Opioid Dependence
Conditions
Keywords
opioid dependence, buprenorphine, isradipine, opioid withdrawal, opioid detoxification
Brief summary
This application seeks to address the problem of opioid withdrawal by examining the utility of the L-type calcium channel blocker (CCB) isradipine as an adjunct to BUP detoxification. This project will address the need for improved detoxification strategies by assessing the tolerability and preliminary efficacy of adjunct isradipine during a BUP detoxification in opioid-dependent participants. This pilot clinical trial will determine the potential utility of the L-type CCB isradipine to improve treatment outcomes in up to 60 opioid-dependent individuals undergoing a BUP detoxification procedure. Specifically, this study will determine the efficacy of isradipine to reduce withdrawal symptoms, craving, and illicit use of opioids in opioid-dependent individuals undergoing BUP detoxification and determine the tolerability and safety of controlled-release isradipine (10 mg/day) in opioid-dependent individuals undergoing BUP detoxification. Currently, the only FDA-approved medications for opioid withdrawal are the opioid agonists methadone and BUP, both of which have abuse liability. Our findings, if positive, will support a larger phase II clinical trial.
Detailed description
Opioid dependence continues to be a serious public health problem, particularly with the dramatic rise in prescription opioid abuse. Traditional methods of detoxification from opioids, including tapering off the opioid agonist methadone or buprenorphine (BUP) and supportive treatment of symptomatology with the alpha2-adrenergic receptor agonists, are limited by the high relapse rate and/or lack of efficacy in relieving subjective symptoms. In addition, transitioning individuals from methadone to BUP maintenance has been limited by the need to drastically taper the methadone maintenance dose of methadone-maintained individuals prior to switching to BUP maintenance, which can precipitate opiate withdrawal and relapse. This application takes a novel approach to address the problem of opioid withdrawal by examining the utility of the L-type calcium channel blocker (CCB) isradipine as an adjunct to BUP detoxification. L-type CCBs have been shown to alleviate opioid withdrawal in opioid-treated nonhumans, to be safe and effective in alleviating withdrawal symptoms in human detoxification trials, and to have low abuse potential. Moreover, isradipine was the most effective of several CCBs tested and was more effective than the alpha2-adrenergic agonist clonidine in blocking naloxone-induced behavioral effects without producing self-reported effects associated with high potential for abuse. Thus, this project will address the need for improved detoxification strategies by assessing the tolerability and preliminary efficacy of adjunct isradipine during a BUP detoxification in opioid-dependent participants. The aim of this 8-week randomized, placebo-controlled pilot clinical trial is to determine the potential utility of the L-type CCB isradipine to improve treatment outcomes in up to 60 opioid-dependent individuals undergoing a BUP detoxification procedure. The specific aims are to (Aim 1) determine the efficacy of isradipine to reduce withdrawal symptoms, craving, and illicit use of opioids in opioid-dependent individuals undergoing BUP detoxification and (Aim 2) determine the tolerability and safety of controlled-release isradipine (10 mg/day) in opioid-dependent individuals undergoing BUP detoxification. Currently, the only FDA-approved medications for opioid withdrawal are the opioid agonists methadone and BUP, both of which have abuse liability. Our findings, if positive, will support a larger phase II clinical trial. Ultimately, this work could impact the addiction field by providing another pharmacological tool that is efficacious for treating opioid withdrawal while having minimal abuse liability. This would shift clinical practice, establishing an effective adjunct regimen for BUP detoxification as well as having the potential to enhance transition to naltrexone therapy.
Interventions
DRUGIsradipine
Isradipine extended release formulation
DRUGPlacebo
Placebo will consist of microcrystalline cellulose.
Sponsors
National Institute on Drug Abuse (NIDA)
University of Arkansas
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 65 Years
Healthy volunteers
No
Inclusion criteria
1. Availability to attend clinic 6 days a week for approximately 30-60 minutes per day. 2. Participants must fulfill DSM-IV criteria for 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. 3. Participants must submit a urine sample negative for drugs of abuse other than opioids or marijuana prior to starting the study.
Exclusion criteria
1. Unstable medical condition or stable medical condition that would interact with study medications or participation. 2. History of major psychiatric disorder (psychosis, schizophrenia, bipolar) 3. Pregnancy or plans to become pregnant or inadequate birth control (adequate birth control includes abstinence, condoms, birth control pills, etc). 4. Present or recent use of over-the-counter psychoactive drug, prescription psychoactive drug or any drug that would have major interaction with drugs to be tested. 5. Liver function tests greater than 3 times normal; BUN and Creatinine outside normal range. 6. EKG abnormalities including but not limited to: bradycardia (\<60 bpm); prolonged QTc interval (\>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. 7. Physical dependence on alcohol or drugs other than opioids, marijuana or tobacco (as determined by physician assessment). 8. Pre-existing severe gastrointestinal narrowing.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change Over Time in Illicit Opioid Use Via Urine Toxicology Screens During Buprenorphine Taper (Wks 5-6) | thrice weekly for approx 2 weeks (taper) | Illicit results via urine toxicology screens for heroin and several opioids will be measured thrice weekly during the taper |
Countries
United States
Participant flow
Pre-assignment details
96 consented to screen under a separate screening protocol. Of these, 28 signed consent for this clinical trial. Of 28 signing informed consent, 3 signed informed consent but did not start the trial: one was assigned to ISR and one to PLA. One was lost to follow up before they could be cleared for study entry
Participants by arm
| Arm | Count |
|---|---|
| Isradipine Isradipine controlled-release formulation, 10 mg/day maintenance dose, will be administered according to the following dose procedures: Isradipine ingestion will occur under supervision 6 days per week, and a take-home dose will be given on Saturday for participants to take on Sunday. The initial dose of isradipine or placebo will be given on Day 3 of Week 1. The initial dose of isradipine will be 5 mg/day; the dose will increase to 10 mg/day on Day 3 of Week 3 and will continue through Day 2 of Week 7. On Day 3 of Week 7, isradipine will be decreased to 5 mg/day for 7 days. On Days 3-5 of Week 8, all participants will receive placebo. If ISR side effects are too severe at the 10-mg dose, isradipine will be decreased to 5 mg/day. If ISR side effects are too severe at 5 mg/day, isradipine will be discontinued and the participant will be discharged from the study and referred to local treatment agencies.
Isradipine: Isradipine extended release formulation | 11 |
| Placebo Placebo will consist of microcrystalline cellulose. Two placebo capsules will be administered per day starting week 1 day 3 through the end of the isradipine taper.
Placebo: Placebo will consist of microcrystalline cellulose. | 14 |
| Total | 25 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Buprenorphine Taper (W5 to W6D3) | noncompliance - missed medication | 3 | 5 |
| Isradipine Taper (W7-8) | Lost to Follow-up | 0 | 1 |
| Isradipine Taper (W7-8) | Withdrawal by Subject | 0 | 1 |
| Study Medications Induction (W1-4) | Blood pressure issues | 0 | 1 |
| Study Medications Induction (W1-4) | noncompliance- missed medications | 3 | 1 |
| Study Medications Induction (W1-4) | Vitals outside of ISR dosing parameters | 3 | 2 |
| Study Medications Induction (W1-4) | Withdrawal by Subject | 0 | 2 |
Baseline characteristics
| Characteristic | Isradipine | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 11 Participants | 14 Participants | 25 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 11 Participants | 14 Participants | 25 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 | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 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 | 11 Participants | 13 Participants | 24 Participants |
| Region of Enrollment United States | 11 participants | 14 participants | 25 participants |
| Sex: Female, Male Female | 5 Participants | 4 Participants | 9 Participants |
| Sex: Female, Male Male | 6 Participants | 10 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 11 | 0 / 14 |
| other Total, other adverse events | 10 / 11 | 8 / 14 |
| serious Total, serious adverse events | 0 / 11 | 0 / 14 |
Outcome results
Primary
Change Over Time in Illicit Opioid Use Via Urine Toxicology Screens During Buprenorphine Taper (Wks 5-6)
Illicit results via urine toxicology screens for heroin and several opioids will be measured thrice weekly during the taper
Time frame: thrice weekly for approx 2 weeks (taper)
Population: Urine data of subjects that received at least one dose of isradipine and returned for at least one visit in which a urine drug screen was obtained were included in the analysis
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Isradipine | Change Over Time in Illicit Opioid Use Via Urine Toxicology Screens During Buprenorphine Taper (Wks 5-6) | -1.25 opioid-positive urine | Standard Error 0.74 |
| Placebo | Change Over Time in Illicit Opioid Use Via Urine Toxicology Screens During Buprenorphine Taper (Wks 5-6) | -0.36 opioid-positive urine | Standard Error 0.58 |
p-value: 0.42Mixed Models Analysis