, Post-Traumatic Stress Disorder - Traumatic Brain Injury Clinical Consortium

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.

Recruitment & Eligibility

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

Arm && Interventions

Group	Intervention	Description
Placebo capsule	Placebo	Lactose encapsulated to match appearance of experimental drug
Tramadol ER	Tramadol	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

Primary Outcome Measures

Name	Time	Method
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).
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.

Secondary Outcome Measures

Name	Time	Method
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.