Pioglitazone to Treat Opioid Withdrawal Symptoms

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.