Opioid Dependence
Conditions
Keywords
Drug Abuse
Brief summary
The purpose of this study is to examine the effect of memantine and buprenorphine on opioid abusing behavior, to determine the effect of memantine and buprenorphine on early relapse and to evaluate the tolerability of memantine co-administrated with buprenorphine. The study seeks to determine if combined treatment of memantine and buprenorphine may provide shorter-term treatment for opioid dependence.
Detailed description
Opiate dependence is an increasing problem among young adults (18-25 years old) whose rates of current use of illicit drugs are generally high (19.7 %)according to data from the 2007 National Survey on Drug Use & Health (Substance Abuse and Mental Health Services Administration 2008). Young adults start using heroin around this age range, and more recently have had increasing rates of prescription-type drug use. Given that young adults with opiate dependence who are seeking treatment are relatively treatment naïve, have a shorter period of addiction, and are more likely to choose buprenorphine over methadone, developing short-term buprenorphine treatment alternatives to long-term methadone agonist treatment is needed.
Interventions
DRUGMemantine
30mg/day Memantine orally everyday for 12 weeks
DRUGPlacebo
Placebo orally everyday for 12 weeks
Sponsors
National Institute on Drug Abuse (NIDA)
University of Massachusetts, Worcester
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 25 Years
Healthy volunteers
No
Inclusion criteria
* Men and women between 18-25 years old * Opioid dependence as evidenced by signs of opiate withdrawal, self-reported history of opioid dependence for a consecutive 12 month period and positive urine for opioids
Exclusion criteria
* Current diagnosis of other drug or alcohol dependence (other than opiates, cannabis or tobacco) * Serious medical illness (e.g. major cardiovascular, renal, endocrine, hepatic disorder) * Current serious psychiatric illness or history of psychosis, schizophrenia, bipolar type I disorder and participants with suicidal or homicidal thoughts * Women who are pregnant, nursing or refuse to use a reliable form of birth control or refuse monthly pregnancy testing * Screening liver function tests (SGOT or SGPT) greater than 3 times normal
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change of Opioid Use From Week 1 to 13 | Weekly from week 1 to 13 | The primary outcome variable was the change from baseline of the mean proportion of weekly opioid use assessed by self-reported days of use and/or positive urine drug screen during the previous week using the time-line followed-back method (TLFB) . A positive urine counted as 1, as did each self-reported day of use. Each participants total was divided by 8. Mean proportion by group were calculated by averaging the proportions across participants in that group. |
| Number of Participants Who Were Estimated to Have Survived as Assessed by Survival Curve of Relapse Rate After Achieving Complete Abstinence on Week 8 | Weeks after buprenorphine discontinuation week 9 | Calculated survival curve from abstinence in Week 8 to first positive opioid urine screen or first reported relapse to opioid use to evaluate the effect of memantine on reducing early relapse and after rapid buprenorphine discontinuation on week 9. The last observation carried forward (LOCF) was used to perform our event survival analyses. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Treatment Retention | Weekly | Treatment retention during the stabilization period weeks 1 to 8 and after buprenorphine / naloxone discontinuation weeks 9 to 13. |
Countries
United States
Participant flow
Recruitment details
Recruitment was done by newspaper advertising, referrals from the University of Massachusetts Addiction and Comorbidity Treatment Service (ACTS) and from community-based substance abuse clinics.
Pre-assignment details
229 individuals of the 354 persons who were interested in the study were assessed not eligible to participate. Of the 125 subjects that were screen over one week, only 87 subjects meet criteria for study participation. Reason for exclusion included: declined (N=22), psychiatric (N=6), other SUD (N=6), abnormal labs (N=3) and medical reason (N=1)
Participants by arm
| Arm | Count |
|---|---|
| Memantine 30mg/Day + Buprenorphine Participants were inducted onto buprenorphine/naloxone sublingual tablets during the first week of study participation. The dose was titrated from bup/nal 8mg to bup/nal 16mg in three days where it will remain until the last day of week 8. The 7-day discontinuation of buprenorphine-naloxone on week 9 was 12mg, 10mg, 8mg, 6mg, 4mg, 2mg, 2mg and stopped.
Memantine 5mg in the morning was started on week 2. The dose was titrated on a twice a day schedule until the target dose of 30 mg/day was achieved by week 4. The medication was discontinued over a one-week period on week 13. Patients received a 7-day supply of their medication each week.
Memantine: 30mg/day Memantine orally everyday for 12 weeks | 27 |
| Memantine 15mg/Day + Buprenorphine Participants were inducted onto buprenorphine/naloxone sublingual tablets during the first week of study participation. The dose was titrated from bup/nal 8mg to bup/nal 16mg in three days where it will remain until the last day of week 8. The 7-day discontinuation of buprenorphine-naloxone on week 9 was 12mg, 10mg, 8mg, 6mg, 4mg, 2mg, 2mg and stopped.
Memantine 5mg in the morning was started on week 2. The dose was titrated on a twice a day schedule until the target dose of 15 mg/day was achieved by week 4. The medication was discontinued over a one-week period on week 13. Patients received a 7-day supply of their medication each week.
Memantine: 15 mg/day Memantine orally everyday for 12 weeks | 24 |
| Memantine 0mg/Day + Buprenorphine Participants were inducted onto buprenorphine/naloxone sublingual tablets during the first week of study participation. The dose was titrated from bup/nal 8mg to bup/nal 16mg in three days where it will remain until the last day of week 8. The 7-day discontinuation of buprenorphine-naloxone on week 9 was 12mg, 10mg, 8mg, 6mg, 4mg, 2mg, 2mg and stopped.
Matching placebo capsule was started on week 2. The placebo capsules were given on a twice a day schedule until week 12 and then discontinued over a one-week period on week 13. Patients received a 7-day supply of their medication each week.
Placebo: Placebo orally everyday for 12 weeks | 29 |
| Total | 80 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Administrative | 0 | 3 | 0 |
| Overall Study | Adverse Event | 1 | 1 | 0 |
| Overall Study | Legal Problem | 2 | 0 | 0 |
| Overall Study | Lost to Follow-up | 15 | 13 | 18 |
| Overall Study | Pharmacy issue | 1 | 3 | 3 |
| Overall Study | Withdrawal by Subject | 3 | 2 | 1 |
Baseline characteristics
| Characteristic | Total | Memantine 0mg/Day + Buprenorphine | Memantine 15mg/Day + Buprenorphine | Memantine 30mg/Day + Buprenorphine |
|---|---|---|---|---|
| Age, Continuous | 22.6 years STANDARD_DEVIATION 1.9 | 22.4 years STANDARD_DEVIATION 2.1 | 22.4 years STANDARD_DEVIATION 2 | 23 years STANDARD_DEVIATION 1.9 |
| Barratt Impulsivity Questionnaire | 70.8 units on a scale STANDARD_DEVIATION 11.3 | 69.7 units on a scale STANDARD_DEVIATION 12.7 | 70.4 units on a scale STANDARD_DEVIATION 10.3 | 72.4 units on a scale STANDARD_DEVIATION 10.9 |
| Center for Epidemiologic Studies Depression scale (CES-D) | 22.4 units on a scale STANDARD_DEVIATION 9.9 | 22.8 units on a scale STANDARD_DEVIATION 11 | 20 units on a scale STANDARD_DEVIATION 9.7 | 23.6 units on a scale STANDARD_DEVIATION 9 |
| Clinical Opiate Withdrawal Scale (COWS) | 9.2 units on a scale STANDARD_DEVIATION 3.1 | 9.1 units on a scale STANDARD_DEVIATION 2.7 | 8.3 units on a scale STANDARD_DEVIATION 2.8 | 10.4 units on a scale STANDARD_DEVIATION 3.7 |
| Heroin Craving Questionnaire - Short Form 14 (HCQ-SF-14) | 4.3 units on a scale STANDARD_DEVIATION 1 | 4.3 units on a scale STANDARD_DEVIATION 1 | 4.5 units on a scale STANDARD_DEVIATION 1 | 4.2 units on a scale STANDARD_DEVIATION 1.1 |
| Inhibitory Control (mean % error) | 0.21 mean percentage of error (prosaccade) STANDARD_DEVIATION 0.17 | 0.2 mean percentage of error (prosaccade) STANDARD_DEVIATION 0.17 | 0.2 mean percentage of error (prosaccade) STANDARD_DEVIATION 0.11 | 0.24 mean percentage of error (prosaccade) STANDARD_DEVIATION 0.2 |
| Opioid use Heroin use | 17 participants | 5 participants | 7 participants | 5 participants |
| Opioid use Opioid analgesic use | 63 participants | 24 participants | 17 participants | 22 participants |
| Race/Ethnicity, Customized Caucacian | 73 participants | 27 participants | 21 participants | 25 participants |
| Race/Ethnicity, Customized Hispanic | 7 participants | 2 participants | 3 participants | 2 participants |
| Region of Enrollment United States | 80 participants | 29 participants | 24 participants | 27 participants |
| Severity of Dependence Scale | 11.5 units on a scale STANDARD_DEVIATION 2.4 | 11.7 units on a scale STANDARD_DEVIATION 2.5 | 11.7 units on a scale STANDARD_DEVIATION 2.5 | 11.2 units on a scale STANDARD_DEVIATION 2.1 |
| Sex: Female, Male Female | 27 Participants | 9 Participants | 10 Participants | 8 Participants |
| Sex: Female, Male Male | 53 Participants | 20 Participants | 14 Participants | 19 Participants |
| Years of opioid use Heroin use | 1.08 years STANDARD_DEVIATION 2.1 | 1.1 years STANDARD_DEVIATION 2.3 | 1 years STANDARD_DEVIATION 1.6 | 1.1 years STANDARD_DEVIATION 2.5 |
| Years of opioid use Opioid Analgesic use | 3.2 years STANDARD_DEVIATION 1.9 | 3.7 years STANDARD_DEVIATION 2.2 | 2.9 years STANDARD_DEVIATION 1.3 | 2.8 years STANDARD_DEVIATION 2.1 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 18 / 27 | 15 / 24 | 23 / 29 |
| serious Total, serious adverse events | 0 / 27 | 0 / 24 | 0 / 29 |
Outcome results
Primary
Change of Opioid Use From Week 1 to 13
The primary outcome variable was the change from baseline of the mean proportion of weekly opioid use assessed by self-reported days of use and/or positive urine drug screen during the previous week using the time-line followed-back method (TLFB) . A positive urine counted as 1, as did each self-reported day of use. Each participants total was divided by 8. Mean proportion by group were calculated by averaging the proportions across participants in that group.
Time frame: Weekly from week 1 to 13
Population: 80 subjects intent-to-treat.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Memantine 30mg/Day + Buprenorphine | Change of Opioid Use From Week 1 to 13 | 0.00 Mean Proportion of Opioid Use in Week 13 | Standard Error 0 |
| Memantine 15mg/Day + Buprenorphine | Change of Opioid Use From Week 1 to 13 | 0.27 Mean Proportion of Opioid Use in Week 13 | Standard Error 0.1 |
| Memantine 0mg/Day + Buprenorphine | Change of Opioid Use From Week 1 to 13 | 0.39 Mean Proportion of Opioid Use in Week 13 | Standard Error 0.14 |
Comparison: We modeled the mean proportion of weekly opioid use using a mixed-effect linear regression approach to assess the treatment effect, the time effect and the interaction of time x treatment effect while adjusting for the baseline mean proportion of weekly opioid use with baseline COWS, Addiction Severity Index (ASI) psychiatric and legal composite scores as covariates.p-value: =0.00874Mixed Models Analysis
Primary
Number of Participants Who Were Estimated to Have Survived as Assessed by Survival Curve of Relapse Rate After Achieving Complete Abstinence on Week 8
Calculated survival curve from abstinence in Week 8 to first positive opioid urine screen or first reported relapse to opioid use to evaluate the effect of memantine on reducing early relapse and after rapid buprenorphine discontinuation on week 9. The last observation carried forward (LOCF) was used to perform our event survival analyses.
Time frame: Weeks after buprenorphine discontinuation week 9
Population: Participants that achieved complete abstinence by self-report that was confirmed with negative urine toxicology at week 8.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Memantine 30mg/Day + Buprenorphine | Number of Participants Who Were Estimated to Have Survived as Assessed by Survival Curve of Relapse Rate After Achieving Complete Abstinence on Week 8 | 5 participants |
| Memantine 15mg/Day + Buprenorphine | Number of Participants Who Were Estimated to Have Survived as Assessed by Survival Curve of Relapse Rate After Achieving Complete Abstinence on Week 8 | 1 participants |
| Memantine 0mg/Day + Buprenorphine | Number of Participants Who Were Estimated to Have Survived as Assessed by Survival Curve of Relapse Rate After Achieving Complete Abstinence on Week 8 | 8 participants |
p-value: 1.2Log Rank
Secondary
Treatment Retention
Treatment retention during the stabilization period weeks 1 to 8 and after buprenorphine / naloxone discontinuation weeks 9 to 13.
Time frame: Weekly
Population: Intent-treat-sample (ITT) that was inducted onto buprenorphine / naloxone and received one dose of study medication on week 2.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Memantine 30mg/Day + Buprenorphine | Treatment Retention | 9.3 weeks in treatment |
| Memantine 15mg/Day + Buprenorphine | Treatment Retention | 9 weeks in treatment |
| Memantine 0mg/Day + Buprenorphine | Treatment Retention | 9.7 weeks in treatment |
p-value: 0.64Log Rank