Pioglitazone to Treat Opioid Withdrawal Symptoms

Opioid-Related Disorders Clinical Trial

Official title: Pioglitazone as an Aid During Buprenorphine Taper

Status Terminated

Clinical Trial Summary

Background:

• Opioid-withdrawal symptoms include runny nose, body aches, chills, sweating, and diarrhea. Many people have these symptoms when trying to stop using opioid drugs. Long-acting opioids like methadone and buprenorphine are used to help people stop using other opioids, but these drugs can cause the same withdrawal symptoms. There are no non-opioid drugs that are approved specifically to treat those symptoms.

• Pioglitazone is a drug used to treat type 2 diabetes. In a research study, the drug allowed heroin users to decrease their methadone dose faster without much discomfort, and stay abstinent from heroin. Researchers want to learn more about how pioglitazone helps treat opioid withdrawal symptoms.

Objectives:

• To test whether pioglitazone can reduce opioid withdrawal symptoms.

Eligibility:

• Individuals between 18 and 65 years of age who will be using buprenorphine to treat opioid dependency.

Design:

• This study will last up to 17 weeks. Participants must come to the study clinic every day for at least 13 weeks.

• Participants will be screened with a physical exam and medical history. They will also answer questions about drug use habits, and provide blood and urine samples.

• Participants will take buprenorphine daily for 7 weeks. For the first 3 weeks, the dose will be increased to a level that should help stop the use of opioids. For the next 4 weeks, the dose will be decreased. Blood, urine, and breath samples will be collected at different study visits. Participants will also fill out questionnaires about mood, drug craving, and withdrawal symptoms.

• After 1 week on buprenorphine, participants will start the study pill (pioglitazone or a placebo) every day. They will take the study pill for 13 weeks.

• During the treatment period, participants will have drug counseling once a week for 30 minutes.

• Some participants have other tests as part of this study. These tests include functional magnetic resonance imaging scans to look for changes in brain activity and giving samples of cerebrospinal fluid to study brain chemistry.

• Participants will have a final followup phone call 3 weeks after the last clinic visit.

Clinical Trial Description

Background:

Some individuals successfully maintained on buprenorphine or methadone are appropriate candidates for dose tapering and transition to medication-free follow-up care. For such individuals, the physical discomfort of the dose taper can be a barrier to a successful transition. Recent data suggest a novel approach: the FDA-approved diabetes medication pioglitazone (Actos), which activates the gamma (g) subtype of peroxisome-proliferator-activated receptors (PPARs). Pioglitazone acts not only in peripheral tissue, but also in brain regions associated with drug tolerance and withdrawal. In animal models, pioglitazone prevents signs of opioid withdrawal. In a small, preliminary open-label clinical study, opioid-maintained outpatients given pioglitazone were remarkably successful in transitioning comfortably to a medication-free state, after prior unsuccessful attempts without pioglitazone. These initial data provide proof of principle and indicate that pioglitazone merits evaluation in a randomized-controlled study.

Scientific goals:

(1) To determine whether, compared to placebo, pioglitazone increases successful completion of an opioid agonist/antagonist taper in patients who are physically dependent on opioids. (2) To determine the neural mechanisms by which such an effect may occur.

Participant population:

A total of up to 120 opioid-dependent participants (80 evaluable) will be enrolled. Evaluable participants are defined as those who are randomized to one of the two main experimental groups (pioglitazone or placebo). Target enrollment will include 25% women and 70% minorities (mostly African-American).

Experimental design and methods:

The study will be a randomized, double-blind clinical trial with two treatment groups (40 per group): pioglitazone (45 mg oral daily) and placebo. The study will last up to 10 weeks. All participants will receive 27 days of buprenorphine/naloxone (referred to hereinafter as buprenorphine) - 14 days of stabilization and a 13-day taper. Pioglitazone/placebo will be initiated in week 2 and continue for 5 weeks (3 weeks concurrently with buprenorphine and 2 weeks without). Participants will have two follow-up assessments: a clinic visit (week 7 or one week post-pioglitazone/placebo) and a phone follow-up (week 10 or 4 weeks post-pioglitazone/placebo). Participation will be conducted as a combination of outpatient and inpatient portions: first two weeks (pre-buprenorphine taper) as outpatients; 18 days on an inpatient unit (JHBC CRU) during and for approximately 5 days after the buprenorphine taper; and 10 daily visits and two follow-up visits outpatient. Throughout the study, participants will receive weekly individual counseling, including case management to prepare for post-study treatment. Data on opiate-withdrawal symptoms and craving will be collected daily. Data on self-reported drug use, with urine specimens for drug testing, will be collected three times weekly. A subset of participants will undergo functional magnetic-resonance imaging (fMRI) and magnetic-resonance spectroscopy (MRS): one training session in the mock scanner and two scanning sessions that will occur at the end of the first week of buprenorphine and during the second week of the buprenorphine taper. Another subset of participants (largely overlapping with the subset who undergo fMRI/MRS) will undergo one lumbar puncture so that we can measure levels of neurotransmitters, metabolites, and proinflammatory cytokines in cerebrospinal fluid (CSF). At the lumbar-puncture visit, blood will also be drawn so that we can compare analyte levels in CSF and blood. At the end of the study, all participants will be offered assistance to transfer to another treatment program, either drug-free treatment or opioid-agonist treatment (OAT). The primary outcome measures will be opioid-withdrawal severity as measured on the SOWs and COWs. Secondary outcome measures will include overall proportions of opioid-negative urines, proportions of participants needing adjunct medications, time to resumption of opioid use following discharge from the residential unit, status at follow-up, and (in the subset of participants who agree to undergo lumbar puncture) CSF levels (and corresponding blood levels) of proinflammatory cytokines and other analytes, which we hypothesize will predict outcome and thereby clarify pioglitazone s mechanism of action. In the subset of participants who agree to undergo fMRI/MRS and lumbar puncture, we will attempt to determine the neural mediators of pioglitazone s therapeutic effects, or (if pioglitazone is not effective) to determine predictors of treatment outcome. Post-treatment outcome measures are expected to be affected only indirectly by pioglitazone; we anticipate that pioglitazone will reduce withdrawal symptoms, enhance initial abstinence during the buprenorphine taper, and address possible protracted withdrawal.

Benefits to participants and/or society:

Participants will receive buprenorphine taper and drug counseling. There may be incidental benefits from the buprenorphine and counseling, because they are likely to reduce participants' use of opioids and risk of infectious diseases such as HIV or hepatitis B and C.

Risks to participants:

Participants may experience side effects from pioglitazone and/or buprenorphine/naloxone and are likely to experience some discomfort from opioid withdrawal. The subset of participants who agree to undergo lumbar puncture and fMRI/MRS may experience side effects from those procedures. ;

Related Conditions & MeSH terms

• Opioid-Related Disorders

• NCT number: NCT01517165
• Study type: Interventional
• Source: National Institutes of Health Clinical Center (CC)
• Status: Terminated
• Phase: Phase 1
• Start date: January 4, 2012
• Completion date: February 2, 2015