Pioglitazone to Treat Opioid Withdrawal Symptoms

* INCLUSION CRITERIA: 1. Age between 18 and 65 2. Evidence of physical dependence on opioids (determined by a combination of self-report, urine screen, and/or physical exam) 3. Seeking detoxification treatment for opioid dependence 4. Able to attend the clinic 7 days/week and undergo an 18-day residential stay 5. For women: 1. post-menopausal or surgically sterile (tubal ligation or hysterectomy) or 2. if sexually active with a male partner and able to get pregnant, documented agreement to use an IRB-approved form of birth control. Acceptable forms of contraception for this study include: hormonal contraceptives (birth-control pills, injectable hormones, vaginal-ring hormones); IUD; diaphragm with spermicide; condom with spermicide. EXCLUSION CRITERIA: 1. Any medical illness that in the view of the investigators would compromise participation in research (determined by Medical History; Physical Examination; Blood and Urine Laboratory tests; see details under Screening measures below), including, but not limited to: * Diabetes mellitus Type I or Type II * Past or current diagnosis of congestive heart failure * Signs and symptoms consistent with congestive heart failure including but not limited to fatigue, exercise intolerance, decreased peripheral perfusion, orthopnea, dyspnea on exertion, paroxysmal nocturnal dyspnea, peripheral edema, elevated jugular-venous pressure, pleural and pericardial effusions, hepatic congestion, ascites, elevated BUN and creatinine, hyponatremia, and elevated serum levels of hepatic enzymes. * Cardiovascular disease (e.g., history of congenital heart defect, heart disease, symptomatic coronary-artery disease, heart attack, irregular heartbeat, etc.) * Cerebrovascular disease * Unexplained history of syncope * History of seizures, except for febrile seizures at childhood * History of head injury with loss of consciousness of more than 30 minutes or with postconcussive sequelae lasting more than two days, regardless of loss of consciousness * Chronic renal failure as estimated by glomerular filtration rate (GFR) \<60 mL/min/1.73 m(2) * CD4 \< 200 or evidence of severely compromised immune system /AIDS * Active bladder cancer or history of bladder cancer 2. Allergy, hypersensitivity, or intolerance to buprenorphine, pioglitazone, other TZDs, or the metabolites of any of those drugs (determined by Medical History) 3. Pregnancy or breastfeeding (Urine Pregnancy Test; self-report) 4. Diabetes medications (e.g., sulfonylureas, metformin, insulin, etc.) 5. Contraindicated medications (Medical History): Gemfibrozil (inhibitor of CYP2C8) and Rifampin (inducer of CYP2C8), atorvastatin, ketoconazole, nifedipine, topiramate, and diazepam. 6. Psychiatric history: A) Cognitive impairment severe enough to preclude informed consent or valid responses on questionnaires B) Current diagnosis of: schizophrenia or any other DSM-IV psychotic disorder, bipolar disorder, or Major Depressive Disorder (Self-Report; SCID Screen Patient Questionnaire * Extended (SSPQ-X)) 7. Current physical dependence on alcohol or sedative-hypnotics, e.g. benzodiazepines (self-report; ASI; alcohol CAGE questions; and pattern of positive drug screens or BAL for alcohol) 8. Body Mass Index (BMI) of 40 or higher Additional Exclusion Criteria for the fMRI portion of the Study: Exclusion from the MRI component of the study will be based on the criteria outlined below. Participants who do not qualify or who do not agree to participate in the fMRI portion of the study will not be excluded from the main study. Exclusion criteria will be assessed during screening under NIDA-IRP screening protocol 06-DA-N415. Participants will be excluded from the fMRI portion of the study if they: 1. are left handed. Justification: Some of the neural processes assessed in this protocol may be lateralized in the brain. In order to reduce potential variance, participants will be required to be right-handed. Assessment tool(s): Edinburgh Handedness Inventory. 2. over the age of 55 years. Justification: Many cognitive processes change with age. In addition, the likelihood of difficult-to-detect medical abnormalities such as silent cerebral infarcts increases with age. Therefore, older individuals, defined as those over 55, will be excluded from the present study. 3. have certain implanted devices (cardiac pacemaker or neurostimulator, some artificial joints, metal pins, surgical clips or other implanted metal parts), body morphology, or claustrophobia. Justification: Implanted devices may increase the risk of MRI scanning and/or adversely affect the quality of the data; body morphology may prevent optimal positioning in the scanner and thus affect the quality of the data; participants with claustrophobia may find the MRI scan too unpleasant and may exhibit excess movement that will adversely affect the quality of the data. Assessment tool(s): Prospective participants will fill out an MRI screening questionnaire and undergo an interview with an MR technologist. Questions concerning suitability for scanning will be referred to the MR Medical Advisory Investigator. Prospective participants will be questioned about symptoms of claustrophobia and placed in the mock scanner during their first visit to assess for possible difficulty tolerating the confinement of the scanner and for ability to fit into the scanner. 4. have conditions restricting their ability to lie flat for several hours (such as coagulopathies, superficial or deep vein thrombosis, or musculoskeletal abnormalities). Justification: MR scanning sessions require participants to lie flat on their backs and remain perfectly still for approximately two hours. Therefore, conditions that would make that difficult (e.g. chronic back pain, significant scoliosis) or dangerous (e.g. familial hypercoagulability syndrome, history of thrombosis) will be exclusionary. Assessment tool(s): History and physical examination by a qualified IRP clinician, supplemented with a trial of lying in the mock scanner to assess comfort. 5. are cognitively impaired or learning disabled. Justification: Cognitive impairment and learning disabilities may be associated with altered brain functioning in regions recruited during laboratory task performance. Assessment tool(s): History of placement in special education classes as a consequence of serious learning problems and not solely as a consequence of behavioral problems, assessed during the History and Physical screening assessment. 6. have HIV or Syphilis. Justification: HIV and syphilis can each have CNS sequelae, introducing unnecessary variability into the data. Assessment tool(s): Oral HIV followed by blood test if oral test is + and Syphilis Treponemal Test (STT) without history of adequate treatment. 7. regularly use any medications that would alter CNS function, cardiovascular function, or neuronal-vascular coupling. This includes prescription medications (e.g., antidepressants, benzodiazepines, antipsychotics, anticonvulsants, barbiturates), over-the-counter medications (e.g., cold medicine), or herbal medications (e.g., Kava, Gingko biloba, St. John s wort). The only exceptions are the study medications. Justification: The use of these substances may alter the fMRI signal and/or neural functions of interest. Assessment tool(s): History and comprehensive urine drug screening to detect antidepressants, benzodiazepines, antipsychotics, anticonvulsants, and barbiturates. 8. have any current or prior neurological illnesses including, but not limited to, those listed in the main exclusion criteria. Justification: Neurological diseases alter CNS function and, possibly, the neuronal-vascular coupling that forms the basis of the fMRI signal. Assessment tool(s): History and physical examination by a qualified IRP clinician, adult ADHD Self-Report Scale, urine drug screening for anticonvulsants not disclosed by history. 9. have any other major medical condition that in the view of the investigators would compromise the integrity of the data. Justification: Many illness not explicitly covered here may alter important outcome measures. Assessment tool(s): History and physical examination by a qualified IRP clinician and CBC, urinalysis, NIDA chemistry panel (liver function tests, electrolytes, kidney function). Determination of exclusionary status will be based on laboratory values outlined in Table I for the main study, but the MAI will retain discretion to exclude participants from the fMRI/MRS secondary study based on less extreme lab results. After the screening process has been completed, the MAI will take into account all data collected in order to decide if there is an existing medical illness that would compromise participation in this research. Additional Exclusion Criteria for the lumbar-puncture portion of the study 1. Bleeding diathesis/coagulopathy 2. Platelet count \<50,000 and INR (International Normalized Ratio) greater than or equal to 1.5, or on Warfarin (coumadin) 3. Evidence of intracerebral mass based on history, neurologic exam, or papilledema on fundoscopic exam 4. Clinically significant lumbar spine disease by history, e.g. degenerative disk disease, ankylosing spondylitis or previous lumbar surgery 5. History of abnormal cranial CT scan or MRI scan, suggesting the possibility of increased intracranial pressure