Opioid Addiction, Opioid Dependence, Opioid Related Disorders
Conditions
Brief summary
This is a study of tramadol as an agent for short-term opioid withdrawal treatment. A randomized, double blind clinical trial comparing the efficacy and safety of tramadol to clonidine and buprenorphine in the short-term treatment of opioid withdrawal will be conducted. Opioid dependent participants will be treated on a residential unit. The primary outcome measure is opioid withdrawal symptoms.
Interventions
DRUGBuprenorphine/naloxone
up to 8/2 mg Sublingual (SL) per day
DRUGClonidine
up to 0.8 mg per day (oral)
DRUGTramadol ER
up to 600 mg per day
Sponsors
National Institute on Drug Abuse (NIDA)
Johns Hopkins University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
Inclusion/
Exclusion criteria
* Participants in this study will be males and females between the ages of 18 and 60 years. * Applicants must be opioid dependent based upon the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) (SCID); in addition, they must have an opioid positive urine during the screening process (or have evidence of opioid withdrawal). * They must be healthy, with no significant medical illnesses (e.g., insulin dependent diabetes), and without significant psychiatric illness (e.g., schizophrenia) besides their drug dependence. * Females will have a pregnancy test prior to study enrollment, and if found to be pregnant will be excluded and referred to a substance abuse program for pregnant women (the Center for Addiction and Pregnancy) on the campus. * Volunteers will also be excluded if they have pre-admission hypotension (due to the use of clonidine in the study). * Applicants with a history of seizures (including substance-related seizures, such as alcohol withdrawal related) will be excluded. * Alcohol and/or sedative dependence will be specific exclusionary criteria (given the small risk of seizures associated with tramadol use). * Allergies to any of the study medications will be grounds for exclusion.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Ratings on Clinical Opiate Withdrawal Scale (COWS) Measure of Withdrawal During Double-blind Taper (7-days) and Post-taper (7-days) Period. | 14 days total | Outcomes represent mean peak withdrawal as rated on the Clinical Opiate Withdrawal Scale (COWS) total score. Withdrawal was collected 7 times daily and daily peak values were identified for each participant and averaged together as a function of group. Primary outcomes were mean peak results from the 7-day taper period and first 7 days post-taper. The COWS is an 11-item observer-rated measure of opioid withdrawal severity. Items are rated on individual Likert scales and the total score range is 0-47. Higher values indicate more severe withdrawal. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Buprenorphine Sublingual buprenorphine/naloxone tablets (or placebo)
Buprenorphine/naloxone: up to 8/2 mg SL per day | 31 |
| Tramadol ER Oral tramadol tablets (or placebo)
Tramadol ER: up to 600 mg per day | 36 |
| Clonidine Oral clonidine tablets (or placebo)
Clonidine: up to 0.8 mg per day (oral) | 36 |
| Total | 103 |
Baseline characteristics
| Characteristic | Buprenorphine | Tramadol ER | Clonidine | Total |
|---|---|---|---|---|
| Age, Continuous | 41.1 years STANDARD_DEVIATION 10.9 | 40.9 years STANDARD_DEVIATION 9.7 | 41.5 years STANDARD_DEVIATION 10.5 | 41.2 years STANDARD_DEVIATION 10.4 |
| Race/Ethnicity, Customized Caucasian | 38.7 percentage of participants | 47.2 percentage of participants | 41.6 percentage of participants | 42.5 percentage of participants |
| Sex: Female, Male Female | 4 Participants | 5 Participants | 6 Participants | 15 Participants |
| Sex: Female, Male Male | 27 Participants | 31 Participants | 30 Participants | 88 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 31 | 0 / 36 | 0 / 36 |
| other Total, other adverse events | 28 / 31 | 31 / 36 | 32 / 36 |
| serious Total, serious adverse events | 0 / 31 | 0 / 36 | 0 / 36 |
Outcome results
Primary
Mean Ratings on Clinical Opiate Withdrawal Scale (COWS) Measure of Withdrawal During Double-blind Taper (7-days) and Post-taper (7-days) Period.
Outcomes represent mean peak withdrawal as rated on the Clinical Opiate Withdrawal Scale (COWS) total score. Withdrawal was collected 7 times daily and daily peak values were identified for each participant and averaged together as a function of group. Primary outcomes were mean peak results from the 7-day taper period and first 7 days post-taper. The COWS is an 11-item observer-rated measure of opioid withdrawal severity. Items are rated on individual Likert scales and the total score range is 0-47. Higher values indicate more severe withdrawal.
Time frame: 14 days total
Population: Repeated measures ANOVA
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Buprenorphine | Mean Ratings on Clinical Opiate Withdrawal Scale (COWS) Measure of Withdrawal During Double-blind Taper (7-days) and Post-taper (7-days) Period. | Post Taper Day 4 | 5.49 units on a scale | Standard Error 1.66 |
| Buprenorphine | Mean Ratings on Clinical Opiate Withdrawal Scale (COWS) Measure of Withdrawal During Double-blind Taper (7-days) and Post-taper (7-days) Period. | Taper Day 6 | 4.06 units on a scale | Standard Error 1.63 |
| Buprenorphine | Mean Ratings on Clinical Opiate Withdrawal Scale (COWS) Measure of Withdrawal During Double-blind Taper (7-days) and Post-taper (7-days) Period. | Taper Day 3 | 4.76 units on a scale | Standard Error 1.77 |
| Buprenorphine | Mean Ratings on Clinical Opiate Withdrawal Scale (COWS) Measure of Withdrawal During Double-blind Taper (7-days) and Post-taper (7-days) Period. | Post Taper Day 3 | 6.23 units on a scale | Standard Error 1.75 |
| Buprenorphine | Mean Ratings on Clinical Opiate Withdrawal Scale (COWS) Measure of Withdrawal During Double-blind Taper (7-days) and Post-taper (7-days) Period. | Taper Day 7 | 3.51 units on a scale | Standard Error 1.28 |
| Buprenorphine | Mean Ratings on Clinical Opiate Withdrawal Scale (COWS) Measure of Withdrawal During Double-blind Taper (7-days) and Post-taper (7-days) Period. | Taper Day 2 | 6.16 units on a scale | Standard Error 2.03 |
| Buprenorphine | Mean Ratings on Clinical Opiate Withdrawal Scale (COWS) Measure of Withdrawal During Double-blind Taper (7-days) and Post-taper (7-days) Period. | Post Taper Day 2 | 5.62 units on a scale | Standard Error 1.9 |
| Buprenorphine | Mean Ratings on Clinical Opiate Withdrawal Scale (COWS) Measure of Withdrawal During Double-blind Taper (7-days) and Post-taper (7-days) Period. | Post Taper Day 1 | 4.82 units on a scale | Standard Error 1.62 |
| Buprenorphine | Mean Ratings on Clinical Opiate Withdrawal Scale (COWS) Measure of Withdrawal During Double-blind Taper (7-days) and Post-taper (7-days) Period. | Post Taper Day 5 | 5.87 units on a scale | Standard Error 1.69 |
| Buprenorphine | Mean Ratings on Clinical Opiate Withdrawal Scale (COWS) Measure of Withdrawal During Double-blind Taper (7-days) and Post-taper (7-days) Period. | Taper Day 4 | 4.21 units on a scale | Standard Error 1.77 |
| Buprenorphine | Mean Ratings on Clinical Opiate Withdrawal Scale (COWS) Measure of Withdrawal During Double-blind Taper (7-days) and Post-taper (7-days) Period. | Post Taper Day 7 | 4.91 units on a scale | Standard Error 1.69 |
| Buprenorphine | Mean Ratings on Clinical Opiate Withdrawal Scale (COWS) Measure of Withdrawal During Double-blind Taper (7-days) and Post-taper (7-days) Period. | Taper Day 1 | 7.79 units on a scale | Standard Error 1.68 |
| Buprenorphine | Mean Ratings on Clinical Opiate Withdrawal Scale (COWS) Measure of Withdrawal During Double-blind Taper (7-days) and Post-taper (7-days) Period. | Taper Day 5 | 4.31 units on a scale | Standard Error 2.11 |
| Buprenorphine | Mean Ratings on Clinical Opiate Withdrawal Scale (COWS) Measure of Withdrawal During Double-blind Taper (7-days) and Post-taper (7-days) Period. | Post Taper Day 6 | 4.91 units on a scale | Standard Error 1.62 |
| Tramadol ER | Mean Ratings on Clinical Opiate Withdrawal Scale (COWS) Measure of Withdrawal During Double-blind Taper (7-days) and Post-taper (7-days) Period. | Post Taper Day 4 | 3.13 units on a scale | Standard Error 0.24 |
| Tramadol ER | Mean Ratings on Clinical Opiate Withdrawal Scale (COWS) Measure of Withdrawal During Double-blind Taper (7-days) and Post-taper (7-days) Period. | Taper Day 1 | 8.41 units on a scale | Standard Error 0.7 |
| Tramadol ER | Mean Ratings on Clinical Opiate Withdrawal Scale (COWS) Measure of Withdrawal During Double-blind Taper (7-days) and Post-taper (7-days) Period. | Taper Day 2 | 6.10 units on a scale | Standard Error 0.72 |
| Tramadol ER | Mean Ratings on Clinical Opiate Withdrawal Scale (COWS) Measure of Withdrawal During Double-blind Taper (7-days) and Post-taper (7-days) Period. | Taper Day 3 | 3.77 units on a scale | Standard Error 0.35 |
| Tramadol ER | Mean Ratings on Clinical Opiate Withdrawal Scale (COWS) Measure of Withdrawal During Double-blind Taper (7-days) and Post-taper (7-days) Period. | Taper Day 4 | 4.25 units on a scale | Standard Error 0.52 |
| Tramadol ER | Mean Ratings on Clinical Opiate Withdrawal Scale (COWS) Measure of Withdrawal During Double-blind Taper (7-days) and Post-taper (7-days) Period. | Taper Day 5 | 3.25 units on a scale | Standard Error 0.37 |
| Tramadol ER | Mean Ratings on Clinical Opiate Withdrawal Scale (COWS) Measure of Withdrawal During Double-blind Taper (7-days) and Post-taper (7-days) Period. | Taper Day 6 | 3.39 units on a scale | Standard Error 0.45 |
| Tramadol ER | Mean Ratings on Clinical Opiate Withdrawal Scale (COWS) Measure of Withdrawal During Double-blind Taper (7-days) and Post-taper (7-days) Period. | Taper Day 7 | 3.69 units on a scale | Standard Error 0.53 |
| Tramadol ER | Mean Ratings on Clinical Opiate Withdrawal Scale (COWS) Measure of Withdrawal During Double-blind Taper (7-days) and Post-taper (7-days) Period. | Post Taper Day 1 | 3.36 units on a scale | Standard Error 0.44 |
| Tramadol ER | Mean Ratings on Clinical Opiate Withdrawal Scale (COWS) Measure of Withdrawal During Double-blind Taper (7-days) and Post-taper (7-days) Period. | Post Taper Day 2 | 4.48 units on a scale | Standard Error 0.6 |
| Tramadol ER | Mean Ratings on Clinical Opiate Withdrawal Scale (COWS) Measure of Withdrawal During Double-blind Taper (7-days) and Post-taper (7-days) Period. | Post Taper Day 3 | 3.28 units on a scale | Standard Error 0.28 |
| Tramadol ER | Mean Ratings on Clinical Opiate Withdrawal Scale (COWS) Measure of Withdrawal During Double-blind Taper (7-days) and Post-taper (7-days) Period. | Post Taper Day 5 | 2.75 units on a scale | Standard Error 0.24 |
| Tramadol ER | Mean Ratings on Clinical Opiate Withdrawal Scale (COWS) Measure of Withdrawal During Double-blind Taper (7-days) and Post-taper (7-days) Period. | Post Taper Day 6 | 2.57 units on a scale | Standard Error 0.26 |
| Tramadol ER | Mean Ratings on Clinical Opiate Withdrawal Scale (COWS) Measure of Withdrawal During Double-blind Taper (7-days) and Post-taper (7-days) Period. | Post Taper Day 7 | 2.30 units on a scale | Standard Error 0.23 |
| Clonidine | Mean Ratings on Clinical Opiate Withdrawal Scale (COWS) Measure of Withdrawal During Double-blind Taper (7-days) and Post-taper (7-days) Period. | Post Taper Day 6 | 2.91 units on a scale | Standard Error 0.31 |
| Clonidine | Mean Ratings on Clinical Opiate Withdrawal Scale (COWS) Measure of Withdrawal During Double-blind Taper (7-days) and Post-taper (7-days) Period. | Post Taper Day 3 | 3.68 units on a scale | Standard Error 0.38 |
| Clonidine | Mean Ratings on Clinical Opiate Withdrawal Scale (COWS) Measure of Withdrawal During Double-blind Taper (7-days) and Post-taper (7-days) Period. | Taper Day 5 | 3.32 units on a scale | Standard Error 0.41 |
| Clonidine | Mean Ratings on Clinical Opiate Withdrawal Scale (COWS) Measure of Withdrawal During Double-blind Taper (7-days) and Post-taper (7-days) Period. | Taper Day 4 | 4.70 units on a scale | Standard Error 0.57 |
| Clonidine | Mean Ratings on Clinical Opiate Withdrawal Scale (COWS) Measure of Withdrawal During Double-blind Taper (7-days) and Post-taper (7-days) Period. | Post Taper Day 4 | 3.82 units on a scale | Standard Error 0.46 |
| Clonidine | Mean Ratings on Clinical Opiate Withdrawal Scale (COWS) Measure of Withdrawal During Double-blind Taper (7-days) and Post-taper (7-days) Period. | Taper Day 3 | 5.85 units on a scale | Standard Error 0.66 |
| Clonidine | Mean Ratings on Clinical Opiate Withdrawal Scale (COWS) Measure of Withdrawal During Double-blind Taper (7-days) and Post-taper (7-days) Period. | Taper Day 1 | 8.28 units on a scale | Standard Error 0.71 |
| Clonidine | Mean Ratings on Clinical Opiate Withdrawal Scale (COWS) Measure of Withdrawal During Double-blind Taper (7-days) and Post-taper (7-days) Period. | Post Taper Day 5 | 3.27 units on a scale | Standard Error 0.35 |
| Clonidine | Mean Ratings on Clinical Opiate Withdrawal Scale (COWS) Measure of Withdrawal During Double-blind Taper (7-days) and Post-taper (7-days) Period. | Taper Day 2 | 8.00 units on a scale | Standard Error 0.46 |
| Clonidine | Mean Ratings on Clinical Opiate Withdrawal Scale (COWS) Measure of Withdrawal During Double-blind Taper (7-days) and Post-taper (7-days) Period. | Post Taper Day 1 | 3.27 units on a scale | Standard Error 0.37 |
| Clonidine | Mean Ratings on Clinical Opiate Withdrawal Scale (COWS) Measure of Withdrawal During Double-blind Taper (7-days) and Post-taper (7-days) Period. | Taper Day 7 | 3.86 units on a scale | Standard Error 0.64 |
| Clonidine | Mean Ratings on Clinical Opiate Withdrawal Scale (COWS) Measure of Withdrawal During Double-blind Taper (7-days) and Post-taper (7-days) Period. | Post Taper Day 7 | 2.41 units on a scale | Standard Error 0.31 |
| Clonidine | Mean Ratings on Clinical Opiate Withdrawal Scale (COWS) Measure of Withdrawal During Double-blind Taper (7-days) and Post-taper (7-days) Period. | Post Taper Day 2 | 4.09 units on a scale | Standard Error 0.6 |
| Clonidine | Mean Ratings on Clinical Opiate Withdrawal Scale (COWS) Measure of Withdrawal During Double-blind Taper (7-days) and Post-taper (7-days) Period. | Taper Day 6 | 3.57 units on a scale | Standard Error 0.57 |
Comparison: A power analysis determined 40 participants in each group would detect a moderate effect size, assuming an alpha of 0.05 and 80% power. Due to the expiration of buprenorphine tablets, recruitment was terminated after enrolling 103 participants. This study utilized an Intent-to-Treat (ITT) analysis. The ITT analysis includes all volunteers who signed informed consent, were randomized into the study's treatment conditions, and took at least 1 dose of study medication.p-value: 0.275ANOVA
p-value: 0.03ANOVA
p-value: 0.092ANOVA