Drug Dependence
Conditions
Brief summary
Overall, this proposal seeks to improve treatment strategies for the significant public health problem of prescription opioid dependence by determining whether gabapentin, a non-narcotic pharmaceutical agent with minimal abuse potential and preliminary efficacy, will be effective in ameliorating withdrawal symptoms, craving and illicit drug use in prescription opioid dependent participants undergoing a 10-day detoxification from buprenorphine. In addition, the acceptability and feasibility of transitioning to depot naltrexone therapy will also be determined. If successful, this study would provide data to support further development of gabapentin as a pharmacological tool for improved outcomes during opioid detoxification as well as an integrated outpatient approach for treating prescription opioid dependence.
Detailed description
Opioid dependence is a serious public health problem, particularly with the dramatic rise in prescription opioid abuse, but long-term opioid agonist maintenance with methadone or buprenorphine (BUP) may not be optimal for many prescription opioid abusers. Yet current opioid detoxification strategies are limited by high relapse rates and/or lack of efficacy in relieving subjective symptoms. In addition, antagonist maintenance with naltrexone (NTX), which may be an optimal longer-term strategy for this population, requires prior opioid detoxification and has been associated with relatively poor outcomes in heroin abusers. This application takes a novel, broad approach to address the problem of prescription opioid dependence by determining the 1) utility of adjunct gabapentin (GBP) during outpatient BUP detoxification to improve initial outcomes and 2) feasibility of transitioning prescription opioid -dependent patients to depot NTX following detoxification, which may improve longer-term outcomes. GBP, an N-type calcium channel blocker with low abuse potential, potentiates opioid analgesia, decreases both postoperative morphine consumption and movement-related pain, and reverses tolerance to the antinociceptive effects of morphine. GBP is also well tolerated and effective in reducing craving and illicit opioid use in pilot detoxification trials. The efficacy and tolerability of adjunct GBP during BUP-assisted detoxification and the feasibility of subsequent transition to depot NTX therapy in prescription opioid -dependent participants will be assessed. This 12-week, randomized, placebo-controlled clinical trial will determine the potential utility of adjunct GBP in 150 prescription opioid -dependent individuals undergoing outpatient BUP detoxification and whether transition to short-term depot NTX therapy is feasible. Our three specific aims are to determine (1) the efficacy and tolerability of GBP to reduce craving and illicit use of opioids in prescription opioid-dependent individuals undergoing outpatient BUP detoxification; (2) acceptability and feasibility of transition to, and short-term maintenance on, depot NTX following detoxification; and (3) prognosticators of completion of the BUP taper, successful induction onto depot NTX, symptomatology, and longer-term outcomes. Currently, the only Food and Drug Administration (FDA)-approved medications for the treatment of opioid withdrawal are the opioid agonists methadone and BUP, both of which have abuse liability, and NTX, which can produce low levels of withdrawal-like symptoms, especially early in treatment. Findings, if positive, will support further development of GBP as an adjunct medication as well as provide an integrated, seamless approach to outpatient prescription opioid-dependence treatment. Ultimately, this work could impact the addiction field by providing both procedural and pharmacological tools for treating prescription opioid dependence that significantly improve outpatient detoxification outcomes and markedly enhance access and transition to NTX therapy. This would shift clinical practice, establishing an effective adjunct regimen for BUP detoxification and an integrated approach for transition to NTX therapy. GBP may also be clinically useful for other situations where opioid withdrawal is a concern.
Interventions
DRUGGabapentin
N-type calcium channel blocker being examined for its potential efficacy to alleviate opioid withdrawal during buprenorphine-assisted detoxification and transition to depot naltrexone.
DRUGBuprenorphine
All participants are stabilized on buprenorphine and then undergo a 10 day taper off buprenorphine.
DRUGClonidine
All participants who successfully taper off buprenorphine receive Clonidine (0.1 mg) prior to induction onto oral naltrexone.
All participants receive increasing doses of oral naltrexone over a 3 day period (day 1: 6.25 and 6.25 mg; day 2: 25 mg; day 3: 50 mg)
All participants who tolerate oral naltrexone at 50 mg will receive the naltrexone injection on either the same day as the 50 mg dose or the day after.
DRUGPlacebo
Microcrystalline cellulose
Sponsors
National Institute on Drug Abuse (NIDA)
University of Arkansas
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
1. be between the ages of 18-65 2. be available to attend clinic 6 days a week for approximately 30-60 minutes per day during the first 4 3 weeks 3. fulfill Diagnostic Statistical Manual-5 criteria for moderate to severe opioid dependence. These criteria will be ascertained in the following manner: the physician will determine whether the individual is appropriate based on several clinical assessments that are routinely employed by methadone program physicians, including history and severity of opioid use, presence of track marks, prior treatment history, self-reported and/or observed signs and symptoms of opioid withdrawal. If any individual's degree of opioid dependence is questionable, that person will be excluded from further consideration as a participant. 4. submit a urine sample negative for benzodiazepines or barbiturates prior to starting the study.
Exclusion criteria
1. report having had a severe adverse reaction to study medications 2. have an unstable medical condition or stable medical condition that would interact with study medications or participation, including a current chronic pain or other medical condition that requires ongoing opioid agonist treatment (determined by physician assessment) 3. have a major psychiatric disorder (psychosis, schizophrenia, bipolar) 4. have major depression or anxiety disorder requiring psychoactive medication (as determined by physician) 5. physiological dependence on alcohol or drugs other than opioids, tobacco or marijuana (as determined by physician assessment) 6. are pregnant, plan to become pregnant or have inadequate birth control, if relevant 7. report ongoing use of over-the-counter or prescription drug (including Maalox) that would have major interaction with study drugs 8. have any of the following: liver function tests \>3 times normal, blood urea nitrogen and Creatinine outside normal range; electrocardiogram abnormalities including but not limited to: bradycardia (\<50 bpm); prolonged QT interval corrected for heart rate (\>450 msec); Wolff-Parkinson White syndrome; wide complex tachycardia; 2nd degree, Mobitz type II heart block; 3rd degree heart block; left or right bundle branch block; pre-existing severe gastrointestinal narrowing (pathologic or iatrogenic). Individuals with anxiety or depression will not be excluded unless they are taking prescription medication for their disorder under a physician's care or findings during screening indicate a need for immediate treatment determined by the study physician and/or the Columbia-Suicide Severity Rating Scale.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Detoxification Phase: Changes in Percent of Illicit Opioid-positive Urine Samples Over Time | Week 1 day 1 (study entry) through Week 4 day 1 (first day of NTX transition) | Thrice weekly urine samples obtained during weeks 1-3; data include assessments from week 1 day 1 through week 4 day 1 (up to 10 total samples per participant) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| NTX Transition Initiation | 3 days (wk 4 day 1 - week 4 day 3) | % of Participants who completed the detox and started the NTX transition |
| Vivitrol Injection Receivers | 5 days (week 4 day 1 to week 4 day 5) | % of participants starting the NTX transition who received Vivitrol injection |
| Detox Phase Completers | 3 weeks (week 1-3) | % of enrolled participants who completed the Detox Phase |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Gabapentin Gabapentin started on day 3 of week 1, increased up to a maximum dose of 800 mg BID by day 3 of week 2 and maintained for 2 weeks followed by 5-day taper.
Buprenorphine (BUP) stabilization up to 12 mg (day 2 of week 1) then a 10-day BUP taper by the end of week 3.
During week 4, detoxed subjects get 0.1 mg of clonidine followed by oral naltrexone (NTX) at 6.25 mg and another 6.25 mg (day 1), 25 mg (day 2) and 50 mg (day 3) then depot NTX injection (later on day 3 or day 4).
Gabapentin: N-type calcium channel blocker being examined for its potential efficacy to alleviate opioid withdrawal during buprenorphine-assisted detox and transition to depot naltrexone.
Buprenorphine: All participants are stabilized on buprenorphine and then undergo a 10 day taper off buprenorphine.
Clonidine: All participants who successfully taper off buprenorphine receive Clonidine (0.1 mg) prior to induction onto oral naltrexone.
Naltrexone (oral): All participants receive increasing doses of oral naltrexone over a 3 day period (day 1: 6.25 and 6.25 mg; day 2: 25 mg; day 3: 50 mg)
Naltrexone (depot): All participants who tolerate oral naltrexone at 50 mg will receive the naltrexone injection on either the same day as the 50 mg dose or the day after. | 60 |
| Placebo Participants in this arm begin receiving placebo (microcrystalline cellulose) in twice daily capsules on day 3 of week 1 and continue to do so through the beginning of week 5.
Buprenorphine (BUP) stabilization up to 12 mg (day 2 of week 1) then a 10-day BUP taper by the end of week 3.
During week 4, detoxed subjects get 0.1 mg of clonidine followed by oral naltrexone (NTX) at 6.25 mg and another 6.25 mg (day 1), 25 mg (day 2) and 50 mg (day 3) then depot NTX injection (later on day 3 or day 4).
Buprenorphine: All participants are stabilized on buprenorphine and then undergo a 10 day taper off buprenorphine.
Clonidine: All participants who successfully taper off buprenorphine receive Clonidine (0.1 mg) prior to induction onto oral naltrexone.
Naltrexone (oral): All participants receive increasing doses of oral naltrexone over a 3 day period (day 1: 6.25 and 6.25 mg; day 2: 25 mg; day 3: 50 mg)
Naltrexone (depot): All participants who tolerate oral naltrexone at 50 mg will receive the naltrexone injection on either the same day as the 50 mg dose or the day after.
Placebo: Microcrystalline cellulose | 57 |
| Total | 117 |
Baseline characteristics
| Characteristic | Total | Placebo | Gabapentin |
|---|---|---|---|
| Age, Continuous | 32.7 years STANDARD_DEVIATION 7.8 | 32.5 years STANDARD_DEVIATION 7.3 | 33.0 years STANDARD_DEVIATION 8.3 |
| Education Level College Degree or higher | 13 Participants | 5 Participants | 8 Participants |
| Education Level High School/Some College/Vocational School | 89 Participants | 46 Participants | 43 Participants |
| Education Level Less than High School | 12 Participants | 4 Participants | 8 Participants |
| Education Level Unknown | 3 Participants | 2 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 7 Participants | 4 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 110 Participants | 53 Participants | 57 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 12 Participants | 6 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 102 Participants | 50 Participants | 52 Participants |
| Region of Enrollment United States | 117 Participants | 57 Participants | 60 Participants |
| Sex: Female, Male Female | 53 Participants | 25 Participants | 28 Participants |
| Sex: Female, Male Male | 64 Participants | 32 Participants | 32 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 60 | 0 / 57 |
| other Total, other adverse events | 43 / 60 | 37 / 57 |
| serious Total, serious adverse events | 0 / 60 | 0 / 57 |
Outcome results
Primary
Detoxification Phase: Changes in Percent of Illicit Opioid-positive Urine Samples Over Time
Thrice weekly urine samples obtained during weeks 1-3; data include assessments from week 1 day 1 through week 4 day 1 (up to 10 total samples per participant)
Time frame: Week 1 day 1 (study entry) through Week 4 day 1 (first day of NTX transition)
Population: those starting on study medication
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Gabapentin | Detoxification Phase: Changes in Percent of Illicit Opioid-positive Urine Samples Over Time | 35.0 percentage of urine positive samples | Standard Deviation 36.7 |
| Placebo | Detoxification Phase: Changes in Percent of Illicit Opioid-positive Urine Samples Over Time | 41.6 percentage of urine positive samples | Standard Deviation 38.5 |
p-value: 0.7795% CI: [-0.72, 0.53]Regression, Logistic
Secondary
Detox Phase Completers
% of enrolled participants who completed the Detox Phase
Time frame: 3 weeks (week 1-3)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Gabapentin | Detox Phase Completers | 41 Participants |
| Placebo | Detox Phase Completers | 34 Participants |
p-value: 0.32Chi-squared
Secondary
NTX Transition Initiation
% of Participants who completed the detox and started the NTX transition
Time frame: 3 days (wk 4 day 1 - week 4 day 3)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Gabapentin | NTX Transition Initiation | 33 Participants |
| Placebo | NTX Transition Initiation | 29 Participants |
p-value: 0.58Chi-squared
Secondary
Vivitrol Injection Receivers
% of participants starting the NTX transition who received Vivitrol injection
Time frame: 5 days (week 4 day 1 to week 4 day 5)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Gabapentin | Vivitrol Injection Receivers | 12 Participants |
| Placebo | Vivitrol Injection Receivers | 12 Participants |
p-value: 0.69Chi-squared