Improving Buprenorphine Detoxification Outcomes With Isradipine

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.

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.